Winter 2017/2018 | THE CURE ISSUE

POSITIVELY AWAREAWARE HIV Treatment, Prevention, and support from TPAN

The challenge of defining an HIV cure Bringing research in to The real world Sp eaking the Same Language Women are Essential To finding WHat does a cure an HIV cure

Charles Sanchez, star and co-creator mean to of the HIV musical comedy web series, Merce, in a scene about a cure for HIV. you? WINR TE 2017/2018 VOLUME 27 NUMBER 7

G uest Editors’ note Features 1 Handle with care 2 The challenge of defining 11 Time out Speaking the language an HIV cure Treatment interruption: A risky but of an HIV cure. Different roads to the holy grail. essential step in cure research by David Evans c by Ri hard Jefferys by Josh Tager and Richard Jefferys and David Evans 6 Measuring the HIV reservoir Front cover back story Current tests for sizing up 14 Speaking the same language viral hideouts. Advocate Michael Louella talks 21 It’s important we c by Ri hard Jefferys about ‘50 shades of cure.’ keep hope alive By Josh Tager The star and co-creator of the 7 Latent tendencies musical web series Merce on the New strategies target dormant HIV. 15 What does a cure mean to you? importance of an HIV cure. c by Ri hard Jefferys Four individuals share their hopes by Jian Huang and fears. 8 Enhancing immunity by Jian Huang Manipulating the immune system to tackle HIV. 17 Better late than never c by Ri hard Jefferys Pioneering scientists prove women Oon the c ver POSITIVELY AWARE Charles are essential to finding a cure. Sanchez, 8 Collaborating on a cure by David Evans co-creator Six groups focused on the task. and star of the web 19 Bringing HIV cure research series Merce, 10 Gene therapy in HIV cure research into the real world photographed Modifying immune system cells Looking at the need for including on location to resist, attack, or remove HIV social science. in New York City by Gerald altogether. by Josh Tager Warhaftig. c by Ri hard Jefferys

CONTRIBUTORS

David Evans is the Director of Research Treatment Action Group (TAG) in Josh Tager works as a private investigator Advocacy for Project Inform. A long-time 2001, and directs TAG’s Basic Science, and freelance journalist. A recipient of the HIV science advocate and educator, his Vaccines, and Cure Project. 2017 Idyllwild Writers Week Fellowship, written work for the HIV community has he’s written for numerous magazines, appeared online and in print at Pos y itIVel Jian Huang is a Los Angeles-based writer including POZ, Glamour, and Time Out Aware, A IDSmeds, POZ and The Body. His and the recipient of a 2016 PEN Emerging New York. His reporting has included scientific work on HIV cure has appeared Voices fellowship in nonfiction. Her work health topics as varied as pharmaceutical in top medical journals. has appeared in the Los Angeles Review advertising and PrEP (for Pos y itIVel of Books, the Los Angeles Public Library’s Aware), and his HIV advocacy work Richard Jefferys began working in the ALOUD author series, and A ngel City stretches back to the early 1990s in HIV/AIDS field in 1993 as a volunteer Review, among others. You can find her on San Francisco. at the nonprofit AIDS Treatment Data Twitter: @jenhuangg. Network in New York City. He joined THI S ISsue IS SUPPORTED BY FUNDING FROM GILEAD SCIENCES, INC.

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We accept submission of articles covering medical or personal aspects of HIV/AIDS, and reserve the right to edit or decline submitted articles. When published, the articles become the property of TPAN, Positively Aware, and its assigns. You may use your actual name or a pseudonym for publication, but please include your name, email address, and phone number with your story. Although Positively Aware takes great care to ensure the accuracy of all the information it presents, Positively Aware staff and volunteers, TPAN, or the institutions and personnel who provide us with information cannot be held responsible for any damages, direct or consequential, that arise from use of this material or due to errors contained herein. Opinions expressed in Positively Aware are not necessarily those of staff or TPAN, its supporters and sponsors, or distributing agencies. Information, resources, and advertising in Positively Aware do not constitute endorsement or recommendation of any medical treatment or product. TPAN recommends that all medical treatments or products be discussed thoroughly and frankly with a licensed and fully HIV- informed medical practitioner, preferably a personal physician. A model, photographer, or author’s HIV status should not be assumed based on their appearance in Positively Aware, association with TPAN, or contributions to this journal. Gtirues Ed to s’ Note POSITIVELY AWARE Di av d EVAns & JOURNALISM. INTEGRITY. HOPE. Richard Jefferys

Gsue t editors Handle with care Ddv avi E aNS Richard Jefferys Speaking the language of an HIV cure edt i or-in-Chief Jreff Ber y @P Aeditor to this special issue of played some role in pushing for the associate editor E nid Vázquez Welcome @enidvazquezpa Positively Aware Von HI cure renewed emphasis on cure research, research. and the websites of Project Inform Creative director R ick GuASCO (projectinform.org) and Treatment Action @rickguasco Coming of age in New York and San Group (treatmentactiongroup.org) are Francisco in the early 1990s, we lived potential jumping off points for delving proofreader J asON Lancaster through the horrors of the early epidemic deeper into the subject, as is the online conb tri uting writers just like so many, and the idea that three version of this issue of Positively Aware. David Evans, Richard Jefferys, decades later we’d be centrally involved in One word of caution about main- Jian Huang, Josh Tager the search for a cure is sometimes surreal. stream media coverage of HIV cure photographer For a long time, the challenge of curing research: while it’s good that there is Gerald Warhaftig HIV infection was seen as so insurmount- interest, the eagerness of news websites able that the c-word was almost never to draw visitors has led to some wildly Advertising manager mentioned. But that has changed over the misleading headlines (in the language of Lorraine Hayes [email protected] past decade, and this area of research is the internet: clickbait). now a central priority within the overall Given how much we all want a cure, Distribution & Subscriptions HIV/AIDS portfolio, especially the U.S. it’s understandable that people embrace Denise Crouch government’s research arm and private and share encouraging stories (such as [email protected] industry. Encouragement has come from one that promised a gene therapy cure a single case of an HIV cure—Timothy within three years), but it’s also important A world Positively Aware Ray Brown—and subsequently, several to be alert to the possibility of hype, in of HIV and related conditions. examples of prolonged remission from order to avoid the emotional rollercoaster detectable virus in the absence of ongo- that can result from cycles of hope and SINCE 1989. PUBLISHED BY ing treatment. disappointment and the risk of contribut-

YEARS But the science remains complex ing further to that cycle. and challenging, as is the relationship But evaluating media coverage can be 5537 N. Broadway that many have with the words cure and difficult, even for those of us who live and Chicago, IL 60640-1405 remission. Those concepts have varied and breathe the research. One thing to always (773) 989-9400 fax: (773) 989-9494 nuanced meaning for people living with look for is perspectives from independent [email protected] HIV and the diversity of affected com- scientists who are not involved in whatev- positivelyaware.com @PosAware munities from which they come. Meaning er work is being described. The HIV cure that is sometimes different from scien- research website created by the National TPN A was founded in 1987 in Chicago tists and funders. We’ve tried to provide Association of People with HIV Australia as Test Positive Aware Network, when some insights from across the spectrum, (hivcure.com.au) has some additional 17 individuals gathered in a living room to share information and support in response to from the nerdily scientific to the practical helpful tips for sorting fact from fiction. the HIV/AIDS epidemic. Positively Aware and human. More than anything, we come from is the expression of TPAN’s mission to share There is so much work underway that a long tradition of people living with HIV accurate, reliable, and timely treatment it is not possible to fully capture all the and their allies who insisted on playing information with anyone affected by HIV. knowledge relevant to the pursuit of an a role in the design and conduct of HIV cure within these pages, or all the biomedical research, and not in being candidate interventions being evaluated. compliant patients who were relegated We encourage those interested to seek to taking whatever pills happened to make additional information online. We’re both it to market. We hope you will see this fortunate to work at HIV/AIDS advocacy issue of Positively Aware as an invitation LET’s CONNECT organizations that have collaboratively to take part in that tradition. Positively Aware 5537 N. Broadway St. Chicago, IL 60640-1405 [email protected] @PosAware D avid Evans Richard Jefferys

positively aware Winter 2017/2018 1 The challenge of defining an HIV cure D ifferent roads to the holy grail byc Ri hard Jefferys

hat does a cure for HIV infection look like? It sounds like a simple question, but because of the way the virus can per- sist in the body, there are significant chal- lenges associated with trying to define if a Wcure might have been achieved. As the research effort to develop a safe, effective, broadly accessible HIV cure expands, the issue of how to measure success remains central, and is important to understand.

Ttimo hy Ray Brown described as homozygous for CCR5Δ32, and the con- There is one individual who sequence is that their cells is considered to be the first cannot produce a particular and, so far, only person to be protein named CCR5 (people cured. The case of Timothy who inherit the mutation from Ray Brown has been widely only one parent have lower publicized, but is worth levels of CCR5). revisiting. The relevance for HIV Brown had been HIV- is that the most common positive since 1995 and on strains of the virus use CCR5 combination antiretroviral as a latch to gain entry into therapy (ART) for four years the cells it targets for infec- when, in 2006, he developed tion—predominantly CD4 the life-threatening cancer T cells, which are a vital com- acute myelogenous leukemia ponent of the immune system. (AML). The diagnosis led Scientists studying gay men to the need for a stem cell who had been highly exposed transplant, a risky treatment to HIV but remained uninfect- that essentially creates a ed discovered the CCR5Δ32 new immune system in the mutation in the mid-1990s. recipient by transferring bone Gero Hütter assessed marrow cells from a donor. many potential stem cell Chemotherapy drugs and donors for Timothy Ray radiation are used to wipe out Brown and was fortunate the existing immune system to eventually find a match and make way for the donor who was homozygous for cells. The procedure is limited CCR5Δ32. The treatment was to use in life-threatening can- tortuous, with Brown requir- cers because it carries a high ing two stem cell transplants risk of death, approximately and experiencing graft- system was made of cells The first report on 20–30% (one out of five to versus-host disease (GVHD), homozygous for CCR5Δ32, so Brown’s case was made in one out of three individuals which occurs when the newly they lacked CCR5. ART was a poster presentation at the undergoing it). transplanted immune system stopped during the proce- Conference on Retroviruses Brown’s doctor, Gero attacks the recipient’s cells, dures and—although Hütter and Opportunistic Infections Hütter, had the idea to look requiring management with had cautiously hoped for the (CROI) in 2008. For those for a donor with a rare genetic immune suppressants. outcome—it was neverthe- unfamiliar with scientific trait called the CCR5Δ32 Ultimately, however, the less a welcome surprise to conferences, much of the (CCR5 delta 32) mutation. stem cell transplants suc- find that IH V viral load had action takes place in sessions People who inherit this muta- ceeded and the AML was not rebounded despite the where researchers orally tion from both parents are cured. Brown’s new immune absence of ongoing treatment. present results to a seated

2 Winter 2017/2018 positively aware The challenge of defining an HIV cure

(referred to in reports simply as “The Berlin Patient”), disclosed his identity shortly afterward and has become a champion for the search for a cure. He has also been incredibly selfless in agree- ing to participate in studies aiming to better understand his case. There was briefly some controversy in 2012 when analyses of blood and multiple body tissues by several different laboratories identified a few samples that appeared to contain trace amounts of HIV genetic material, but Brown recently celebrated a decade since his stem cell transplants with no sign of any HIV viral load rebound, and this remains the best evidence that a cure has been achieved. Even now, though, it is not possible to know for sure if all HIV capable of replicating has been eradicated, or if there is some residual inactive virus—technologies capable of surveying the entire body do not exist.

‘h T e Mississippi baby’

W hile clearly great news and encouraging for the HIV research field, Brown’s example also highlights that, currently, the question of whether a person is cured can only be answered by following audience. But there are also mucosal tissue for over 285 about the results for the them for many years. This has poster halls, where stud- days—nearly 10 months. organization’s website. The also been underscored by a ies deemed preliminary or Many people failed to news exploded into public number of individuals who potentially less important are notice the presentation, or awareness about a year later, have shown signs of being described on paper pinned to perhaps were skeptical. But with articles in the Wall Street cured, only to later experi- plasterboards. Hütter’s poster activist Martin Delaney, Journal and a formal case ence viral load rebounds after described Brown’s case, and founder of Project Inform, report published by Hütter in months or even years off ART. o t noted that—at that point—he was already advocating for the New England Journal of The most famous of these o h had been off ART without a renewed research focus Medicine. remission cases is “the

ockP detectable HIV rebound in on curing HIV infection and Brown, who had ini- Mississippi baby.” Born to a

iSt blood, bone marrow, or rectal he drew attention by writing tially remained anonymous mother whose HIV infection

positively aware Winter 2017/2018 3 was not diagnosed until Resting CD4 T cells can individuals, like Brown, also in labor, the neonate was become activated for a num- developed some GVHD after started on ART within hours ber of reasons, most com- their transplant, which was of delivery. The treatment monly due to encountering thought to have potentially was maintained for around an infectious agent or other contributed to the clearance 18 months, at which time the substance that they recognize of HIV-infected cells. ART was mother and baby temporarily and respond to—part of their eventually interrupted, and in stopped attending medical job as immune system cells. one case HIV remained unde- follow-up visits. When they The outcome in the tectable for 12 weeks, and in Can we do it returned, doctors learned Mississippi baby emphasized the other 32 weeks, before that ART had been interrupt- that HIV can persist at levels viral load reemerged and again? ed in the infant but, surpris- undetectable by current tech- treatment was reinstituted. Attmt e p s to Repeat ingly, HIV viral load remained nologies (see “Measuring the At the 2017 CROI, Timothy Ray Brown’s undetectable. The case drew HIV Reservoir,” page 6) and researchers from Mayo Clinic Outcome in Additional HIV-Positive Individuals widespread media coverage, that long-term monitoring is in Rochester, Minnesota Requiring Stem Cell and there was optimism that essential even if it might ini- described another HIV-positive Transplants it represented another cure. tially appear that an individual man with similarities to the The initial theory was that has been cured. Boston patients. Also a recipi- Understandably, the rapid institution of ART ent of a stem cell transplant researchers are may have prevented the for- Th e Boston Patients from a donor lacking the pursuing the possibility mation of the HIV “reservoir,” CCR5Δ32 mutation as part of of duplicating the results which consists primarily of Several adult cases have treatment for cancer, the indi- obtained in Timothy long-lived CD4 T cells that since mirrored the experience vidual continued on ART after Ray Brown in other have become infected by the of the Mississippi baby. The the procedure and displayed HIV-positive people virus but then entered a de- closest echo is a recent report declining levels of HIV reser- who require stem cell activated or resting state that of an individual who was voirs that ultimately became transplants to treat allows HIV genetic material diagnosed with HIV extremely undetectable. A little over two cancers. Several ongoing to persist in a silent or “latent” early (within approximately years after the procedure, an research programs form (see “Latent Tendencies” 10 days), due to acquiring analytical treatment interrup- (such as the amfAR- on page 7). the infection during a short tion was performed leading supported international Latently-infected CD4 window of time between to a period of remission from IciStem collaboration) T cells, as they are called, screening for a pre-exposure detectable HIV that lasted are attempting to find can become active if ART prophylaxis (PrEP) demonstra- 288 days. Viral load tests then appropriate donors who is interrupted, leading to tion project and the day they revealed that HIV replication are homozygous for the renewed virus production and were started on the first dose had restarted, and the indi- CCR5Δ32 mutation for viral load rebound. In essence, of the PrEP drug Truvada. vidual resumed ART. HIV-positive individuals in the cells act as a hiding place Combination ART was These five cases of tempo- this situation. A number for the virus, from which it begun as soon as the diagno- rary remission are linked by of transplants have been can emerge when the coast is sis was confirmed and main- the fact that all appeared to performed but, so far, clear of ART. For this reason, tained for 34 months before result from the HIV reservoir no other cases of HIV they are seen as the most an analytical treatment being very small at the time cures have been publicly important obstacle to accom- interruption was undertaken of ART interruption. The size reported. plishing an HIV cure. (see “Time Out” on page 11). in the two Boston patients A publication by Gero The Mississippi baby HIV remained undetectable has been estimated as 290– Hütter has summarized six remained off ART for a little for 224 days off ART, but then 2,900 latently infected cells cases in which over two years with no mea- viral load rebounded. and 40–730 latently infected HIV-positive individuals surable HIV, but then experi- The Boston patients are cells, respectively (an esti- received stem cells from enced a return of detectable two HIV-positive men who, mated reduction of more than donors homozygous for viral load necessitating the like Timothy Ray Brown, 1,000-fold compared to the the CCR5Δ32 mutation, restarting of treatment, required stem cell transplants pre-transplant baseline). but all died due to either confounding the hope that to treat cancers. They did This is important because it the cancers or complica- the virus had been cleared. not receive cells from donors indicates that a central goal of tions of the procedures— Researchers believe that the with the CCR5Δ32 mutation, HIV cure research—shrinking illustrating the risks of the very early start of ART had but nevertheless HIV became the size of the HIV reservoir— approach, and its limited greatly limited the size of the undetectable after the proce- can at least significantly delay applicability as a curative reservoir of latently infected dures. ART was maintained the rebound of HIV when ART intervention. CD4 T cells, but a few likely throughout, leading research- is interrupted. Mathematical —c Ri hard Jefferys were present in a resting state, ers to suspect that their new modeling studies suggest that and eventually one or more donor-derived immune sys- achieving even greater reser- became activated, leading tem cells may have been pro- voir reductions—on the order to renewed HIV production. tected from the virus. Both of over 10,000-fold (greater

4 Winter 2017/2018 positively aware than 99.99%)—could lead to attention in mainstream the performance of CD8 T a lifelong cure in the majority media coverage of HIV cure cells are of individuals. So while the research. known to increase the likeli- task may be daunting, there Typically referred to hood of becoming an elite C heat sheet Key points to know is a target to aim at. Another as virologic remission or controller. about HIV cure implication of the modeling post-treatment control, the Unfortunately, however, research work is that complete eradi- best-known examples are the studies have found that elite cation of latent HIV—which VISCONTI cohort, an unusual control is not necessarily O ne person, Timothy Ray some scientists believe is likely group of HIV-positive individu- completely protective against Brown, is considered impossible—may not be a als identified in France who disease progression. The cured and there are sev- prerequisite for a cure. began ART early in infection, efforts of the immune system eral other cases where The experience of the continued for several years, to control HIV can be associ- HIV viral load did not Boston and Mayo Clinic and then interrupted and ated with increased levels rebound for an extended patients also provides evi- have maintained viral loads of inflammation and a slow period after an ART dence that receipt of a stem at low or undetectable levels, decline in CD4 T cell numbers, interruption (referred to cell transplant from a donor in some instances for over ultimately leading to AIDS, as remission) homozygous for the CCR5Δ32 a decade. albeit it at a far slower pace mutation was likely key for A number of other indi- than is observed in individu- These outcomes remain Timothy Ray Brown’s cure, vidual case reports have als with higher viral loads. rare and resulted from which offers encouragement broad similarities, including Prospects for long-term exceptional circum- to researchers pursuing gene a perinatally infected French health may therefore be stances—stem cell therapy approaches (see teenager and a nine-year-old better in instances where transplants for HIV- “Gene Therapy in HIV Cure South African child who have remission is associated positive people with Research,” page 10). displayed control of HIV viral with latently infected cells cancers or extremely load for 12 and 8.75 years, remaining dormant (or, ideally early initiation of ART— R emission vs. respectively, after limited being eliminated entirely), but they are providing Post-treatment periods of ART. as opposed to HIV being important clues to control Post-treatment controllers actively controlled by immune researchers working to generally display immune responses—it is early days, develop a cure The other link among these responses against HIV, however, and firm conclu- There are more numer- five cases is that the period including antibody and CD4 sions cannot yet be drawn. ous—but still rela- of remission seems to have and CD8 T cell responses, Notably, there is a subset tively rare—examples been caused by the few although there is consider- of elite controllers who exhibit of individuals who have latently infected CD4 T cells able individual variability. The extraordinarily strong control controlled HIV viral load that were present remaining prevailing belief is that these of HIV, and they may offer to low levels either natu- dormant (asleep), rather than cases represent some sort cure researchers a model of rally (elite controllers) or the immune system actively of active containment of HIV immune-mediated contain- after an ART interruption controlling HIV. replication by the immune ment without the potential for (typically after beginning No significant immune system. Attempting to induce detrimental effects. treatment early), but it responses against HIV could immunological control of HIV is uncertain how long be detected in any of the indi- is another avenue being pur- Looking ahead this immune-mediated viduals, which was expected sued by cure researchers (see control can last and if it by researchers because of “Enhancing Immunity,” page 8). The complexities associated may come at some cost the swiftness with which ART with discerning what an HIV to long-term health was started in the Mississippi Elite controllers cure looks like with some baby and PrEP demonstration degree of certainty can be While many different project cases (suppressing One concern about post- headspinning, but should not therapeutic approaches the virus before the immune treatment control as a model be disheartening. Even having are being studied, so system mounted a response), for an HIV cure relates to cured just one person, and far no broadly usable and due to the fact that the the parallels with rare attained temporary remis- interventions have led to Boston and Mayo Clinic HIV-positive individuals sion in several more, is a far cures or remission—the patients developed new known as elite controllers, from trivial achievement. The best reported results immune systems—which had who suppress viral replication increasingly global expansion involve small reductions not yet encountered HIV— to undetectable levels for of cure research promises to in the HIV reservoir (its from their HIV-negative stem many years without ART. bring answers to the difficult hiding places in the cell transplant donors. This phenomenon is associ- questions that still face the body) and some cases of The absence of immune ated with strong and effective field, and hopefully draws an short-term control of HIV responses appears to make immune responses targeting easily taken, effective, and viral load to low levels this type of remission distinct the virus, particularly CD8 T scalable cure ever closer. after ART interruption from a somewhat different cells and CD4 T cells. Certain form that has also received genetic traits that influence

positively aware Winter 2017/2018 5 Measuring the HIV reservoir C urrent tests for sizing up viral hideouts c by Ri hard Jefferys

For researchers working to develop Van HI cure, it is important to into the genome of CD4 T cells, but also have some way of measuring the effects of a potential therapy.I n par- cannot ascertain if it is replication-compe- ticular, there is a need to accurately quantify the pockets of virus (latent tent or not. Nevertheless these tests are frequently employed to give a rough idea HIV reservoir) that persist in the body after ART suppresses viral load to of the size of the HIV reservoir. undetectable levels. There are a variety of technologies available that are Attempts to accurately measure the currently employed in studies, but each has pros and cons. HIV reservoir are complicated by the fact that the vast majority of latently infected T he “gold standard” test for assessing replication-competent latent HIV that is cells are known to reside in lymph tissues the size of the latent HIV reservoir is called present in the sample. It is now estimated rather than the blood. For this reason the quantitative virus outgrowth assay that there is likely about 60–70 times more some studies look to collect lymph biop- (qVOA). Performing qVOA requires tak- replication-competent latent HIV than is sies, and new technologies are being ing a large blood sample (in the range of detected by qVOA. developed to better quantify the amount 120–180 ml) and extracting resting CD4 At least two improved variants of the of virus in tissues. Sampling from the T cells, which are then activated in the qVOA that are cheaper and require less central nervous system (CNS) is another laboratory in order to induce HIV produc- blood volume have more recently been challenge, considered important due to tion by any latently infected cells that are described—including a new assay that evidence that HIV may persist in the brain. present. The amount of HIV generated is may address the problem of under- There is uncertainty regarding whether measured, and a statistical approach used estimating the frequency of latently HIV can become latent in cell types other to calculate the number of latently infected infected cells (developed by Anwesha than CD4 T cells, such as macrophages, CD4 T cells that were in the sample—the Sanya and colleagues at the University of and whether additional tests may be need- result is expressed as infectious units per Pittsburgh)—but these new approaches ed to evaluate the contribution of non-CD4 million cells (IUPM). The test takes a total have yet to undergo extensive evaluation. cells to the reservoir—ongoing research is of 14 days to perform. The T at/Rev-induced limiting dilu- aiming to answer this question. The advantages are that qVOA tion assay (TILDA) is a relatively new (but An overarching problem with HIV res- measures latent HIV that is capable of increasingly popular) approach to quan- ervoir measurement is highlighted by the replicating (described as “replication- tifying the HIV reservoir. TILDA has some cases of temporary remission described competent”)—this is important because similarities to qVOA but measures particu- in “The Challenge of Defining an IH V it has been shown that the majority of HIV lar forms of HIV RNA after CD4 T cells are Cure” (see page 2). In these individuals, DNA that can be found integrated into the activated in the laboratory—it is thought the HIV reservoir could not be detected DNA of resting CD4 T cells is mutated in to preferentially capture replication- by any current test, even for a period ways that render it defective. These defec- competent HIV but may also pick up some after an ART interruption. But we know tive HIV DNA copies cannot produce new defective viruses. from the eventual viral load rebound that viruses capable of infecting other cells. Several more straightforward tests look latently infected cells were still present The disadvantages of qVOA include for HIV genetic material in different ways. somewhere in their bodies. This limitation the requirement for large volumes of The most common measures levels of HIV in the ability of scientists to detect small blood and the length of time it takes to DNA in a sample using polymerase chain HIV reservoirs is a big part of the reason perform, as well as the cost (approximately reaction (PCR), but this technique cannot why ART interruptions are still considered o $1,000). Additionally, it has recently been distinguish between defective and replica- important in some cure research studies t o

discovered that activating resting CD4 tion-competent HIV. A more complicated (see “Time Out,” page 11). p

T cells—the key step in the test—does adaptation of this approach can specifi- ock t

not induce HIV production by all the cally quantify HIV DNA that is integrated Ish

6 Winter 2017/2018 positively aware L atent tendencies N aew str tegies target dormant HIV

W hen combination antiretroviral therapy R(A T) first became HDAC inhibitors can activate latent HIV to available in the mid-1990s, there were hopes that suppressing HIV replication for a some degree in people, but it has not sig- few years would be enough time for all virus-infected cells to die off, resulting in a cure. nificantly affected the size of theH IV res- Those hopes were dashed by the discovery that HIV can persist in long-lived cells in a ervoir. This has led to studies of the “shock latent (dormant) form—particularly in a type of immune system cell called a memory and kill” or “kick and kill” approach, which CD4 T cell. As their name suggests, the normal job of memory CD4 T cells is to remem- combines HDAC inhibitors (or potentially ber a past infection and respond quickly if it recurs (vaccines work partly by generating other LRAs) with immune-based thera- memory CD4 T cells against a particular infectious agent). pies intended to help promote clearance of latently infected cells that have been How HIV latency works R eversing HIV latency induced to produce HIV (see “Enhancing Ev ery cell in the body, with the A major focus of HIV cure research Immunity,” page 8). exception of red blood cells, contains a is on reversing HIV latency—essentially Beyond HDAC inhibitors, scientists copy of the entire genome. The genome switching on the latent virus’s DNA are also looking at other candidate LRAs, consists of DNA and can be thought of as machinery so that it starts making including compounds known as PKC a production line capable of manufactur- proteins. The aim is to cause the death of agonists, but only very limited testing has ing all the protein components that make the latently infected cell, either by making taken place in people due to concerns up your body (this is done via an interme- it visible to the immune system because regarding potential side effects. diate step, wherein the DNA makes RNA HIV components are being produced, or The design of safe and effective which then makes proteins). Different due to the toxic effects of viral activity. LRAs remains a major goal for HIV cure cells just employ the parts of the DNA A variety of approaches to reversing researchers. production line that they need to make the HIV latency are being studied, referred to proteins that allow them to do their job, e.g. collectively as latency reversing agents B lock and lock: kidney cells make the proteins they use in (LRAs). Among the leading candidates are Latency reversal in reverse clearing waste and immune system cells HDAC inhibitors, a type of cancer drug A number of research groups are like CD4 T cells make proteins involved in that has demonstrated an ability to induce investigating whether it might be possible the work they do responding to infections. the production of HIV proteins by latently to pursue a strategy that is the opposite of Memory CD4 T cells can be in an infected memory CD4 T cells. The HDAC reversing HIV latency: locking down latent activated state when they are respond- inhibitors vorinostat, panobinostat, and HIV to prevent it from being able to ever ing to something—this requires the DNA romidepsin are all currently being tested reactivate. For an interview with Susana production line to be busy, making the in clinical trials but are being given in short Valente from the Scripps Research proteins the cell needs to go about its courses because they can cause a range Institute, a leader in these efforts, go to work. But memory CD4 T cells can also of unpleasant side effects including head- the online version of this special issue of de-activate into a resting state, which ache and gastrointestinal upset. P ositivELy Aware. causes the DNA production line to largely So far researchers have evidence that —c Ri hard Jefferys shut down. HIV prefers to replicate in activated memory CD4 T cells, because it hijacks Block-and-lock strategy for an HIV-1 cure A schematic diagram of the approach under development by Susana Valente and the busy DNA production line to manu- colleagues at the Scripps Research Institute in Florida. A drug called a Tat inhibitor facture more viruses, which can then exit is being employed to try and permanently prevent latent HIV from being able to and infect other cells. But if HIV infects a reactivate and produce new viruses (a state they describe as “deep latency”). memory CD4 T cell when the DNA produc- tion line is in the process of shutting down (or is shut down), the virus essentially becomes trapped in the machinery, and can only start making viruses if the CD4 T cell becomes activated again and the mmons o DNA production line cranks back up. C e In technical terms, HIV DNA becomes iv t integrated into the DNA genome of the ea r resting memory CD4 T cell. While the cell C remains resting, HIV stays latent and is of y s invisible to the immune system because e t no virus proteins are being made. The total number of latently infected CD4 T cells in the body that contain replication- competent HIV is around 100 million, a

Di gram cour according to recent estimates.

positively aware Winter 2017/2018 7 8

Wi n t e r 2017/2018 E e immune system can be a potent weapon apotent be can e immune system rd Je T c P n b M immune-based therapies can promote control of viral load after A after load of viral control promote can therapies immune-based es can deliver the “kill” the deliver in &kill.” “kick can es immunity. anti-viral coordinating T CD4 compromises and isthat of virus it infects the of properties the one rupted. rupted. that H stimulated are to produce of the immune cells systemlatently tothe infected recognizedestroy and designed (the ingto agents with interventions “kick”) enhance the ability H against immune response the to attempting enhance involves avenue of cure amajor research and cells, the component of the immune system normally responsible for for responsible normally of immune the system component the cells, y h a

Multiple clinical trials are investigating whether immune-based approach Multiple immune-based investigating whether clinicalare trials R nhancing i positi i h t next p t next A c (See a u l a v h t e ff l r i y n er a g ys w th ar e e a g i I e) V m . T mune s I h V e task is challenging, not least because because ischallenging,e task notleast . R

e T searchers are also studying whether whether studying also are searchers im h is strategy combines latency-revers combines is strategy y s t munity e m rou Si for acure Collaborating Beth Beth University of California, of California, University University of North Carolina, Chapel Hill Chapel Carolina, of North University of eac of Combination Combination expanded to six, which are supported for the next five years: five next the for supported which are to six, expanded in his honor. Collaboratories Delaney Martin the named programs, such three fundingthe of first the I cure H for a developing on focused specifically programs research tive Science in journal the article an co-authored subsequently activism.”of treatment Delaney More in DARE defeatH IC CARE : BE BEAT tioned A W E “ article: magazine statingin a2001 cure for research, advocate of Project of Project Hutchinson Cancer n 2 t I ngineer ngineer s t a 4: x g ’s again to make ‘Cure time once A o L shington, D.C. shington, m 011, U the Combined Combined IE t en I -H against disease, disease, against sr : : V Collaboratory of A Collaboratory a Delaney A Delaney h E ael Deaconess Medical Center, Medical Boston Deaconess ael I f co ck I V : V: or V Bench to Bed to Bed Bench I I V i n Delaney Collaboratory to Cure H Collaboratory Delaney Cell and Gene Gene and Cell ral ral l . m form, who died on January 23, 2009, was a staunch astaunch was 2009, 23, January on died who form, l p R l I S a e H m T a s f E National National tion isinter in the main article in this issue, Martin Delaney Delaney Martin in this issue, in main the article b I radication - George -George radication munotherapy - munotherapy m o I D munologic Approaches to Cure H Approaches munologic ra IV ocused on on ocused S on on R

t R e o - search Center, e - th r - search search S E I y I n a nhanced nhanced D can can e s T n Francisco (UC n Francisco stitutes of Health (N of Health stitutes S h calling for the funding calling the of for collabora-

erapy for H for erapy p R e e E W b c searchers for for searchers nterprise to Curenterprise H e f i is f i tar tar th L c r ound on ound W y I mphocyte mphocyte L D a S I a esearc e shington University, n e S st year the number was was number the year st I attle stitute, Philadelphia now!’ the primary goal goal now!’ primary the V t Cure -Fred S a I F V l sk ) i - E 1 n h I radication - radication H e. e. focus I I n n ) announced ) announced fusions to fusions fection by fection I I V V - - 1 -

Isallu tr tion: Istockphoto Current candidate immune-based therapies App roach Description Examples Status Broadly neutralizing A ntibodies capable of potently inhibiting the VRC01 In early phase trials, antibodies (bNAbs) replication of diverse HIV variants including in dual 3BNC117 combinations There is evidence that some bNAbs can promote 10-1074 clearance of HIV-infected cells via mechanisms Two trials are investigating called antibody-dependent cellular cytotoxicity PGT121 a “kick & kill” combination (ADCC) and antibody-dependent cellular of 3BNC117 with the HDAC phagocytosis (ADCP)—the antibodies bind to HIV inhibitor romidepsin, a proteins expressed on the outside of cells that have latency-reversing agent been induced to produce virus, flagging them for destruction by the immune system Therapeutic vaccines D esigned to induce more effective immune MVA.HIVconsv Many different clinical

responses against HIV than those seen in natural ChAdV63.HIVconsv trials, including in infection combinations with the Ad26.Mos.HIV latency reversing agents Particular emphasis on promoting CD8 T cell (killer romidepsin and vorinostat T cell) responses capable of recognizing and killing MVA-Mosaic virus-infected cells iHIVARNA-01 Plans to combine

GTU-MultiHIV B-clade therapeutic vaccination with the TLR-7 agonist MVA HIV-B vesatolimod Adoptive immunity The extraction and expansion of anti-HIV CD8 T HIV 1 antigen expanded In trials both alone and cells from HIV-positive individuals, followed by specific T cell therapy in combination with the reinfusion (HXTC) latency-reversing agent vorinostat Immune checkpoint A ntibodies targeting molecules known to be durvalumab Almost exclusively being inhibitors expressed by dysfunctional “exhausted” T cells (anti-PD-L1 antibody) studied in HIV-positive individuals requiring Goal is to revive the activity of these T cells against nivolumab treatment for cancers due their targets (e.g. virus-infected cells or cancerous (anti-PD-1 antibody) to potential risks cells) ipilimumab Several are FDA approved as cancer therapies, but (anti-CTLA-4 antibody) One trial is studying carry some risk of life-threatening side effects due a single dose of to induction of autoimmunity pembrolizumab pembrolizumab in (anti-PD-1 antibody) HIV-positive people Studies suggest some immune checkpoint without cancer inhibitors may also have latency-reversing activity Toll-like receptor Toll-like receptors (TLRs) are elements of the vesatolimod Gilead Sciences is testing (TLR) agonists immune system capable of recognizing certain (TLR7 agonist) the effects of a TLR7 structural features shared by many different agonist in HIV-positive pathogens MGN1703 individuals, having seen (TLR9 agonist) promising results in animal TLRs play a role in generating immune responses studies to infections, and can be stimulated with products known as TLR agonists Researchers at Arhus University in Denmark are There are indications that certain TLR agonists studying a TLR9 agonist can both stimulate latent HIV and bolster immune responses to the virus Cytokines S ignaling proteins produced by immune system ALT-803 Multiple ongoing trials cells with a multiplicity of potential effects (recombinant human super agonist IL-15 Certain cytokines may be able to bolster anti-HIV complex) immune responses IL-2 Interest in interleukin-15 due to evidence it can Alpha-interferon also have latency-reversing effects A ntibodies designed to target anti- integrin, a vedolizumab Initial trial underway Anti-α4β7 integrin α4β7 antibodies molecule involved in the trafficking of CD4 T cells at the National Institutes to the gut of Health (NIH) Studies in animal models suggest administration may contribute to enhanced control of viral replication after an ART interruption Chimeric antigen T cells genetically modified to better recognize and Preclinical receptor (CAR) T cells kill HIV-infected cells (see “Gene Therapy in HIV (not yet in trials) Cure Research,” page 10) May need to be delivered in combination with CD4 T cells genetically modified to resist HIV entry

positively aware Winter 2017/2018 9 Gene therapy in HIV cure research Modifying immune system cells to resist, attack, or remove HIV altogether byc Ri hard Jefferys

T here is a great deal of interest in exploring the potential of gene therapy to cure HIV. This area of research has received encouragement from recent successes in the cancer field—the FDA has just approved the first two gene therapies for hard-to-treat malignancies.

Multiple different gene people who need stem cell therapy strategies for HIV are transplants to treat cancers. under investigation. A leading The hope is to use gene therapy approach involves genetically to generate an HIV-resistant modifying immune system cells immune system, akin to what to resist HIV infection, with was achieved in Timothy Ray the aim of preventing the virus Brown using stem cells from from being able to cause dis- a donor homozygous for the ease even if the latent reservoir CCR5Δ32 mutation. is not reduced or eliminated. Plans are also afoot to test a Sangamo Biosciences has type of gene therapy known as a conducted studies involving chimeric antigen receptor (CAR) extracting CD4 T cells from HIV- T cell against HIV—this involves positive individuals, genetically equipping immune system cells altering them in the laboratory with receptors that allow them so that they can no longer dis- to better recognize and kill HIV- play the HIV co-receptor CCR5, infected targets. The recently and then re-infusing them in FDA-approved gene therapies large numbers. Some evidence for cancers comprise CAR T of enhanced control of HIV viral cells engineered to recognize load after ART interruption has malignant cells. been reported, but it appears While trials are likely further that further work is needed to down the road, there is excite- increase the number of gene- ment about the possibility of modified cells. using a new gene-editing tech- The company Calimmune nique called CRISPR/Cas9 to try is testing a dual gene therapy and specifically excise HIV DNA that inhibits both CCR5 expres- from latently infected cells. The sion and HIV fusion with target approach has shown promise in cells. In an ongoing trial, CD4 the laboratory, but it is not yet T cells and stem cells are being known if it can be successfully extracted, genetically modified, delivered into the body. and then re-infused. For additional information on At least seven clinical trials gene therapy research, see the (including several conducted interview with Paula Cannon in by the defeatHIV collaboratory) the online version of this issue of are testing genetic modification Positively Aware. of stem cells for HIV-positive

10 Winter 2017/2018 positively aware TEIM OUT Treatment interruption: A risky but essential step in cure research By Josh Tager and David Evans

interrupting ART is a dicey proposition If there is ever to be that could bring health risks, both an HIV cure, first there biological and psychological. must be people with HIV But not only are treatment inter- who are willing to interrupt ruptions risky for participants, they are potentially risky for their sex their antiretroviral therapy partners. Studies have confirmed the (ART). It’s a risky maneuver, potency of an undetectable viral load for sure, but utterly essential in preventing transmission from a to test whether an experimental person living with HIV to others. intervention is effective. It’s a big ask to enroll any HIV posi- tive person in a cure study, especially For a study participant, there are several because the world’s top public health levels of health risk. First, the drug being experts are finally declaring that peo- o t tested might not be effective, and in any case, ple with undetectable viral loads are o

p it might induce harmful side effects. Second, essentially unable to pass on HIV to ock iSth

positively aware Winter 2017/2018 11 Studies have proven that people who participate in Point/Counterpoint Biomedical concerns about clinical trials tend to overestimate the likelihood that analytical treatment interruptions they’ll benefit from the study, even when it’s clearly Immune activation asserted ahead of time that they won’t.

ConcERN: Chronic immune activation causes more harm to the body than direct killing of immune cells by others, offering the tantalizing promise for decreased HIV. In fact, the SMART study and others have shown stigma and discrimination for people with HIV. that HIV keeps the cells so revved up that they can Reconciling the risks with the benefits—which can contribute to heart problems, diabetes, cancer, and vary from one community to another—will require an more. Some experts worry that interrupting ART could exhaustive process that includes scientists, ethicists increase people’s risk for these problems. and community advocates. And though biomedical and social science input is required to design and imple- CoNSIDERATION: Immune activation occurs even when ment these studies, it’s community members who are ART suppresses HIV to extremely low levels and in putting their bodies on the line. people who naturally control HIV without medication. Richard Jefferys points out in “Measuring the IH V Treatment interruption studies that allow the virus to Reservoir” on page 6 that there is currently no accurate rebound to very low levels before resuming treatment way to measure the reservoir if it reaches extremely may not be worse than staying on ART, but there have low levels. That means the only way to detect whether been deaths associated with immune activation in stud- the virus is still present is to take people off ART...and ies with longer interruptions. wait. In scientific parlance this is called an analytical treatment interruption (ATI). Expanding the HIV reservoir Understandably, much of what’s been reported on ATIs, even in the lay press, focuses on the physical ConcERN: As pointed out in “Measuring the HIV health dangers to the study participants. Potential Reservoir” in this issue, the size of the reservoir dangers include lasting effects from immune activa- may determine who can achieve a cure or long-term tion (heart problems for one) as well as the potential remission off ART. Some experts worry that taking for the virus to develop resistance to ART medications. people off treatment, even for short amounts of time, Less has been reported about the psychological conse- could increase the size of the reservoir —possibly quences for participants and the practical implications rendering them less likely to benefit from cure/remission for their sex lives and relationships. strategies in the future. James McMahon, the Head of the Clinical Research Unit at the Alfred Hospital and Monash University near CoNSIDERATION: So far, it does not appear that allowing Melbourne, Australia, has well-considered the knotty the virus to return for a period after being suppressed by challenges of designing studies involving temporary ART leads to a larger reservoir than was present before cessation of ART. ART was stopped. “The difficulty with this is that each cure interven- tion is different, and TA I parameters and frequency Acute Retroviral Syndrome (ARS) of monitoring may need to be individualized for each study,” he said. ConcERN: Many people have symptoms when they first “At the moment, there is no standard protocol for become infected—a reaction called Acute Retroviral a clinical study utilizing an ATI. Some studies test viral Syndrome (ARS), where the body is working on hyper- load and CD4 counts twice a week, others [every two drive trying to control the virus. Most often, people weeks]. Some restart ART when the viral load [first simply feel like they’ve got a bad flu, but the syndrome becomes] detectable, others when it reaches maybe can sometimes be serious. So, experts worry the risk of 5,000 copies or 10,000 copies for over 2 weeks.” ARS could be serious if an ATI allows a person’s virus to In fact, the AIDS Clinical Trials Group (ACTG), a peak before they resume treatment. free-standing HIV clinical trials network funded by the National Institutes of Health, has launched a new study, CoNSIDERATION: In the natural course of disease out- ACTG5345, that will seek to answer some of these ques- side of HIV cure studies, it’s relatively rare for a person to tions. For example, what are the underlying factors that develop serious symptoms if they have an acute reaction might predict which people can maintain control of the to the virus. However, people who start antiretroviral virus when they go off ART? therapy very early (within days or weeks of infection) Liz Barr, an HIV treatment activist and a commu- never develop an immune response to HIV. That means nity advisor to the ACTG, acknowledged the tension going off treatment could lead to a rapid spike in virus, between the need to answer some of the critical with a corresponding—and potentially harmful—activation questions that stand in the way of HIV cure-oriented of the immune system. research and the need to protect people with HIV and their partners from harm.

12 Winter 2017/2018 positively aware Point/Counterpoint Psycho-social concerns about analytical treatment interruptions

Increased transmission risk

ConcERN: A person with fully suppressed HIV has “ Researchers and advocates were torn from the effectively no chance of transmitting the virus to sex beginning about the study,” she said. “We had a lot of partners, such that top health experts have joined the conversations about how to proceed, whether to pro- declaration that undetectable equals untransmittable ceed, how to satisfy the most concerns possible. As you (U=U). But a person who interrupts ART could have a know, the hope with the study is to provide some guid- rapid viral rebound, thereby losing the certainty that they ance as to where cure research might go in the future.” can’t pass on HIV to others. Barr said that the team of researchers, clinicians and community advisors carefully considered not only CoNSIDERATION: Even constant monitoring for viral the health risks involved for study participants, but also rebound (2–3 times per week) won’t eliminate the risk the potential psychological and social repercussions. that the virus could climb high enough to allow someone For one, studies have proven that people who to transmit HIV to their partner(s) before it is detected participate in clinical trials tend to overestimate the and they can restart ART. Right now, top researchers are likelihood that they’ll benefit from the study, even when grappling with what to do about this, including possibly it’s clearly asserted ahead of time that they won’t. This providing full prevention services—including PrEP and dynamic could be even more complicated with HIV PEP—to HIV-negative partners of study participants. cure trials that involve an indefinite period off ART, and where the desire to be cured is so intense. Emotional and psychological harms If someone goes off of antiretroviral therapy and maintains viral suppression for even a couple of months, ConcERN: The likelihood of receiving any health benefit, it’s understandable they might wonder if they’ve been let alone being cured or achieving very long-term remis- cured, or even convince themselves of it, whether or not sion, is exceptionally low with early HIV cure-oriented it’s true. Gary Steinkohl, an HIV-positive New Yorker who studies. Experience in the few people who’ve had at least interrupted therapy following a stem cell transplant, had a few months of viral control before rebounding has exactly this experience. As his virus stayed suppressed shown that people often have profound emotional reac- for weeks and then months, he reported feeling a pro- tions when the virus eventually returns. found sense of ease and hope. When the virus returned, he recounted feeling “devastated.” CoNSIDERATION: Unfortunately, there aren’t existing The stakes are further raised in an ATI study, protocols for how to prepare people for this kind of because a person’s viral load could climb high enough emotional blow if they are one of the rare individuals who to transmit the virus but before it’s detected by the sustains viral suppression off of ART for several months study investigators. or longer. While models for this do exist, particularly in “Even if there was the potential for long-term viral cancer, there have been too few HIV cure studies that control off ART due to the study intervention, the involved an ATI for guidelines for researchers and trial risk of onward transmission may still be there,” said designers to be developed. McMahon. “If potential participants are correctly informed and have concerns about onward transmis- Difficulties reinitiating ART sion they may well choose not to participate. “ When asked about whether PrEP could be given to ConcERN: People who have an interruption in a health- a participant’s sex partners, he points out the practical maintenance behavior (exercise, diet, medicine taking, and ethical challenges. Should people with HIV who’d etc.) often struggle to resume that behavior at the end like to participate be turned down if their sex partners of the interruption. Resuming ART is no different. There refuse to use PrEP? Should HIV-negative partners be have been too few cases to know if this will be difficult asked to consent to the study too? after ART interruptions from HIV cure studies, but previ- We’re in uncharted territory, which both Barr and ous non-cure-related ATI studies have found this to be McMahon humbly acknowledge, though both have the true, and can lead to emergence of HIV drug resistance. same solution for now—extensive discussion among all stakeholders, especially people living with or at risk CoNSIDERATION: There are a number of interventions for HIV. that have proven effective in helping people reinitiate “I’m not sure how this is best practically done,” health-maintenance behaviors, including restarting ART McMahon said, although he echoed some of the ACTG after stopping for one reason or another. Ensuring that study practices. “Clear, open, and honest communica- they are incorporated into HIV cure studies could mini- tion will be critical to the successful conduct of these mize risks in this regard. trials.

positively aware Winter 2017/2018 13 Louel l a: “It’s a tightrope we all must learn to walk. Keeping a balance between hope and current reality.”

Speaking the same language A dvocate Michael Louella talks about ‘50 shades of cure’ by Josh Tager

An HIV cure is a real possibility, but not a given. One way to hasten about an HIV cure, in particular, words effective research is to make certain cure researchers and the community like “cure” or “remission”? speak the same language. What’s the difference if one researcher says People working in the cure social sciences “cure” and another says “remission,” and what do various community have become cautious, more precise in the members hear? ways we describe the research effort.I t’s a tightrope we all must learn to walk. Keeping T he application of technical jargon Michael Louella, a 50-year-old educator a balance between hope and current reality. versus plain language (depending on and activist, is spurring the conversations You want people to hear the good context) carries staggering consequences, that need to be had. He currently serves news, you want them to get informed, get both positive and negative. Take the word as both the Outreach Coordinator for the inspired, and get involved with the cure “remission.” That word alone could make Seattle AIDS Clinical Trials Unit as well as effort. But if you’re not careful, in a heady the difference between a person consent- the project coordinator for one of six NIH- rush of excitement you may find yourself ing or declining to participate in a clinical funded public/private HIV cure science col- beginning to sound like a preacher preach- trial; it can determine whether a person laborations. A close witness to the factors ing a gospel of cure. living with HIV decides to try a new treat- that lead some communities to distrust That’s when you begin to use qualifiers,

ment; it can have community-wide implica- science or feel disengaged from it, he’s or different words altogether. The danger a

tions in subverting HIV stigma. applied his natural facility for poetry and here is that people notice the shift in ll

Effective cure-oriented research man- storytelling to examine how people with tone, and often suddenly are plunged into oue L l

dates that scientists—especially those HIV respond to the complex terminology despair. You want people to understand e a

who don’t live with HIV—listen to those of cure science, and most importantly, to fully the scientific challenges facing us. h c

who do with perfect sincerity and serious- help medical scientists and the commu- But to be able to do this effectively, while Mi f f

ness. In turn, the community must ask nity speak the same language. not squashing all hope. o y s

questions, and ask more still so they can e serve as effective advocates and get the A s someone who’s been engaged in the D o you think when medical scientists t o

results they want: a meaningful cure. cure social sciences since the beginning, talk about cure they mean the same C o

what are some of the biggest changes thing as people living with HIV or t o h

you’ve seen in how different groups talk affected communities? P ur

14 Winter 2017/2018 positively aware N o. I think when scientists talk, they we’ve given up on cure. And that’s unac- That night I think Seattle finally implicitly understand that there are fifty ceptable to them. To them, functional cure grasped that sometimes when scientists shades of cure. Because they talk science is like sitting with a time bomb that could say cure they really mean remission— and think science all the time, they better go off at any moment, hurting themselves and by remission what people hear, is understand how both clinical research of course, but what’s most dreaded is the temporary. and the human body work, and better idea of transmitting the virus and hurting Our emcee, a local journalist named appreciate the limits to each. They know someone they love. Nina Shapiro, captured this startling rev- science is baby steps, and that progress elation of the night in a blog post the next toward a cure will be lots and lots of baby A lright, so what are the benefits of day in Seattle Weekly: “HIV ‘Cure’ Likely steps. They know this and accept this. using language that is consistent with to Be Temporary, Says Leading Scientist Non-scientists don’t know this. Not how most people living with HIV and their Robert Siliciano.” understanding the processes and meth- communities think about that language? ods of a scientist allows them to think of How does it play out when people react science as more akin to magic. S peaking the same language opens up that way? the potential to collaborate and grounds W hat are the consequences of this? relationships to endure in the face of chal- T here will be no people to participate in lenges and setbacks. studies and help scientists determine a T he real disconnect comes from serosta- curative strategy that works for everyone. tus and the stigma, rejection, and discrimi- W hat about the opposite? What are There will be distrust. Conspiracy theories nation people confront in varying degrees the consequences if language isn’t will be seen as truth. Disparities will grow. every day and, many assume, for the rest consistent? Despair will rule our hearts, and dreams of their lives. To live with HIV is far different will be deferred. than to work in HIV. Scientists may feel I often think back to 2014 when we were Remember, no one longs to listen to empathy, but I bet if they lived with HIV in lucky to have Dr. Robert Siliciano—who a litany of data from a scientist. What we their bodies, they might talk about and use was visiting Seattle to present a science really want is what all humans beings love the c-word differently. talk—agree to participate in a commu- above all else, which is a good story told When people with HIV hear “functional nity Q&A about HIV cure research. The by a good storyteller. HIV cure research cure” or “remission,” I can sometimes defeatHIV CAB partnered with BABES has some great stories that await to be sense an immediate distrust rising, a silent Network-YWCA to bring 70 of our commu- told. Just be careful with the things you accusation in the way they start to look at nity members together to listen and to ask say and the way you tell it, because we are me that says, “Wait a sec, your eyes done questions about the science. Dr. Siliciano all listening—especially people living with slipped from the prize.” They don’t want fielded a wide range of questions from our HIV. us to rest at remission or functional cure. audience with grace, and answered them When we talk about remissions, they think plainly and clearly. Wa h t does a cure mean to you? Four individuals share their hopes and fears by Jian Huang

Le Sherri James

e Sherri James is a 35-year- the social stigma that comes with old mother of two. She’s the disease. been living with HIV since “Growing up in the black commu- 2000 when, at the age of 17, nity, what happens at home stays at she was raped by an HIV- home,” she says. She says the culture Lpositive man who later died of AIDS. of not talking about HIV extends to Today, James works to support other ethnic groups as well. Cultural James i

rr other HIV-positive women at the AIDS factors can intensify the loneliness e h Foundation of Chicago. She echoes for many people, and she says lots S the sentiment that a cure for HIV of women with whom she works are

of Le would change the world, and that afraid to talk about HIV with family; y s e talking about it is essential. instead, they struggle alone. t Her 14-year-old daughter and four- For James, deepening the conver- year-old son are both HIV-negative. sation about HIV with an awareness o c t LeSherri’s HIV-status is especially of how women and people of color o h

P our difficult for her daughter because of think differently about the virus is a

positively aware Winter 2017/2018 15 >> What does a cure mean to you?

major part of the cure. HIV is still heavily treatment, but how fragile our gains are. a successful career as an engineer. Then stigmatized and there is often little sup- She is particularly worried about the con- he lost everything. Shallow and his part- port, even from families. James says a stant threats now to tear down the health ner sold their two homes and many of cure means these families would get their care and social service programs that their possessions to pay for expenses. loved ones back. have begun to cut infections and deaths He fought to stay alive after the diag- For her personally, a cure would come in a significant way, programs needed to nosis and volunteered his time helping with many emotions: knowing that her help deliver a cure. others to do the same. At Project Inform, children could live without stigma, that When asked what we could do to help Shallow answered calls from thousands James herself would not have to take find a cure, Adimora offers this sugges- of people across the United States to help daily medications, cost savings from doc- tion. “I urge people to stay ‘woke,’” she them make informed treatment decisions. tor visits, and most importantly, a second says. “We are in danger. They need to When asked what it would mean to chance at life. “I wouldn’t be ‘LeSherri make sure that they stay abreast of this have a cure, Shallow, whose long-time James with HIV’ anymore,” she says. stuff and pay attention and go to the partner remains HIV-negative, struggled “I would just be LeSherri James again.” polls. And support access to healthcare to hold back tears. “I can’t even imagine, for all—and research.” but I do have hope.” A daora A. Adimora, MD, MPH Jack Shallow K en Lazarus e’ve come a long way in treat- ment and prevention since the ack Shallow wants today’s en Lazarus is a minister in W height of the HIV epidemic, but young people to keep HIV in the Atlanta, Georgia. Now 54 years old, for Dr. Adaora Adimora, the need to find Jconversation. He tested positive Khe was diagnosed with HIV in 1986. a cure is obvious in the work she does. in 1985 and has been living with HIV for With a background in Public Health Adimora is a physician at the more than three decades, but for him, the and Social Justice, Lazarus’ goal to bring University of North Carolina at Chapel war is not over. He sees HIV awareness, more equity for the most vulnerable Hill, and has been working in infec- and the search for a cure, as paramount. populations extends to the conversation tious diseases since the 1980s. In 2013, At 71 years old, Shallow has lived around HIV. she was appointed to the President’s through some of the worst periods of As an African American man living Advisory Council on HIV/AIDS. the epidemic, and fears that as more with HIV, Lazarus is aware of the added “I have been close to a lot of people people from his generation disappear, stigma and social pressures HIV/AIDS has who have HIV, in the course of my work the conversation about a cure diminishes within communities of color. He believes and my personal life,” she says. “One in priority. community engagement in discussions thing that may be very powerful around Shallow was among the first in San about an eventual cure for HIV are a having a cure, and may be the most Francisco to receive Social Security necessity. This includes mentoring more important thing, in addition to the obvi- Disability resulting from his AIDS people of color, and bringing them into ous health benefits, is the extent to which diagnosis in the 1980s. Prior to testing leadership and decision-making positions. it will get rid of the stigma that has so positive, he had spent 20 years building More funding is needed and shifts in allo- often and unreasonably been associ- cation must happen as well, he says. ated with HIV.” Lazarus knows it is a difficult task Jack Shallow The road to finding a cure is to achieve, but it is also well worth a complicated process and past the effort. research has primarily included men. Lazarus is unsure that a cure Though she doesn’t describe herself will happen in his lifetime, though as a cure researcher, she has given it he remains hopeful. For him, a cure a great deal of thought. would mean freedom from the “As a physician, my major motive disease physically, emotionally, and is to eliminate pain and suffering in financially. He estimates that his whatever way possible and [a cure] current medication costs are up would go a long way towards this,” to $20,000 annually. “A cure would she says. For Adimora, it is impor- bring back a state of normality and tant for research to be inclusive health,” he says. “It would mean I from the beginning rather than to wouldn’t have to be subjected to w o

have a cure developed that benefits my daily regimen of medication. I l l one segment of the population, such would be able to return to a differ- a as men, and not others, such as ent place.” Sh women. Likewise, research must Until a cure is found, Lazarus fJack fJack

include people of color and take into wants health care professionals, o y s

consideration the widening dispari- government, communities, and e ties in our access to health. individuals to keep having this t o

Adimora reminds us to keep important conversation on the need C o o

in mind both how far we have for a cure. “Let’s have a cure,” he t o h

progressed in HIV research and says. “Let’s kick this out!” P ur

16 Winter 2017/2018 positively aware B ETTer late than never pi oneering scientists prove women are essential to finding a cure by David Evans

A lthough women who are not of trans experience, ciswomen, make sex hormones don’t have a huge effect… up more than half of the 34.5 million people living with HIV globally, a 2016 on our physical appearance, of our neuro- review of the scientific literature found that they made up only 21% of the logical makeup, and this is true across the board whether you are cis or trans,” she participants in HIV cure-oriented studies, and that a substantial number of says, “To suggest that it [might not] have studies recruited no women at all. For transgender women, the numbers are an impact on other biological processes is even worse. Out of more than 15,655 participants in the 2016 review, only really farfetched.” one person was identified as transgender.B ut the failure to include cis- and And we’ve actually known this for a transgender women doesn’t just pose medical and social harms to them, it long time. Ciswomen tend to respond runs the risk of crippling the search for a cure for all. much more robustly to vaccines of all types. They are also more prone to diseases that are related to a hyperactive Human biology 101 although her colleagues often went to response to one’s own cells or tissue, such great lengths to control for variations in as lupus and irritable bowel disease. Eileen Scully, MD, PhD, an assistant the immune system associated with age or And with HIV, we see that ciswomen’s o t professor of medicine at Johns Hopkins length of HIV infection, one of the biggest immune systems exert much stronger o h University, is both a laboratory scientist differences—a person’s sex—kept getting control over the virus soon after infection, p and clinician. Initially interested in looking pushed to the side. but later burn out due to over-activation. ock

St at models of the human immune system She makes the point somewhat ironi- More recently, Scully and a colleague, i in the lab, she did what most systems cally, joking, “Maybe short people and tall John Karn from Case Western University, scientists strive to do: remove variables people are just as different so we should confirmed the significant impact of female that might be so distracting that they control for height,” but then continues in a hormones on the persistence—and possi- e

p prevent the truth from shining through. more serious vein. bly one day the elimination—of HIV. What

Peo l Images/ She observed early on, however, that “No one in the world would argue that Karn found, based on intensive screening,

positively aware Winter 2017/2018 17 is that the female hormone estrogen W hy does science perpetually have to be cognizant of that and build that diminished the effect of drugs designed struggle to include women? into our research paradigm for how we to kick HIV out of its resting and hidden treat research participants.” state. Scully followed up on this work soon Catalina Ramirez is the Director of the That means having a budget for the after, and determined that female sex had University of North Carolina’s site for the things that women might need and ask for, a profound role on the state of the immune Women’s Interagency HIV Study (WIHS), a Ramirez says, which in WIHS can include system in ciswomen compared with cis- decades-old cohort of women living with not only transportation or reimburse- men and how sex differences affected the HIV who return every six months to provide ment for expenses, but also food if an reservoir of latent HIV. blood and tissue samples and to complete appointment is going to take a long time. According to Ramirez, the median yearly income of women in the WIHS study is less than $12,000. Studies have found that food ‘No one in the world would insecurity is rife among people with HIV argue that sex hormones and alone can contribute to poor health don’t have a huge effect… outcomes. Asking someone who may be on our physical appearance, struggling to eat enough under normal cir- cumstances to go without food for hours is of our neurological makeup, asking quite a lot. and this is true across the Yet, Ramirez says she sees a preoc- board whether you are cis cupation with defining fair compensation or trans. To suggest that it in the realm of HIV research that carries higher risk and lower rewards. This alludes [might not] have an impact to the fear that excessive compensation on other biological processes could unethically induce someone to par- is really farfetched.’ ticipate in a clinical trial. —l Ei een Scully, MD, PhD “We need to think of all the other disciplines [that] have done this, such as cancer,” she says. “I mean, cancer is indis- criminate, people of all levels of income These striking results, which Scully surveys. WIHS has contributed some of the get cancer, and yet we never seem to have and others have stressed should not be most important findings on HIV and HIV- these same discussions about whether surprising, have finally led to resources related complications in the history of HIV compensation is fair.” to determine their significance to the IH V research. It is also historical in another way, That’s not to say that research in cis- cure research enterprise. In fact, she is in that it has routinely managed to keep women in particular is straightforward, now heading up a study sponsored by the more than 85% of its all female participants especially if it involves the potential for the AIDS Clinical Trials Group that will see if engaged for five or more years. effect of sex hormones. Female hormones blocking estrogen production with the Because of this, Ramirez disputes that can fluctuate greatly in pre-menopausal anti-cancer drug tamoxifen could boost enrolling and retaining women in studies ciswomen, and not always on the same the activity of vorinostat, which has been is a challenge that can’t be overcome. Nor calendar. Scully has made the point that used in other studies to “kick” the virus. does she believe it has anything to do with designing a study that can accommodate It’s good news that at least some a lack of desire to participate. this isn’t straightforward. researchers are devoted to understanding “I don’t necessarily think that there are However, she’s managed to design how sex and sex hormones impact how sex or gender differences related to levels a study with post-menopausal women, the HIV reservoir persists despite being of altruism, but there are things that we which at least is a first step to begin driven down by antiretroviral drugs to just can do to make someone’s participation dipping our toes into the influence of hor- one infected cell per million cells, and are fair and equitable,” she says. mones on cure, and it’s the commitment committed to constructing studies that Scully concurs, saying, “Many years ago to be creative that’s key. account for sex and gender. I saw a patient with a new diagnosis and For 59-year-old Vanessa Johnson, who But Karn’s finding in 2015 that sex hor- she was isolated in many ways. I offered her is the cofounder of Ribbon Consulting mones affected the activity of a drug that entry into a clinical trial... and she declined. Group, and who has been living with HIV has been under investigation in HIV cure “Then she came back two weeks later… since 1990, our failure to make the study research for nearly ten years—and that we she had read about how women don’t par- of women high enough of a priority to use didn’t know it—has two worrisome impli- ticipate in clinical trials and she came back our ingenuity to overcome any barriers lly

cations. Most obviously, it leads one to to me and said, ‘I feel so bad that I didn’t do that might exist really comes down to how u c S question how other strategies being used this. I didn’t know how helpful it could be.’ ” society feels about women.

will help or harm cis- and transwomen. The key, says Ramirez, is attending to “There is an underlying belief that een

But if sex hormones affect the immune what women want and need. “If you want women are not as valued as men,” she Eil f f system and its battle with HIV so much, women to be in research then you have to says. “In fact, it’s not belief. It’s a reality o y s

then promising strategies that didn’t work listen to what will help them do it.” and that’s evident by the funding.” e in men could have been prematurely dis- She says, “We ask people to come and “The problem is that we live in a society t o carded, simply because they were never do things that may take hours and if you that is based on a scarcity model and not C o tested in women. couple that with the demands of a per- an abundance model. Truthfully there t o h

son’s employment and childcare…we just should be enough for everyone.” P ur

18 Winter 2017/2018 positively aware Bringing HIV cure research in to The real world Looking at the need for including social science by Josh Tager

For advocates, social science is an important compo- process will require additional countries—mostly in nent of effective cure research, one that is often undervalued. funding of social research that Mozambique—developing Whereas biomedical researchers investigate and develop elevates the least represented clinical research capacity for interventions, and establish that they work in optimal condi- communities. future HIV vaccine trials. In tions, social scientists make sure these interventions are A few of these studies have HIV prevention research, there effective in the real world and are embraced by affected been completed or are under- was already a rich tradition for communities. way (see page 9), and more biomedically-relevant social are in the pipeline. Rather sciences and community T he use of language, even is at the core of treatment than a catalogue of research, engagement. a single word, poses an ethical and cure research, but the we compiled a catalogue of When I started working in conundrum in clinical research benefits of this work are ampli- unanswered questions ( see HIV cure research, I noticed (see “Speaking the same fied and risks mitigated when “HIV cure social science 2.0,” the lack of research in this language,” on page 14). Take done in tandem with social page 20). area. Most of the HIV cure the word “cure.” It may seem scientists and community research field is dominated by like a word most people can representatives. biomedical research, with little agree upon, but that’s simply Funders now have a chance Q&A with attention paid to the accept- not true. What one biomedical to demonstrate forward-look- Karine Dubé ability of potentially high-risk researcher thinks of as a cure ing leadership with grants that Asis s tant Professor at interventions. can be very different from foster collaboration between the University of North I was interested in factors what a person living with social and biomedical scien- Carolina Gillings School that would make the imple- é b HIV thinks. This disparity can tists focused on cure. If we fail of Global Public Health mentation of HIV cure research u D inform who participates in to integrate social science into both effective and ethical, and e n i clinical trials; some people HIV cure-related clinical trials, in the patient and community r What sparked your a

K might consent to participation it will be people with HIV who professional and personal perceptions of this complex

of underestimating risks while most suffer the consequences interest in HIV cure social body of science. y s e another might decline by over- of missed opportunities. science research? t estimating them. The same is Efficacy without effec- We’ve studied people’s will- o

C true of possible future cures tiveness doesn’t cut it. But I started my research work ingness to participate in HIV o t and how they’re delivered. meaningful, systemic change in the HIV prevention field. cure studies, but I suspect o h

P Certainly,ur biomedical work to the scientific research I worked in nine African there are many unanswered

positively aware Winter 2017/2018 19 questions. Which are most pressing?

W e want to better understand HIV Cure what motivates people living Social Science 2.0 with HIV who are doing well Social science research is on treatment to be willing to now taking place around undergo risk for a specific IH V the globe. In the United cure research strategy, and States, researchers are tar- what is the risk threshold for geting geographic locations these various interventions. that haven’t been reached, Some risks are predictable, such as the Southeast, as whether they are great or well as populations that small, while others are merely haven’t been well repre- possible in the long term. sented, including younger We also still have a lot people, cisgender and of unanswered questions transgender women of color, about what makes people and black men who have sex willing to undergo treatment with men. interruptions. Some new social science studies are seeking knowl- S ometimes ethicists don’t edge about perceptions of concern themselves with HIV cure and cure research the direct application of from the wider communities an ethical principle in the that people with HIV come real world—for instance, from as well as the health they dream up thought care providers who care for exercises to make things people with HIV. simple. But at the pace These projects, scat- that cure research is going, tered across Western how should we think about Europe, Australia, China, ethical principles to make Thailand, and South Africa sure trials are as safe as are seeking answers to possible? questions like these:

T his is a great question that n are the attitudes, relates to the intersection of beliefs and motivations social sciences and ethics of people who are research. Social scientists actually in HIV cure are interested in studying Kr a ine Dubé trials substantially humans and their social rela- different than those tionships. Theoretical ethi- who answered previous cists more generally study W e must try to minimize the T he patient and community surveys? aspects of human culture risks as much as possible, voice is so important. One n and its values. As we move while trying to advance this of the obstacles is the sig- How do people with HIV forward, I think we need eth- important body of research. nificant power difference. and those affected by ics to be less philosophically- My fear is that the field of We must build knowledge in HIV in their communities inclined, and more grounded HIV cure research will go too communities, people living view more controversial in the reality of actual HIV far without adequate social with HIV, and other people issues such as treatment cure studies here in the U.S. sciences and applied ethics who should be included in interruptions, which pose Most HIV cure studies research to understand the the process. It’s very hard risks for sex partners? right now will benefit science, non-medical harms. In fact, to change cultures, but it n What effect does stigma but not the physical health of I do not understand why we must happen and active play on willingness é the study participants. Some are not asking these ques- collaboration between mul- b

to participate in cure u participants derive tremen- tions concurrently with the tiple-stakeholders [people D studies? e n dous psychological benefits biomedical science for the affected] is critical to doing i r

n How do mothers of a from participating in studies, most part. it. And of course, community K children with HIV, or their and that must be better engagement, education, and of y

guardians, feel about s understood. The concept of What will lead the way to dialogue must remain a core e non-maleficence, which is better coordination and part of the process along allowing the children to t about doing the least harm collaboration between the way. participate in research? o c possible, is paramount in the biomedical and social t o h

HIV cure-related research. sciences? P our

20 Winter 2017/2018 positively aware Front cover backstory

It’s important that we keep hope alive The co-creator and star of the web series M erce envisions life with an HIV cure by Jian Huang Photo by Gerald warHaftig

Charles Sanchez believes a cure Vfor HI would acknowledges living with HIV can still be a heavy burden change the world, and he’s dedicating his artistic and both physically and emotionally. comedic gifts to this cause. In season two, Merce enters into a relationship with an Sanchez (featured on the cover) has been living with HIV-negative partner, all while the show expands to a greater HIV for 14 years. In 2003 when he found out, he was told conversation about the future of HIV: a cure. “It all started that the disease had already progressed to an AIDS diag- because I had never thought what it would be like to be nosis. “I got very sick,” he says. “I almost died.” Then living cured,” says Sanchez. “It became a conversation in talking in Little Rock, Arkansas, he decided to move back to New to other people. There’s always stuff you find on the internet York City after getting out of the hospital and stabilizing. about some faraway cure, but we never really hear that much Always an artist, musician, and writer, Sanchez started about actual scientific research.I t got my brain buzzing.” doing solo shows, talking on stage, in part, about “crazy The buzz led Sanchez to write one particular episode things that happened with HIV.” His friend Tyne Firmin which follows Merce after a hip replacement surgery. brought in a flipcam and eventually the two created some- Inspired from his own experience of having two replace- thing special: a modern HIV musical comedy show. ments, the show deals with Merce’s struggle with avascu- Five years later, Merce, which Sanchez calls a miracle, is lar necrosis, a condition that occurs when there is blood now in its second season on YouTube. As with the original loss to the bone. “It’s a secondary condition to HIV that we solo shows, he wants to talk about HIV in a way that he feels don’t talk about much either,” says Sanchez. “In the script, others don’t. He created Merce as an original campy web Merce is trying to recover and is doing it all by himself. He series about a middle-aged HIV-positive single man living in can’t and he realizes he needs help, so he calls his boy- New York City. The protagonist Merce (played by Sanchez), friend and breaks down. He says, ‘I wish you didn’t see me his Mama (played by Firmin), and a colorful cast of char- like this. I wish I didn’t need your help.’” acters regularly deal with issues such as family, friends, During an emotionally-charged song, Merce’s boyfriend dating, slutshaming, PrEP, and gay marriage, with joyous replies, “I wish you didn’t have this. I wish there was a musical sequences that echo his background in theater. cure...but until there is a cure, I will be your cure. Love is “Merce is a reflection of me,” he said. “I wanted to your cure.” show a character with HIV who is not sad, sick, or dying. I Sanchez says, “It’s important to keep that hope alive. wanted a character who has a full life with friends, family, You may think you’re alone, but you’re not.” and problems that don’t have to do with HIV.” Even with contemporary medication, however, Watch merce at mercetheseries.com which Sanchez says consists today of a single pill, he

positively aware Winter 2017/2018 21 I am a friend, a dreamer, and an activist. And I am living with HIV.

Hydeia (left) has lived with HIV since 1984.

Get the facts. Get tested. Get involved. www.cdc.gov/Together