HIV/AIDS Research at the NCI: A Record of Sustained Excellence

National Cancer Institute Institute Cancer National

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health HIV/AIDS Research at the National Cancer Institute: A Record of Sustained Excellence

Letter from the Director of the CCR ...... 1

The Early NCI Experience ...... 2

A New Virus Revealed ...... 2

Risk Factors ...... 4

A Tale of Two Diseases ...... 5

Treating the Infection ...... 5

Treating the Cancers ...... 6

HIV and the Immune System: How They Interact...... 8

Susceptibility to Infection, AIDS, and Related Diseases ...... 10

Outsmarting a Formidable Foe: Viral Diversity and Drug Resistance...... 12

HIV Variation ...... 12

HIV Assays ...... 12

The Evolution of Resistance ...... 13

Better Ways to Find Better Drugs...... 14

Structural Biology ...... 14

Taking Advantage of ’s Products ...... 15

Looking Ahead: Vaccines to Prevent Infection ...... 17

DNA Vaccines ...... 17

Neutralizing Antibodies ...... 17

Novel Whole Inactivated Vaccines ...... 18

Live Vector Vaccines ...... 19

Center of Excellence: Bringing It All Together...... 20

The many common threads between cancer and HIV/AIDS underscore the value of NCI’s involvement in HIV/AIDS research. — NCI Director John E. Niederhuber, M.D. Letter from the Director of the Center for Cancer Research

In 1981, the NIH Clinical Center admit­ The NCI IRP collaborates with research­ ted its first patient with acquired immune ers and clinicians in other NIH institutes, deficiency syndrome (AIDS) into the universities, medical centers, and indus­ clinical service of the National Cancer try. To facilitate a broader, cost-effective Institute’s (NCI) Metabolism Branch. AIDS research effort, the NCI intramural Since these earliest days of the deadly program makes many resources developed epidemic, the NCI has been a leader in here available to partners in academic AIDS research. NCI intramural scientists institutions and pharmaceutical companies were able to quickly apply their expertise free of charge. These include: 1) highly in epidemiology, cancer, , cell purified preparations of HIV and other biology, the immune system, and drug retroviruses; 2) biological reagents such as development to this public health crisis. purified , antibodies, recombinant Over two decades later, their commitment DNA vectors and cell lines; 3) natural and and contributions remain strong. synthetic small molecule libraries; 4) highly sensitive methods for HIV detection; and The NCI intramural research program 5) databases, including the HIV Protease (IRP) is a unique nexus for basic, clini­ Database and the Chemical Structure cal, and translational research. Its mission Dr. Robert Wiltrout Lookup Service. Our resource sharing is a is to forge a deeper understanding and critical component of the NCI commit­ to develop more effective means for the ment to speed the development of more After more than two decades of important prevention, diagnosis, and treatment effective treatments. contributions, it seems fitting to take time of cancer and AIDS. In pursuit of this goal, to acknowledge and reflect on the cur­ Progress against HIV infection and AIDS, dedicated researchers work independently rent AIDS research effort and the many diagnoses once perceived as an automatic and in multi-disciplinary teams to make advances that have already been made death sentence, has been striking. Deaths discoveries, develop new technologies and within the CCR and NCI IRP, as these in the United States have dramatically approaches, and translate their advances achievements serve as the foundation declined since the 1990s, when effective into clinical practice. for continued scientific excellence. The combination antiretroviral therapy was research featured on the following pages The NCI IRP, which includes the Center introduced. In 2005, 17,011 people died demonstrates how NCI’s investment and for Cancer Research (CCR), has a unique of AIDS in the U.S.—about one-third sustained commitment to exploration and ability to integrate multiple scientific the 51,414 deaths in 1995. But major discovery has led to, and continues to lead disciplines and approaches in support of challenges remain. People now living to, new approaches and interventions to scientific discovery. Our Centers of Excel­ longer with HIV are facing an increased improve the lives of patients with cancer lence, Faculties, Working Groups, and Pro­ cumulative risk for AIDS-related as well as and HIV/AIDS. grams successfully cut across organizational other cancers; the pandemic of AIDS and boundaries to foster collaborative research. AIDS-associated cancers is a devastating Robert H. Wiltrout, Ph.D. The newly formed Center of Excellence presence in developing countries; and the Director, Center for Cancer Research in HIV/AIDS and Cancer is one virus is notorious for outsmarting existing National Cancer Institute example of this integration. therapies. There is still much to do. National Institutes of Health

HIV/AIDS Research |  The Early NCI Retrovirus Experience

A New Virus Revealed subsequent studies showed these to be the same virus, now called HIV (or human In the years before AIDS appeared as a new disease, investigators in the Laboratory immunodeficiency virus). Drs. Gallo, of Tumor , led by Dr. Robert C. Gallo, were searching for cancer-inducing Mikulas Popovic and other colleagues viruses that might be responsible for human tumors. In 1980, the year before the also developed techniques for continuous first cases of AIDS were reported, Drs. Bernard Poiesz, Frank Ruscetti, Gallo, and culture of the new virus in immortalized T cell lines and demonstrated colleagues at NCI discovered and characterized the first human cancer-causing that patients with AIDS had antibodies to retrovirus, HTLV-1, in a patient with /lymphoma. Soon after, they identified this virus. In collaboration with Dr. Larry HTLV-2 as the second human retrovirus. Arthur at NCI-Frederick, this technology was used to develop a blood test to protect Retroviruses are unusual. Instead of the After the first cases of AIDS were reported, the blood supply. normal cellular process of transcribing Dr. Gallo’s group explored the hypothesis genetic information from DNA into RNA, that this new disease might also be caused 1984 HIV-1 demonstrated as caus- they use the enzyme reverse transcriptase by a human retrovirus, in part because ative agent of AIDS: virus cloned to convert their RNA into DNA HTLV-1 caused immunodeficiency and and characterized for integration into the host’s chromosomal cancer. By 1984, they showed that a new DNA to establish infection. retrovirus could frequently be isolated in After these initial discoveries, Dr. Gallo the blood of patients with AIDS. Drs. Luc and colleagues including Drs. Flossie Montagnier, Jean-Claude Chermann, and Wong-Staal, George Pavlakis, Barbara 1980 First human retrovirus (HTLV -1): co-workers in France had just reported Felber, Genoveffa Franchini, George Shaw, T Lymphocyte cell cultures and isolating a retrovirus from the blood of growth factors Beatrice Hahn, Lee Ratner, Mark Feinberg, patients with an AIDS prodrome, and Suresh Arya, Amanda Fisher, and others defined many key points of the biology of HIV, describing the sequence of the HIV genome, identifying regulatory proteins of HIV, showing that certain strains of HIV could infect macrophages, and elucidating how viral proteins interacted with the host’s

1984 Large-scale production of HIV-1: development of diagnostic blood tests

transcriptional and translational machin­ ery. NCI scientists also helped describe the structures of viral RNAs, as well as critical viral enzymes. Early work by NCI scien­ tists, including Drs. Stephen Oroszlan,

From left, Dr. Genoveffa Franchini, Dr. Robert C. Gallo, Dr. Sandra Colombini, and Ershel Richardson discuss Louis Henderson and Alan Rein, also led their research. to the definition of the components

 | National Cancer Institute HIV Virus Life Cycle

of virus particles, and ongoing studies have period, Drs. Gene Shearer, Mario Clerici, HIV is a retrovirus, belonging to the Lentivirus genus, continued to establish the roles of these and colleagues conducted a number of im­ and, like all retroviruses, replicates by copying its genome RNA into DNA, integrating the DNA into the proteins in virus particle assembly and portant studies defining the immunologic genetic information of the host cell. Host cell machin­ structure. Dr. Marjorie Robert-Guroff and perturbations occurring in HIV infection. ery subsequently makes more copies of genome RNA and proteins, which are then assembled into infec­ colleagues also described the first neutraliz­ Subsequently, Dr. Jay Berzofsky and tious virions. Figure courtesy of Louis Henderson ing antibodies that blocked HIV infection colleagues discovered the first helper and and the first HIV escape mutants selected killer epitopes, facilitating work on by such antibodies. During this same HIV vaccines to induce cellular immunity.

HIV/AIDS Research |  Kaposi’s sarcoma prospective cohort studies of homosexual men, people with hemophilia, and all other lesions most men. Data and specimens from these stud­ risk groups. often develop in the patient’s ies were important contributions to the feet because 1984 co-discovery of HIV. Through studies The team of epidemiologists and statisti­ they are often cians also identified and quantified the hypoxic (low of homosexual men, people with hemo­ oxygen). This condition induces philia, injection drug users, laboratory and prognostic value of CD4+ lymphocyte replication in KSHV-infected cells. health care workers, and pregnant women counts. Drs. Goedert, Biggar, and Thomas Risk Factors and their offspring, these epidemiolo­ O’Brien in the NCI Viral Epidemiology gists and their colleagues helped to define Branch were among the first to apply newly In 1981, clinicians in New York and other developed quantitative polymerase chain coastal cities in the United States began 1989 HIV rev protein demonstrated reaction (PCR) methods to help estab­ seeing a number of cases of Kaposi’s sar­ essential for stability and transport lish the strong relationship between HIV coma (KS) in young men. This disease had of viral mRNA plasma viral load and subsequent risk of previously been extremely rare, occurring AIDS and death. mostly in elderly men from Mediterranean the major risk factors for sexual, blood- countries. This outbreak of KS was one of borne, occupational, and mother-to-infant the first harbingers of the AIDS epidemic. transmission of HIV. Dr. Biggar’s studies in 1984-85 demonstrated the extraordinarily These observations led Drs. James Goed­ high HIV prevalence in several countries of ert, Robert Biggar, and William Blattner, Africa. Along with Dr. Philip Rosenberg, of NCI’s Division of Cancer Epidemiol­ NCI Biostatistics Branch, and colleagues, ogy and Genetics (DCEG), to undertake DCEG scientists provided data indicating that progression of HIV-related immune Human dermal microvascular endothelial cells infected 1985 Discovery and location of HIV deficiency was inexorable and likely to be with recombinant Kaposi’s sarcoma-associated herpes­ transcriptional activator () protein virus (KSHV). Green represents latent infection and red lethal in most cases, and that the disease represents cells undergoing lytic activation (power 10X). progressed at the same rate in homosexual Figure courtesy of Drs. Paula Velasco and David Davis

NCI’s Role in Early Advances in HIV/AIDS Research

n co-discovering HIV n developing first blood test n describing the first neutralization for HIV escape mutants of HIV n proving HIV as the causal agent of AIDS n discovering several of the n discovering the first helper T cell regulatory proteins of HIV and cytotoxic T cell epitopes of HIV n large scale virus culture methods established n describing the first antibodies n describing the first structures to neutralize HIV of HIV-1 protease and reverse transcriptase

 | National Cancer Institute A Tale of Two Diseases

People infected with HIV face a two-pronged risk—the infection weakens the immune system, leading to AIDS and opportunistic infections—and HIV increases the risk of several cancers, including aggressive lymphomas and primary central nervous system lymphoma. These tumors, as well as cervical cancer, confer a diagnosis of AIDS in HIV-infected individuals. Other tumors are also increased in HIV-infected patients, including Hodgkin’s lymphoma, multiple myeloma, lung cancer, and cancers of the liver, lip, and pharynx.

Treating the Infection the treatment of AIDS: (AZT), (ddI), and (ddC). Dr. Untreated HIV infection is one of the Phillip Pizzo and colleagues in the Pediatric major root causes of cancer caused by Branch conducted some of the initial trials of infectious agents. During the early days of these drugs in HIV-infected children. Today, the epidemic, most patients with AIDS- Drs. Robert Yarchoan (upper left), associated cancers had extremely low CD4+ Hiroaki Mitsuya (above, lower left), T lymphocyte counts and were as likely 1991 ddI (didanosine) approved by and Samuel Broder (above, lower FDA as second AIDS drug right), co-discoverers of AZT and ddI. to die of other complications of advanced AIDS as from the malignancy. Successfully In addition, HAART patients benefit from treating these tumors would require effec­ improved prophylaxis and treatment of op­ tive treatment of the underlying AIDS in such drugs, combined with protease (PR) portunistic infections. As a result, advanced addition to treating the tumor itself. and non-nucleoside reverse transcriptase AIDS and opportunistic infections have (RT) inhibitors, form the basis for highly declined dramatically as causes of death in active antiretroviral therapy, or HAART. HIV-infected patients, and cancer is emerg­ 1985 AZT (zidovudine) blocks HIV-1 This therapy reverses the immune suppres­ ing as the most common cause of death. infection & clinical trial initiated sion caused by HIV infection and markedly Although the risk of developing AIDS- (approved for treatment of HIV- extends the lives of HIV-infected patients. related malignancies that tend to occur in infected patients in 1987)

And so, in the earliest days of the epidemic, Success of HAART for AIDS: 1985–2003 a group of intramural researchers at the NCI 100 turned their attention to developing effective AIDS therapy. Soon after HIV was found to 80 HAART begins be the cause of AIDS, Drs. Samuel Broder, 60 Hiroaki Mitsuya, and Robert Yarchoan New Cases showed that certain nucleoside analogs had 40 activity against HIV in the test tube and (Thousands)

No. of Cases/Deaths 20 Deaths rapidly moved to test them in clinical trials in the NIH Clinical Center. Their work 0 yielded the first drugs approved by the U.S. 1985 1989 1993 1996 1999 2003 Food and Drug Administration (FDA) for

HIV/AIDS Research |  patients with very low CD4+ T lymphocyte counts has declined, as patients live longer, Populations of AIDS Patients in the U.S. at Risk for Cancer they have an increasing cumulative risk of 450 developing a variety of other tumors. HAART begins 350 Treating the Cancers 250

Since the development of effective com­ 150 bination antiretroviral treatment began Prevalence (Thousands) 50 extending the lives of people with HIV, CCR researchers have turned their atten­ 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 tion to the AIDS malignancies themselves. Drs. Barbara Ensoli, Shuji Nakamura, and others working with Dr. Gallo investigated the pathogenesis of KS and described the is an effective treatment for patients with Thanks to progress at the NCI, patients importance of angiogenic factors in this advanced KS. Paclitaxel is now approved with AIDS-related lymphoma also face process. In 1995 Dr. Robert Yarchoan and by the FDA as a second-line therapy for a brighter future. During the early days colleagues demonstrated that paclitaxel, KS. More recently, Drs. Yarchoan, Richard of the epidemic, lymphoma was rapidly an anticancer drug that NCI played a Little, and co-workers in the HIV AIDS fatal, taking patients’ lives an average of 4 critical role in discovering and developing, Malignancy Branch (HAMB) have shown months after diagnosis. In 2003, CCR’s that interleukin-12 (IL-12) has clinical activity in patients with AIDS-associated 1995 Paclitaxel active against KS, and a study combining IL-12 and the 2003 EPOCH infusional therapy Kaposi’s sarcoma: receives FDA shown to be highly effective against anticancer drug liposomal doxorubicin in approval in 1997 AIDS lymphoma patients with advanced KS is underway.

Overall Survival of AIDS-NHL: Impact of HAART and EPOCH 100

50 Prevalence (Thousands) NCI EPOCH CD4>99 NCI EPOCH 1997-1998 (HAART) 1991-1994 (pre-HAART) 0 Paclitaxel—space filling molecule (inset, above)—was originally extracted from the 0 6 12 18 24 30 36 bark of the pacific yew tree (taxus brevifolia).Source: George McGregor. Scientists Months are trying to find alternative ways of producing this compound such as using yew See: Besson et al. Blood. 2001; 98: 2339-2344 and Little et al. Blood. 2003; 101: 4653-4659 needles. Source: Dr. Gordon Cragg

 | National Cancer Institute to prevent or treat the cancers they cause. Recently, the FDA approved the first vac- 2006 Interleukin-12 active against cine that protects women against HPV HIV-associated Kaposi’s sarcoma infection. This vaccine was based on work that was initiated by Drs. Douglas Lowy Allan Hildesheim, the NCI is perform- and John Schiller in the Laboratory of ing its own testing of the GSK vaccine in Cellular Oncology (LCO). Cervical cancer Costa Rica, where there is a high rate of is not only an AIDS-related tumor but also cervical cancer. one of the most common tumors caused by an infectious agent. This vaccine may Other CCR investigators are studying the also prevent anal cancer, which has a high basic biology of KSHV and EBV to iden- incidence rate in AIDS patients. tify novel targets for therapy. Dr. Giovanna Tosato, LCO, has identified cytokines The HPV vaccine is based on research produced by KSHV-infected cells that showing that many copies of a single promote development of primary effusion Two decades of work by the groups protein from HPV (the L1 protein) lymphoma, a rare tumor. Dr. Zhi-Ming of Douglas Lowy, M.D. (upper left) could assemble into hollow spheres called Zheng in HAMB has been exploring the and John Schiller, Ph.D. (above right), could help protect millions of women virus-like particles (VLPs). VLPs are not use of small interfering (si) RNAs to sup- around the world from HPV’s cancer- infectious, but cause the body to mount press HPV proteins associated with tumor ous consequences. antiviral immune responses. Immunization development. Drs. Yarchoan and David A. with these particles stimulated produc- Davis are developing treatment strategies Drs. Little and Wyndham Wilson (Metab- tion of antibodies that prevented virus using pro-drugs activated by viral enzymes olism Branch) and colleagues demonstrated infection in both animals and human that specifically target KSHV-infected that a form of combination chemotherapy volunteers. NCI licensed the technology to cells. HAMB scientists are now conduct- called dose-adjusted EPOCH (etoposide, Merck and GlaxoSmith-Kline (GSK), both ing a clinical trial of these strategies to treat vincristine, doxorubicin, cyclophospha- of which have developed HPV vaccines. KSHV-associated multicentric Castleman’s mide, and prednisone) was highly effective Both vaccines protect against HPV types disease (MCD). NCI scientists are also against AIDS-related lymphoma. Nearly 16 and 18, which cause up to 70 percent adding to our basic understanding of the 75% of patients had a complete response, of all cervical cancers worldwide. Merck’s biology of these viruses. Dr. Denise Whitby and more than half were alive and disease Gardasil®, approved by the FDA in 2006, of the AIDS Vaccine Program (AVP) has free after 4 years. CCR researchers are in- demonstrated the presence of conserved vestigating modifications of this approach micro-RNA sequences in KSHV isolates. to improve responses with less toxicity. 2006 FDA approves the first vaccine to prevent HPV infection Variation in these sequences, which are Most AIDS-associated malignancies are believed to help regulate viral gene expres- caused by DNA viruses such as Epstein- sion, may correlate with and help explain Barr virus (EBV), Kaposi’s sarcoma herpes- also protects against HPV types 6 and 11, different disease presentations in KSHV- virus (KSHV), and human papillomavirus which cause up to 90% of genital warts. infected individuals. (HPV). HIV-related immunosuppression In large-scale trials, the VLP vaccines were reduces host resistance to infection and 100% effective at preventing premalignant tumor development. Scientists have been cervical changes caused by the virus types studying these viruses, looking for ways in the vaccines. Under the direction of Dr.

HIV/AIDS Research |  HIV and the Immune System: How They Interact

The profound immune disruption that is the hallmark of AIDS was clear from evaluation of the earliest patients, and efforts to understand the underlying disease processes that cause this disruption remain an active area of research. HIV preferentially infects cells bearing the CD4 receptor, principally helper T lympho­ cytes, which play a critical role in orchestrating optimal immune responses. The progressive loss of these cells is a clinically useful marker of disease progression. A key and still largely unanswered question in HIV research is the basis for the overwhelming depletion of CD4+ T cells following viral infection and the profound Electron microscopic image of a single human lymphocyte. Source: Dr. Triche immune suppression that occurs as disease progresses.

Although massive infection of CD4+ T ness of immune responses by killing the cells occurs during acute infection, direct cells, impairing their function, or inducing 1987 Identification of Helper T cell viral pathogenesis is not believed to be pathways that suppress antiviral responses. epitopes in HIV proteins the sole mechanism, in part because the number of HIV-infected CD4+ T cells Dr. Gene Shearer and colleagues in the present at any time in an infected indi- Experimental Immunology Branch have genic mechanisms can be blocked by vidual is small relative to the cell deple- shown that the balance between protective small molecules that inhibit HIV-CD4 tion observed. Therefore, indirect effects and pathogenic effects of IFN-a produced binding, suggesting a potential use for caused by immune-mediated mechanisms by plasmacytoid dendritic cells (pDC) inhibition of both HIV infection and im­ (immunopathogenesis) likely contribute to activated by noninfectious HIV particles munopathogenesis. the acute and ongoing depletion of these may be tipped in favor of pathogenesis in cells. Exposure to virus or viral proteins can HIV infection. The high proportion of Mechanisms of depletion of uninfected result in pathological triggering of many non-infectious HIV particles present can CD4+ T cells are also being explored by Dr. immune system cells, limiting the effective- trigger IFN-a-induced apoptosis of HIV- Robert Blumenthal and colleagues of the CCR Nanobiology Program, revealing both mechanisms of HIV-induced bystander 1985 Identification of antibodies apoptosis and strategies to circumvent it. that block HIV infection The group has provided the first direct evidence that HIV-1 -mediated exposed but uninfected CD4+ T-cells. Ex­ hemifusion of infected with uninfected posure of pDC to non-infectious HIV can cells is required and sufficient for apoptosis also upregulate the immunosuppressive, of these bystander T cells. Furthermore, tryptophan-catabolizing enzyme, indole- such apoptosis is not dependent on virus amine 2,3-dioxygenase (IDO). Culture replication but on the phenotype of the of these pDC with CD4+ T cells results Env glycoprotein associated with the virus. in CD4+ T cell suppression. High IDO Mechanistic studies show that Env-medi­ expression in vivo is often associated with ated apoptosis can be prevented by using accumulation of regulatory T cells (Tregs) the PR inhibitor and the fusion Dr. Gene Shearer in lymphoid tissues. These immunopatho- inhibitor . This work may have

 | National Cancer Institute important implications for HIV-1-infected number of virus-specific CTL limiting the individuals treated with enfuvirtide and/or viral control. nelfinavir. Dr Frank Maldarelli, HIV DRP, Dr. Claes Ohlen of the AIDS Vaccine is exploring the applicability of these find­ Program (AVP) is evaluating the impact ings in a clinical setting. of adoptive transfer of large numbers of cloned autologous virus-specific CD8+ 1988 Demonstration that cytotoxic CTL on acute and chronic infection in T (CTL) are important in experiments in non-human primates. These HIV infection studies aim to characterize the potential maximum efficacy of CD8+ CTLs as Other CCR scientists including Drs. an effector mechanism for preventive or Thomas Waldmann (Metabolism Branch), therapeutic vaccines. His aim is to bet­ Francis Ruscetti (Laboratory of Experimen­ ter characterize the immunobiology of Dr. Claes Ohlen tal Immunology), and Joost Oppenheim HIV-specific CTL in infected hosts and to (Laboratory of Molecular Immunoregula­ the chronic phase is eventually lost and lay the foundation for subsequent vaccine tion), have played a role in the discovery infected individuals develop AIDS. It is studies using adoptive T cell transfer in and characterization of immune system not known why all infected cells are not macaque models. components such as natural killer (NK) killed by the immune system and why the cells and NK-T cells, as well as immune infection is consequently never cleared, modulatory cytokines such as IL-2, IL-7, but mechanisms may include: (1) latently IL-15, and TGF-b. Contributions of CCR infected cells hiding from the immune sys­ immunologists have stimulated the investi­ tem through lack of viral replication; (2) gation of additional pathways of how HIV infected cells persisting in tissues where T harms the immune system and laid the cells normally do not traffic; (3) mutations groundwork for designing preventive and in the viral genome leading to viral escape therapeutic strategies. from the T cells; and (4) an insufficient

While HIV is well known for its Virus-specific CD8+ cytotoxic T lympho­ Blood Infection Sexual Transmission destruction of CD4+ T helper cytes (CTLs) play a role in controlling lymphocytes, other immune cell viral replication. Dr. Berzofsky and col­ types such as dendritic cells and Mucosal Tissue macrophages are also thought to leagues have studied the impact of play key roles in viral patho- specificity, receptor avidity, and anatomic Immature DC genesis and spread. Dendritic cells act as immune sentinels, localization on the effectiveness of CD8+ Immature DC HIV capturing invading pathogens in T cells in controlling infection, demon­ the blood and mucosal surfaces Blood Vessels strating the importance of local mucosal to process as and later Lymph Vessels present to CD4+ T cells. However immunity. However, despite a detectable T cells a sizable proportion of HIV that frequency of virus-specific CTLs dur­ Lymphoid Tissue is sequestered by dendritic cells ing the chronic phase, the virus is never escapes degradation and exploits Mature DC the interaction with T cells to completely eradicated. In the absence of facilitate its spread. Figure cour­ drug treatment, control of viremia during tesy of Dr. Vineet KewalRamani

HIV/AIDS Research |  Susceptibility to Infection, AIDS, and Related Diseases

Not everyone responds to HIV in the same way. Although most HIV-infected individuals develop AIDS within 10 years, some take only a few years, while as many as 5% 1997 Mutant CCR5 receptor linked to less rapid progression to AIDS remain relatively healthy for 15 years or more. NCI scientists are trying to decipher which genes are associated with progression or non-progression to AIDS and viral- induced cancers. Diversity (LGD) were among the first to identify a deletion in the CCR5 gene Dr. James Goedert in the Division of in either the viral replication cycle or the (CCR5D32) that protects against infection Cancer Epidemiology and Genetics innate/acquired immune response to the in individuals homozygous for the muta­ (DCEG) with other intramural and extra­ virus. Although some of these genetic ef­ tion. CCR researchers also helped show mural collaborators discovered in 1987 that fects are pronounced, most are weak and that heterozygotes for this variant, while progression was slower in younger than detectable only in large cohorts that are not protected against infection, progress to in older people with hemophilia. Look­ well-defined with regard to clinical param­ AIDS more slowly than individuals homo­ ing closely at AIDS-defining malignan­ eters. Using a candidate gene approach, zygous for wild type CCR5. cies, Drs. Goedert, Robert Biggar, Charles NCI scientists have identified multiple Rabkin, Eric Engels, Sam Mbulaiteye, and host genetic effects on HIV infection or This finding represents the first major their DCEG colleagues conducted a num­ success in identifying a genetic variant that ber of epidemiologic studies exploring the affects HIV infection and has contributed 1992 Host cell proteins incorporated relationship between infection with Kaposi’s to the development of two treatments for into HIV-1 shown to have functional sarcoma associated herpesvirus (KSHV), significance HIV infection: CCR5 antagonists, the also called human herpesvirus-8 (HHV-8), first of which was recently approved by the and KS. This group also showed that KS the rate of disease progression after infec­ FDA and monoclonal antibodies against risk is reduced with cigarette smoking, for tion. The chemokine receptors CCR5 and the CCR5 co-receptor. Furthermore, reasons yet unknown. In recent years, us­ CXCR4 are major cellular co-receptors for CCR5D32 has subsequently been shown to ing data from DCEG’s HIV/AIDS cancer HIV. NCI investigator Dr. Michael Dean influence susceptibility to other diseases, match and other sources, they showed that and others in the Laboratory of Genomic including smallpox and West Nile virus- use of HAART greatly reduced the risk of associated encephalitis. KS and of some types of non-Hodgkin’s lymphoma (NHL), particularly in the Particularly strong genetic associations with brain. Paradoxically, HAART use appears to HIV disease progression have involved increase the risk of Hodgkin’s lymphoma. variation in the highly variable HLA class I genes, which influence resistance/suscepti­ Over the past decade, NCI scientists have bility to AIDS through both acquired and identified variations in numerous host innate immune responses. These genes code genes or gene families that affect the rate of for cell-surface proteins that present foreign disease progression and even susceptibility peptides to the immune system. to HIV infection itself. CCR researchers are exploiting these results to block HIV in The combination of a high mutation rate several ways. and rapid replication enables HIV to adapt in patients with HIV infection, in most Genes containing variants that affect cases regardless of HLA genotype. Never­ outcome of HIV exposure are involved Dr. Mary Carrington theless, specific types of HLA have been

0 | National Cancer Institute 1996 – 2002 Role of MHC and KIR Genes That Affect HIV-1 Infection and AIDS Progression in determining outcome of HIV infection deciphered Gene Genotype Effect

CCR5 D32/D32 Prevent infection In the last decade, LGD scientists have CCR5 +/D32 Delay AIDS described 18 host genetic variants (AIDS CCR2 +/64I Delay AIDS restriction genes) that influence the

RANTES -403A/-28G Delay AIDS outcome of HIV exposure and infection, discoveries that have led to novel salvage HLA HLA- A,-B,-C homozygosity Accelerate AIDS therapy design and implementation. HLA B*35Px Accelerate AIDS Researchers under the direction of Dr. Ste­ HLA B*57, B*27, Bw4 Delay AIDS phen O’Brien have proposed a dense single

KIR/HLA KIR3DS1/HLA-B Bw4-80I Delay AIDS nucleotide polymorphism scan across the entire human genome to search for all gene IL-10 -592A Accelerate AIDS variants that regulate a person’s response to APOBEC3G 186R Accelerate AIDS HIV/AIDS. The goal of this approach is DC-SIGN -336C Susceptibility to infection to identify regulatory host genetic factors

TSG101 HapC Accelerate AIDS required for HIV infection and AIDS pro­ gression that can serve as new targets for CUL5 Cluster II haplotypes More rapid CD4+ T cell loss therapeutic development and even genetic factoring in clinical trials of AIDS vaccines identified that confer relative increases Harvard University and the CCR Cancer and drugs. in protection from or susceptibility to Inflammation Program aim to understand progression to AIDS in HIV-infected how these combinations work. individuals. In some cases, functional work involving HIV antigen presentation Variants in other host immune response by the HLA gene products has explained genes also are associated with disease the genetic associations observed with the progression. One such gene is APOBEC3G, corresponding genes. Recently, several which encodes a protein that inhibits viral investigators have shown that HLA class replication. The HIV protein Vif suppresses I gene products interact with the highly APOBEC3G protein activity by inducing its variable killer cell immunoglobin-like degradation. The observation that a variant receptors (KIRs), which participate in of APOBEC3G is associated with more rapid controlling both natural killer cells and a progression to AIDS supports developing subset of T cells. Investigators in Dr. Mary inhibitors that block Vif-promoted deg­ Carrington’s laboratory showed that spe­ radation of this antiviral cellular protein. cific combinations of HLA gene products Complementary studies by Dr. David Derse, and KIRs interact synergistically in defense HIV Drug Resistance Program (DRP), are Microarray analysis can be used to group genes that are expressed at normal levels (green) or against HIV. Ongoing multi-disciplin­ also investigating the role of APOBEC3G in overexpressed (red) in individuals that are susceptible ary collaborations with investigators at restricting HTLV-1 infection. to HIV infection, AIDS, or related diseases.

HIV/AIDS Research |  Outsmarting a Formidable Foe: Viral Diversity and Drug Resistance

A major challenge in treating HIV is the virus’s ability to mutate and become resis­ tant to therapies. The virus is also adept at living within minute reservoirs in the body at levels undetectable by standard assays. CCR scientists are addressing both of these issues with highly sensitive assays and novel animal models of disease.

HIV Variation leading to a much more diverse viral popula­ tion. DRP researchers are investigating how Like all viruses, HIV can generate genetic this diversity affects disease course and the diversity by mutation when it replicates, efficacy of antiviral therapy. as well as by recombination between genetically distinct viruses. Using model HIV Assays Depiction of an HIV viral particle courtesy of Dr. Louis Henderson cell culture systems, Drs. Vinay Pathak and Wei-Shau Hu, HIV DRP, have found that Therapy that reduces HIV to levels unde­ infection. If therapy is interrupted, even the rate of recombination depends on the tectable by standard “ultrasensitive” assays after many years, residual virus replicates balance between the production of viral (less than 50 copies of virus RNA, or less and viral RNA levels increase. Occasion­ DNA and the destruction of viral RNA. than 25 viral particles, per milliliter of ally, therapy fails due to the appearance of The odds of recombination depend on a blood) can potentially prolong disease-free resistant virus. perfect match between genetically distinct life indefinitely, as long as these low levels viruses in one region of the RNA genome are maintained. HAART does not cure the In collaboration with Dr. John Coffin of —even one base difference between viruses Tufts University, Dr. Palmer’s group has can greatly reduce the likelihood that they developed an HIV assay that is 100 times 2001 Mechanistic basis of AZT will recombine. resistance reported more sensitive than the “ultrasensitive” as­ say in general use. A large study using this CCR scientists also have developed sensi­ assay found that about 80% of patients on tive tools for assessing the genetic varia­ tion within HIV populations. When first Single-Genome Sequencing (SGS) infected, most patients have only a single HIV strain or clone. In contrast, studies by the group of Dr. Sarah Palmer, HIV DRP, indicate that individuals infected with HIV for long periods have a complex mixture of closely related but genetically distinct viruses (called a quasispecies), and that recombina­ tion among these viruses contributes sub­ stantially to this diversity. Through mutation and selection, this clonal virus population Patient plasma Sequence individual Phylogenetic tree rapidly becomes diverse. Occasionally, an in­ sample of viral DNA dividual is infected with two or more viruses Detecting HIV quasispecies through single genome sequencing. cDNA produced from plasma HIV RNA is diluted to from the same quasispecies. In these cases, a single copy. From 11 to 50 single genomes are sequenced per sample and phylogenetic analyses are performed. there is rapid recombination and mutation, Figure courtesy of Dr. Sarah Palmer

 | National Cancer Institute Appearance and Decay of Resistance Mutations 2007 Monkey model for HIV 100 resistance evolution developed

80 large majority of treated pregnant women have detectable mutations that cause this 60 resistance. The HIV DRP’s Dr. Frank Maldarelli is measuring the effect of these 40 mutations on subsequent therapy using the same inhibitors.

20 Percent of Patients with Mutant Evolution of HIV drug resistance is difficult to follow in patients with the kind 0 of detail necessary to fully understand this important process. Carefully designed stud­ ies in experimental animals are necessary, 0 2 4 6 8 10 12 but the model virus, simian immunodefi­ Months after Single-dose Nevirapine ciency virus (SIV), is not sensitive to many commonly used anti-HIV drugs such as long-term suppression therapy can sustain the RT inhibitor . For this reason, very low levels of virus (averaging around 2 2005 Ultrasensitive assays devel- the group of CCR investigator Dr. Vineet viral particles per milliliter of blood) for 7 oped to detect patient virus and KewalRamani, HIV DRP, has developed years or more. Initial experiments suggest drug resistance an HIV-SIV hybrid virus that causes that the detected virus is not a result of disease in monkeys and is fully sensitive to replicating virus that somehow escapes before the initiation of therapy and that efavirenz and other RT inhibitors. Studies from the antiviral drugs. Rather, this res­ have persisted for many years. This virus of virus replication in infected monkeys ervoir comes from cells that were infected is the most likely source of the rekindled treated with such drugs and using the infection when therapy is halted. highly sensitive assays developed in the DRP are beginning to reveal important The Evolution of Resistance details of the way in which resistance mutations can arise and spread through a Treatment of HIV-positive pregnant viral quasispecies. These studies will help women with a single dose of the RT inhibi­ in the design of therapeutic and preventive tor nevirapine is quite effective at prevent­ approaches to HIV infection with a lower ing viral transmission to their newborns, chance of failure from the appearance of and has been important in preventing the drug-resistant virus. spread of HIV in Africa. However, this treatment also leads to the rapid genera­ tion of resistant virus in these women. A Dr. Vineet KewalRamani CCR-developed assay revealed that a

HIV/AIDS Research |  Better Ways to Find Better Drugs

Since initial testing of AZT, ddI, and ddC, NCI researchers continue to search for new anti-HIV drugs. Multi-disciplinary collaborations are exploring the structures of viral proteins, the interaction of these proteins with antiviral drugs, and, finally, testing natural products that exhibit strong inhibition of HIV.

Structural Biology In 1989, the Wlodawer group reported the first structure of HIV-1 PR bound to Detailed structures of HIV proteins a substrate-based inhibitor and since then are important for understanding their has provided important information on function in virus replication as well as drug-resistant variants of this enzyme. At their interaction with antiviral drugs. Structure of HIV-1 RT (green) bound to the inhibitor the same time, his group has studied the Knowledge gained through this process TMC278- (blue). Figure courtesy of Drs. related enzymes of Rous sarcoma, feline Kalyan Das and Edward Arnold, Rutgers University is also critical to the development of immunodeficiency, and human T-cell improved therapeutics and understanding Several drugs interrupt reverse transcrip­ leukemia viruses. The MCL also established the mechanisms by which HIV acquires tion by mimicking nucleotides and insert­ and maintains the HIV Protease Database resistance. CCR scientists Dr. Alexander ing themselves into viral DNA, rendering which is available online to researchers, Wlodawer, Macromolecular Crystallogra­ it useless. However, the ribonuclease H educators, and students. phy Laboratory (MCL), and Dr. Stephen (RNase H) activity of reverse transcrip­ Hughes, HIV DRP, have played a key tase—which removes viral RNA from role in elucidating the structures of the 1989 Structure of an inhibitor bound RNA-DNA duplexes—is also essential enzymes PR, RT, and integrase (IN), that to HIV-1 protease solved for viral DNA synthesis, but has received are essential for HIV replication. little attention as an antiviral target. CCR scientists Drs. Stuart Le Grice, HIV Structure of PR with the Subsequently Dr. Hughes’ group, DRP, and John Beutler, Barry O’Keefe, inhibitor rito- together with Dr. Edward Arnold, Rutgers and Kirk Gustafson, Molecular Targets navir in cyan University, published in 1993 the first Development Program (MTDP), have (right) from Dr. Alexander high-resolution structure of HIV-1 RT identified several classes of RNase H Wlodawer containing double-stranded DNA. This inhibitors. In collaboration with extramu­ (below) long-standing collaboration has made ral scientists in the United Kingdom and important contributions to our under­ the United States, co-crystals of HIV RT standing of the structural and biochemical with two inhibitors have been obtained, basis for the action of, and resistance to, providing an important platform for RT inhibitors. For example, they showed lead optimization. that mutations conferring resistance to AZT create a binding site for the energy The CCR Laboratories of Molecular molecule ATP on HIV RT. Bound ATP Pharmacology (LMP) and Medicinal mediates a reaction promoting DNA synthesis in reverse. This leads to removal 1993 Structure of HIV-1 reverse of the drug from the growing DNA chain transcriptase bound to double- which allows viral DNA synthesis (and stranded DNA solved viral replication) to continue.

 | National Cancer Institute (Prezista®), a novel PR inhibitor developed by Dr. Hiroaki Mitsuya,

HAMB, and Purdue University scientists, was granted accelerated FDA approval

in 2006 for treatment of AIDS patients failing to respond to existing therapies. Cur­

rent PR inhibitors bind at the active site and prevent release of structural proteins

from larger precursors, resulting in non-infectious virions. However, mutations

can easily change the structure of the active site, rendering such drugs ineffec­

tive. Darunavir’s advantage is that it binds tightly to portions of PR that

change little, even with viral mutations that render PR insensitive to

other inhibitors.

Taking Advantage of sin, derived from a red algae, Griffithsia 1997 Cyanovirin-N identified as Nature’s Products sp., is extremely potent against both HIV-1 HIV-1 and HIV-2. functions similar to MTDP and Natural Products Branch cyanovirin and , but has a greater researchers have isolated several anti-HIV number of carbohydrate binding sites, Chemistry (LMC) have been instru­ agents from natural product extracts. which may explain its enhanced potency. mental in drug discovery and structural Working with industrial and academic biology. The LMP-LMC collaboration is partners, potent analogs have been devel­ among the world’s most productive for oped and tested in animal models, and the discovery of inhibitors of the HIV some have moved into clinical studies. IN. Most current drug regimens block ei­ ther RT or PR. Dr. Yves Pommier’s group Cyanovirin and scytovirin, isolated from (LMP) was among the first to evaluate IN the blue-green algae Nostoc ellisosporum and inhibitors, providing mechanistic clues , respectively, act against for developing drugs presently undergo­ a broad spectrum of laboratory and clinical ing clinical trials. Dr. Pommier’s group HIV strains. Both block replication by also has contributed novel biochemical binding to specific carbohydrate groups on assays to probe IN-DNA-drug interac­ the viral envelope glycoprotein. In collabo­ tions. Lastly, the first crystal structures for ration among IRP groups, the structures of the catalytic core domain of IN contain­ both inhibitors have been obtained using ing divalent metal were reported by the nuclear magnetic resonance imaging and NMR Structure of Wlodawer group, while an MCL-LMP x-ray diffraction. Collaborative studies Scytovirin (right) collaboration provided the first high- have also shown that cyanovirin controls from Dr. R. Andrew resolution structure of an IN inhibitor replication in a macaque-based anti-SIV Byrd (above) bound to the enzyme. topical microbicide model system. Griffith-

HIV/AIDS Research |  Dr. Eric Freed

A constant challenge to HIV therapy is developing therapeutics that are effective against drug-resistant virus. Following a collaborative venture between HIV DRP researcher Dr. Eric Freed and Panacos Pharmaceuticals, Gaithersburg, MD., evaluate its efficacy against HIV-1 strains clinical trials are underway for , resistant to PR inhibitors. If further clinical Griffithsia sp., the red algae from which griffithsin a derivative of originally was isolated. Photograph and structure courtesy testing is encouraging, an application for of Dr. David Newman and Dr. Alexander extracted from a Taiwanese herb. Beviri­ FDA approval is scheduled for 2008. Wlodawer, respectively

2006 FDA approves the HIV protease inhibitor Darunavir (Prezista) MA CA NC p6 p55Gag SP1 SP2 mat induces changes in HIV by interfering with proteolytic processing of the gag pre­ cursor polypeptide into structural proteins, leading to defective virus particles. Beviri­ mat is also effective against drug-resistant HIV-1 strains. Results from clinical studies suggest that resistance to bevirimat does Untreated PA-457 PA-457 treated not emerge as rapidly as resistance to other antivirals. Dr. Freed’s group plans to define Bevirimat blocks the cleavage of SP1 from the c-terminus of CA, disrupting virus maturation. bevirimat resistance more precisely and to Figure courtesy of Dr. Catharine Adamson

 | National Cancer Institute Looking Ahead: Vaccines to Prevent Infection

Vaccines are undoubtedly the most effective method for controlling viral infections and epidemics. However, HIV presents unique challenges. The virus integrates into the DNA of an infected host cell, ensuring that infection persists for the life of that cell. This property of integration also allows the virus to exist in a latent state, hidden from the immune system, thus favoring its persistence. In addition, just as the virus mutates to become resistant to drugs, the continuous selection of variants in the face of immune responses leads to enormous diversity in HIV strains, both worldwide and even within a given infected individual over time.

To achieve meaningful protection, a researchers are exploring a vaccine strategy vaccine must therefore elicit broad, cross- in which DNAs encoding both IL-15 and reactive immune responses capable of HIV genes are co-administered, eliciting protecting against multiple variants. A the potent cellular immunity needed to further challenge is the fact that the HIV maintain low viral burdens. Synthetic HIV Vaccines offer the hope of an effective means to envelope glycoprotein is extensively masked protein fragments (peptides) are also being control HIV infection. with sugars and shows extensive variation; used together with IL-15 and other mol­ Neutralizing Antibodies epitopes that are targets of broadly neutral­ ecules, which regulate immune responses in izing antibodies are sequestered and not order to increase vaccine potency. Dr. Dimiter Dimitrov, CCR Nanobiology easily recognized by the immune system. Program has identified several unique With these issues in mind, NCI research­ cross-reactive antibodies against HIV-1 ers are exploring several vaccine strategies 1993 NC protein targeted for and other viruses including SARS CoV, chemical inactivation of HIV -1 as designed to elicit the required cellular (T Hendra, and Nipah viruses, and used vaccine candidate cells) and humoral (antibody) immunity molecular engineering to optimize these prior to infection.

DNA Vaccines

Drs. George Pavlakis and Barbara Felber, Vaccine Branch (VB), are work­ ing to enhance cellular immune responses by developing DNA vaccines with genes designed for high-level production of HIV proteins, combined with DNA for cytokines as molecular adjuvants, to induce strong antiviral immune responses. Dr. Jay Berzofsky, VB, has shown that long- lived, high-avidity cytotoxic T lympho­ cytes (CTLs) can control HIV viremia, and that development of such CTLs can be enhanced by IL-15. Together these Dr. George Pavlakis

HIV/AIDS Research |  Novel Whole Inactivated Vaccines 2002 Systemic immunization with Dr. Jeffrey Lifson and colleagues in the AVP poxvirus vaccine induces mucosal have developed a novel procedure to render T cell responses HIV-1 noninfectious. This strategy arose immunologically important viral envelope from basic studies by Drs. Lou Henderson, glycoproteins structurally and functionally Rob Gorelick, Larry Arthur, and Elena intact. These inactivated virions are being Chertova showing that viral replication used extensively as reagents in immu­ depends on highly conserved sequences nologic assays and studies of basic viral in certain sections of the nucleocapsid biology, while CCR scientists are exploring Structure of aldrithiol-2, a chemical treatment (NC) protein encoded by the HIV gag which covalently modifies internal, but not surface, their potential as vaccine immunogens in gene. Exploiting the intrinsic chemistry of HIV proteins. Figure courtesy of Dr. Michal Legiewicz non-human primate models. retroviruses, the group developed specific chemical treatments that preferentially antibodies. A comparative analysis of the Most recently, Dr. Sriram Subramaniam, covalently modify interior proteins of the sequences of these antibodies suggested a of CCR’s Laboratory of Cell Biology, virus (including NC), eliminating infectiv­ novel challenge in the development of an working with Dr. Lifson, used advanced ity. In contrast to conventional methods of efficacious HIV vaccine—lack or limited 3-D electron microscopy to examine the viral inactivation, this approach leaves the availability of B cells with appropriate initial interactions between HIV and sus­ receptors. Dr. Dimitrov’s group has also ceptible host cells, identifying a consistent developed one of the most potent and structure, named the “entry claw,” that 1997 Replication-competent broadly cross-reactive antibodies against the appears to consist of molecules on the sur­ adenoviral vector vaccines protect HIV-1 envelope glycoprotein. Commercial face of the virus interacting with receptors from HIV infection development of this antibody is underway. on the host cell membrane. Further study

Contact of HIV-1 with T cells. Electron tomographic analysis (left) reveals the architecture of the virus-cell contact region which forms an “entry claw” as shown in the schematic (right). Figure courtesy of Dr. Sriram Subramaniam

 | National Cancer Institute by cessation of the drug regimens led to prolonged intervals of low virus levels.

As HIV is primarily a sexually transmitted disease, vaccines must induce potent im­ munity at rectal and genital sites. The Vaccine Branch’s Dr. Marjorie Robert-Guroff uses adenovirus (Ad) vectors for vaccine development. These vectors infect the epithelial cells lining the airways and gastrointestinal tract, induc­ ing mucosal and systemic immune re­ sponses. A comparative study of replicat­ ing and non-replicating adenovirus vectors in non-human primates established that replicating Ad-HIV recombinants more effectively primed antibody responses and elicited more potent and persistent cellular immunity. A combination regi­ men involving initial Ad-recombinant administration followed by immuniza­ Marjorie Robert-Guroff, Ph.D. The pill she is holding is a prototype version of the adenovirus-based HIV vaccine. tion with HIV envelope protein induced broadly reactive, functional antibodies of this structure should offer important that neutralized a spectrum of HIV clade clues for designing improved anti-HIV 2005 Mucosal vaccine delays virus B isolates, the type found in the United therapies aimed at blocking virus-target dissemination from the mucosal States. The antibodies also mediated cell interactions. site of transmission in a non -human primate model antibody-dependent cellular cytotoxicity, killing cells infected with the more diverse Live Vector Vaccines HIV strains present worldwide.

Poxviruses have been exploited exten­ In preclinical studies, the replicating sively as vaccine vehicles. Dr. Genoveffa Ad-based strategy has elicited potent, Franchini, VB, has advanced this approach durable protection against HIV isolates to prevent infection as well as for therapy. and virulent SIV. As a first test in humans, Dr. Franchini has demonstrated protec­ a phase I trial of this strategy in HIV- tive efficacy of two vaccines in non-human negative volunteers will be conducted at primates infected with SIV and HIV using the NIH Clinical Center in collaboration naturally attenuated (or weakened) canary- with the National Institute of Allergy and pox and molecularly attenuated vaccinia Infectious Diseases. (cowpox) virus vectors. Immunization of

SIV-infected macaques in combination Adenovirus Graphic © Russell Kightley, Russell with suppressive antiviral therapy followed Kightley Media, Canberra, Australia

HIV/AIDS Research |  Center of Excellence: Bringing It All Together

Although this brochure captures only per year worldwide. Of these, approxi­ a limited number of seminal contri­ mately 70% are caused by viruses such butions made by former and current as human papilloma virus, type B and NCI researchers, it nonetheless high­ C hepatitis viruses, Epstein-Barr virus, lights an uninterrupted, institutional and human T-cell leukemia virus. investment in retrovirus biology for more than three decades, with par­ As part of an NCI response to these Dr. Stuart Le Grice ticular emphasis on combating HIV formidable problems, the Center for infection. While we can be proud of Cancer Research has established the internationally, as a means of diversi­ these achievements, the sobering fact Center of Excellence in HIV/AIDS fying the strategies that can be applied remains that the number of newly and Cancer Virology (CEHCV). to these devastating diseases and of HIV-infected adults and children rose As one of several new Centers, the facilitating further efforts in this area. globally from ~3.9 million in 2004 CEHCV will coordinate existing to ~4.3 million in 2006, and the structures and areas of expertise across Finally, continuing the outstanding number of deaths from ~2.7 million the NCI-Frederick and Bethesda quality of basic and clinical research to ~2.9 million over the same period. campuses as a means of rapidly com­ within the NCI requires a commit­ The initial successes of highly active municating advances in the discovery, ment to mentoring junior colleagues antiretroviral therapy (HAART) are development, and delivery of antiviral at all levels. In my opinion, the also being threatened by the rapid and immunologic approaches for strongest testament to our personal emergence of drug-resistant virus, prevention and treatment of HIV accomplishments as scientists is how placing a constant demand for the infection, AIDS-related malignancies, well we have prepared the next genera­ continuous development of alterna­ and cancer-associated viral diseases. tion for the challenges ahead. In the tive and more effective therapeutic The CEHCV will also be challenged current, highly competitive funding and immunological interventions. to lead new initiatives, projects, and environment, our involvement and collaborations, thereby positioning support will be crucial to their success. Recent evidence also suggests that the IRP to play a significant role in Par ticipation of CEHCV members in the increased life expectancy of interdisciplinary and multi-disciplinary events planned for the coming years HIV-infected individuals on HAART translational research. will be essential to such endeavors, may enhance their cumulative risk of and I am confident that we can rise to developing both AIDS-defining and A strong research program within these challenges. non-defining cancers (such as lung the NCI should also seek to nurture Stuart F. J. Le Grice, Ph.D. cancer, Hodgkin’s lymphoma, and partnerships and take advantage of Head, Center of Excellence in anal carcinoma). In addition to the complementary expertise of research­ HIV/AIDS and Cancer Virology important role of these pathogens in ers across the NIH and within the National Cancer Institute the global HIV/AIDS epidemic, ap­ extramural community. The CEHCV National Institutes of Health proximately one in every five human endorses NCI’s longstanding commit­

cancers is caused by infectious agents, ment to making reagents and re­ Center of Excellence in with an estimate of 1.9 million cases sources available, both nationally and HIV/AIDS and Cancer Virology

0 | National Cancer Institute Organizational Investments of the NCI

1987 Established AIDS Vaccine Program at Frederick Cancer Research and Development Center

1993 HIV/AIDS Cancer Match established

1995 Established AIDS Malignancy Consortium to develop approach for the man­ agement of cancers in HIV-positive individuals

1995 Linked AIDS data and Training Opportunities within the Center of Cancer Registries Excellence in HIV/AIDS and Cancer Virology 1995 Established AIDS Cancer Specimen Resource to distrib­ ute tissues from AIDS patients The CEHCV is committed to support- with world-class reputations in basic for basic, translational, and ing and training the next generation of virology, biochemistry, structural biology, epidemiological research HIV/AIDS and cancer virology research- genetics, drug discovery and development, 1996 Established intramural HIV and ers, helping launch careers in science, antiviral resistance, vaccine development, AIDS Malignancy Branch and enabling established investigators to and epidemiology in one of the world’s pursue investigator-initiated research. The leading scientific institutions. Current 1997 Established the HIV Drug CEHCV works to create a high-quality openings for postdoctoral , staff Resistance Program at research environment for scientists and scientists and research fellows in any NCI-Frederick clinicians. Training young investigators CEHCV laboratory in the CCR can be 2005 Established Office of AIDS to address complex scientific questions found online at http://ccr.cancer.gov/careers/ Malignancy Program at the NCI through collaboration and multi-disci- positions.asp while other opportunities 2007 Established Center of plinary approaches is a major goal of the within the NCI can be found at Excellence in HIV/AIDS CEHCV. Trainees at the CEHCV have the http://www.cancer.gov/researchandfunding/ and Cancer Virology unique opportunity to learn from experts intramural. The Center of Excellence in HIV/AIDS and Cancer Virology

The CEHCV is composed of members from across the NCI’s different branches, laborato- ries, and programs. Current research is being conducted in the areas of AIDS malignancies, HIV virology and molecular pathogenesis, immunology/immunopathology, vaccines and immunotherapy, epidemiology, drug develop- ment/resistance, and cancer virology.

Our Mission

The mission of the Center of Excellence in HIV/AIDS and Cancer Virology (CEHCV) is to facilitate and rapidly communicate advances in the discovery, development, and delivery of antiviral and immunologic approaches for the prevention and treatment of HIV infection, AIDS-related malignancies, and cancer - associated viral diseases.

For more information on the CEHCV, the CCR, or NCI please visit: http://ccr.ncifcrf.gov/initiatives/CEHIV/ http://ccr.cancer.gov/ http://www.cancer.gov/

NIH Publication No. 07-6284 Printed October 2007