International AIDS Society–USA Topics in HIV Medicine

Basic HIV Development

David I. Watkins, PhD

The highlight of the 2008 Conference on Retroviruses and Opportunistic mangabys and African green monkeys was a sober assessment of the HIV vaccine field by one of its have high levels of viral replication but pioneers. Desrosiers delivered a plenary session in which he called for show no signs of disease. Desrosiers refocusing our HIV vaccine effort. He suggested that none of the current also called for comparative testing of vaccine candidates in human clinical trials stands a chance against HIV. Thus, in macaques and humans. we need to redirect our efforts to basic vaccine research. This call for a sea Nathanson (Abstract 92) then gave change in how we carry out HIV vaccine research has already had an impact, the second plenary presentation of prompting a recent HIV vaccine summit in Bethesda, MD. This will likely the session and discussed vaccine ap- herald a new era in HIV vaccine research, resulting in a redoubling of effort proaches and animal models. Many to uncover innovative new ways of making an HIV vaccine. of his points supported and expanded those of Desrosiers. Nathanson empha- Desrosiers delivered a candid, and to highly idealized conditions with ho- sized the need to get honest answers some a controversial, assessment of mologous viral challenges. We are 0 for from the nonhuman primate challenge the HIV vaccine field, providing the 3 in clinical vaccine trials, and we have models and wondered if a refocusing sobering highlight of the recent 15th no idea how to elicit a broadly reactive of the vaccine field is necessary. Conference on Retroviruses and Op- neutralizing response. portunistic Infections in Boston. He Desrosiers asked whether we should Pathogenesis Studies with suggested that we do not have a viable be surprised by the failure of the STEP Relevance to Basic Vaccine HIV vaccine candidate in development trial vaccine. He referred to monkey Research currently and that we need to return studies using a trivalent adenovirus to basic research. Only a creative idea type 5 (Ad5) vaccine (Merck & Co, Inc) In the conference session titled “Viral would solve the enormous barriers to that afforded little or no reduction in vi- Pathogenesis and Immune Surveil- an effective vaccine. ral load after challenge with a monkey lance,” several oral presentations ad- virus that was exactly matched in se- dressed T-cell responses to SIV and HIV HIV Vaccine Development: The quence to the vaccine. He went further that might be relevant to vaccine devel- Problems to ask whether any of the products in opment. Loffredo (Abstract 18) suggest- the vaccine pipeline had a reasonable ed that broad CD8+ T-cell responses The enormity of the problems posed chance of showing efficacy, especially might play a role in control of SIV replica- by this virus to the vaccine field was de- against nonhomolgous challenges, and tion in macaques that expressed protec- lineated by Desrosiers (Abstract 91). He again was pessimistic about the likeli- tive major histocompatibility complex began by posing 3 questions: where are hood of success with these products. types. Streeck (Abstract 22) presented we, where are going, and where should Finally, Desrosiers suggested that interesting data from the Altfeld group we be going? He then discussed wheth- we rethink the way in which the Na- suggesting that “polyfunctional” CD8+ er a vaccine for HIV was feasible at this tional Institutes of Health (NIH) spends T-cell responses were a result of anti- time. He pointed out that the natural its HIV vaccine budget. Given the pau- gen load and sequence diversification. response to HIV neither controls viral city of good vaccine candidates cur- Should this prove to be correct, it will replication nor prevents superinfection. rently, we should probably refocus our have implications for assessing CD8+ The enormous sequence diversity and research efforts on basic discovery. T-cell responses in vaccines. the fact that we do not know what a Desrosiers suggested several topics protective immune response is against that should be high priority for discov- Vaccines in Phase I and II Studies this virus make it unlikely that we have ery research. How do we elicit broadly and Therapeutic Vaccines the necessary information to make a reactive neutralizing ? We vaccine at this stage. Furthermore, our Robinson (Abstract 85) presented her need novel vaccine and preventive group’s safety and immunogenicity best vaccine results to date in monkeys concepts. We need to understand what afford only a 1.0- to 1.5-log copies/ data for the clade-B DNA-priming and 10 is responsible in those rare cases in modified vaccinia virus Ankara (MVA) mL reduction in viral replication—and which virus replication is controlled: these trials were conducted under product (GeoVax Labs, Inc). Volunteers in elite controller humans and in ma- were vaccinated with low and high caques vaccinated with attenuated sim- Dr Watkins is Professor in the Department ian immunodeficiency viruses (SIVs) Note: The STEP results of Pathology and Director of the AIDS Vac- that subsequently control replication are summarized in the accompanying cine Research Laboratory at the University of highly pathogenic challenge viruses. report by Susan Buchbinder, MD. of Wisconsin Madison. We also need to understand why sooty

 Conference Highlights - Basic Vaccine Development Volume 16 Issue 1 March/April 2008

doses of DNA and MVA expressing the sugars and is highly variable. In the fi- very important in vaccine design. Hox- Gag, Pol, and proteins. The vaccine nal session on vaccine research, Wyatt ie (Abstract 154) presented his group’s was well tolerated, and the majority of (Abstract 152) discussed the biophysi- data describing a new attenuated SIV volunteers responded to the vaccine cal and antigenic properties of the Env. termed GY, which contains a muta- in the CD4+ (82%) and CD8+ (67%) He showed that stabilization of the tion in the cytoplasmic tail of Env. This T-cell compartments when given the CD4-induced coreceptor binding site mutant in the Env trafficking signal had highest dose. Although it was not clear enhances elicited immune responses no effect on peak viral replication, but whether this vaccine induced T-cell re- to this region. He also analyzed anti- in the chronic phase, virus replication sponses that were significantly differ- body responses generated in animal was undetectable. It offered complete ent from those induced by the Ad5 Gag, models to the soluble trimers. protection from challenge with the ho- Pol, and Nef product (Merck), planning mologous SIV isolate SIVmac239 and for a phase II trial is underway. The First Infecting Viruses afforded some measure of protection Similarly, Schuetz (Abstract 86) pre- from disease after heterologous E660 sented immunogenicity data from 20 Understanding the nature of the first challenge. Indeed, 2 out of 3 pigtailed volunteers vaccinated with the Vaccine infecting virus is central to vaccine de- macaques controlled E660 viral repli- Research Center (VRC) DNA prime/Ad5 velopment. Are people infected by a di- cation. After depletion of CD8+ T cells boost expressing Env proteins from verse swarm or by a single virus? Are in vivo, the challenge virus replicated, clades A, B, and C along with clade these viruses sensitive to immune re- suggesting that CD8+ T cells were B expressing Gag, Pol, and Nef pro- sponses? Shaw (Abstract 153) presented involved in control of replication. The teins. T-cell responses were predomi- evidence of by 1 to 2 viruses animals were then challenged with SIV- nantly against Env (16/20 responders), by sampling very early after infection. mac239, and nothing happened. whereas weaker responses were gener- By making a few assumptions, he and After a subsequent E660 challenge, ated against Nef (5/20) and Pol (3/20). his colleagues could predict the nature 1 animal had a blip of viral replication Unfortunately Gag-specific responses of the starting virus from the diversity and the other had 1000 copies/mL of were not assessed. Again, it was diffi- of the viral sequence at sampling. They E660, and later, low levels (100 cop- cult to assess whether this VRC vaccine found that in 78 of 102 patients infect- ies/mL) of E660. Three more animals induced better immune responses than ed with HIV-1, clade B had evidence of were vaccinated with GY, and 2 of those induced by the failed Ad5-only infection by only a single virus. The oth- 3 completely controlled the vaccine Gag, Pol, and Nef vaccine (Merck). ers were infected by a minimum of 3 to strain in the chronic phase, the other Data from a therapeutic trial of an 5 viruses. The virus population seemed to less than 1000 copies/mL. Anti- Ad5 vaccine expressing Gag were pre- to evolve randomly until CD8+ T cells CD16 antibody was administered with sented by Schooley (Abstract 87). Even exerted pressure and antibodies subse- no viral replication. The animals were though the vaccine was generally safe quently also exerted selective pressure. then challenged with additional E660. and well tolerated, no significant re- Interestingly, there was no evidence for Two of 3 had a peak of viral replication ductions in viral replication were seen adaptation to cell-specific replication. and then controlled viral replication to in vaccines compared with placebo af- Thus, most (80%) of the infections ex- less than 1000 copies/mL. After anti- ter analytical treatment interruption. amined appeared to have been caused CD8 antibody administration in vivo, Finally, efficacy results from the STEP by a single virus that then diversifies. It SIVmac239 replicated in 1 animal. In trial (Abstracts 88LB and 89LB) of the is thus likely that the majority of HIV- the second animal, E660 returned. In Ad5 vaccine (Merck) were presented. 1 clade-B infection is not caused by a the third animal, E660 replicated to 10 These are covered in greater detail in swarm of several viruses, one of which million copies/mL, and the animal sub- Buchbinder’s article, “HIV Testing and is then selected. Interestingly, all viruses sequently died. Thus, this model of at- Prevention Strategies,” on pages 9–14. used CCR5, and transmitted Envs were tenuated virus may prove typical of primary isolates, that is, not informative in our understanding of Frontiers in Vaccine Research easily neutralizable. how attenuated live vaccines might provide protection against heterolo- Antibody Responses A New Attenuated SIV for gous challenge. Understanding the Correlates Financial Disclosure: Dr Watkins has no rel- Inducing a broadly reactive antibody of Protection evant financial affiliations to disclose. response to the envelope glycoprotein (Env) is probably the most important Currently, only 1 vaccine confers com- goal of HIV vaccine research. This has plete protection from homologous A list of all cited abstracts been difficult to achieve for a variety challenge of nonhuman primates. De- appears on pages 69-77. of reasons, including the fact that the lineating the immune responses that conserved sites are difficult to access account for this control in macaques Top HIV Med. 2008;16(1):7-8 by antibody and Env is covered by vaccinated with attenuated SIV will be ©2008, International AIDS Society–USA