Conference Highlights - HIV Pathogenesis and Vaccine Development Volume 13 Issue 1 March/April 2005 HIV Pathogenesis and Vaccine Development R. Paul Johnson, MD New information on the crystal structures of the HIV and the simian immunodefi- After screening different combinations ciency virus (SIV) envelopes represented one of the scientific highlights of the 12th of gp120 core proteins with an intact V3 Annual Conference on Retroviruses and Opportunistic Infections. Numerous presen- loop complexed with CD4 and different tations also underscored the increasing recognition of the central role of gut-associ- antibodies able to bind to the envelope ated lymphoid tissue in AIDS pathogenesis and helped reveal a better understand- only after CD4 binding (CD4-induced ing of the multiple mechanisms underlying CD4+ T lymphocyte depletion in AIDS. antibodies), the Kwong laboratory iden- Progress on vaccine development was largely incremental but was strongly influ- tified a crystal that could be used for enced by the impact of an expanding array of flow cytometric assays that have structural analysis. Several features of revealed significant functional and phenotypic differences in virus-specific CD8+ the resulting predicted structure of the cells. The interplay between host cellular and humoral immune responses and virus V3 loop in the context of an envelope evolution was another prominent theme, and it underscored the challenge facing trimer help explain its relative immuno- host immune responses and vaccine developers in attempting to thwart an ever- mutating virus. genicity, including the fact that this loop is relatively exposed in the envelope trimer and the lack of intermolecular New Insights into Envelope In the unliganded form, the tip of the hydrogen bonds, a feature that confers Structure and HIV-specific CD4 binding site is exposed at the top more flexibility on the loop to interact Neutralizing Antibodies of envelope. Following initial contact with antibodies. with CD4, the resulting conformational Only a handful of monoclonal anti- Designing strategies to foil the ability of change brings together the other bodies are able to provide relatively HIV to evade neutralizing antibodies rep- residues of the CD4 binding site as well broad neutralization of primary HIV iso- resents one of the primary (and still elu- as the chemokine receptor binding site, lates. Based on the premise that elucida- sive) goals of HIV vaccine research. The locking in the remodeled envelope tion of the structure of these rare anti- crystal structure of HIV-1 gp120 pub- around CD4, and exposing the newly bodies could provide clues to the design lished in 1998 analyzed the conforma- formed chemokine receptor binding of modified envelope immunogens that tion of a modified envelope stripped of site. These changes shift a portion of the would be more effective in inducing most of its sugar residues and bound to V1-V2 loop that interacts with gp41, broadly neutralizing antibodies, the CD4 and to an antibody that mimicked thereby helping to release gp41 for sub- structures of several of these antibodies the chemokine coreceptor binding site sequent fusion with the host cell. have been determined over the past sev- (ie, a liganded envelope). Although this The investigators also identified a eral years. However, to date, the hope structure has been quite valuable for deep hydrophobic pocket in the inner that this information would lead to bet- advancing our understanding of HIV domain of the unliganded envelope ter vaccines has yet to be realized. Most envelope function, it does not provide where resistance mutations have been of these antibodies (notably b12 and information on several key points, mapped for a newly identified antiviral 2G12) have relatively unusual structures including the structure of the envelope compound (BMS-78806) that has been that are likely to be difficult to elicit by in its native state prior to binding to shown to inhibit HIV entry. This class of immunization. However, Kwong high- CD4, the point at which it is most sus- inhibitor is therefore likely to inhibit entry lighted the fact that the recently deter- ceptible to neutralizing antibodies. by binding to this pocket and stabilizing mined structure of the 2F5 monoclonal Using crystals of a fully glycosolated the unliganded form of gp120. Although antibody might provide a logical path to SIV gp120 (which was more stable than significant conformational changes in the a better immunogen. The antigen-bind- the HIV version) stripped of the V1-V2 envelope were clearly anticipated prior to ing region of 2F5 contains an extended and V3 variable loops, the Harrison lab the determination of this structure, the hydrophobic region that allows the anti- determined the crystal structure of the availability of a 3-dimensional model to body to bind to a hydrophobic region of unliganded envelope (Abstract 7). The visualize these changes should help guide gp41 that is relatively close to the virion most notable finding was the dramatic efforts to develop new means to interfere surface. In fact, binding of 2F5 to the conformational shift observed in the with viral entry by pharmacologic or HIV envelope is strongly enhanced by inner domain of the unliganded enve- immunologic means. the presence of membrane, suggesting lope compared with the previously Another gap in our understanding of that presentation of the 2F5 epitope in determined liganded envelope structure. envelope structure has been the lack of the context of membrane may be a key solid information on the V3 loop, which factor in eliciting similar antibodies. was deleted in the molecule used for the This observation suggests that use of Dr Johnson is Associate Professor of previously reported crystal structure. a modified envelope immunogen, which Medicine at Harvard Medical School and Kwong (Abstract 110) described recent is locked into place (by introduced disul- Chair of Immunology at the New England success in generating crystals of HIV-1 fide bonds) and presented in the context Primate Research Center. envelopes containing an intact V3 loop. of a membrane (eg, by a virus-like parti- 9 International AIDS Society–USA Topics in HIV Medicine cle or proteoliposome), might be a more gp41. As noted above, these antibodies controversial. In a plenary lecture, Douek effective means to induce antibodies to are atypical, both with respect to their (Abstract 127) provided an insightful and this epitope. structure and ability to mediate relative- entertaining review of different mecha- Alternative approaches to under- ly broad neutralization of multiple HIV nisms contributing to CD4+ cell deple- stand how to elicit broadly neutralizing strains, and are not representative of tion at different stages of HIV infection. antibodies have focused on analysis of neutralizing antibodies found in most Several studies in SIV-infected monkeys antibodies in HIV-infected people that HIV-infected subjects. The subjects, who had previously documented depletion of bind to conserved functional targets, were preselected for HIV isolates sensi- CD4+ cells in the gut within 2 weeks such as the chemokine coreceptor bind- tive to these antibodies, received all 3 after infection. However, there were ing site. Decker (Abstract 87) utilized a neutralizing antibodies 1 day prior to some who interpreted these studies as novel approach to screen for antibodies discontinuation of antiretroviral therapy representing peculiarities of the SIV/ in patient sera able to bind to the and received weekly infusions for a total macaque model rather than insights into chemokine receptor binding site by of 12 weeks. The 8 chronically infected HIV pathogenesis. Recent studies in HIV- preincubating either HIV-1 or HIV-2 patients had undergone previous treat- infected patients, including one from the reporter viruses with soluble CD4 to ment interruptions, thereby allowing a Douek laboratory, have provided com- expose the coreceptor binding site. comparison of the increase in viremia pelling evidence for rapid and profound These CD4-induced neutralizing anti- following monoclonal antibody treat- depletion of CCR5+CD4+ cells in the bodies were able to mediate neutraliza- ment with that observed following previ- gut of patients in the first several weeks tion across numerous HIV-1 clades and ous interruptions. of HIV infection. This depletion of acti- even neutralization of HIV-2 at titers of A significant delay in the rebound of vated CCR5+CD4+ cells occurs most up to 1:100,000 or more. Competition viremia was observed in 2 of the 8 noticeably in the gut, the major reservoir experiments with an antibody (19c) chronically infected patients. The 6 for activated CD4+ cells in the body, but known to bind to the chemokine recep- acutely infected patients had such based on studies in macaques, also tor binding site confirmed that this anti- rebound significantly later than did a ret- occurs at other mucosal sites, including body activity largely or exclusively rospective control group of patients with the pulmonary tract and female repro- reflected antibodies to the chemokine acute HIV infection who underwent ductive tract. Whether these cells are receptor binding site. These results prob- treatment interruption and were not killed by direct infection or indirect ably have greater significance for under- treated with neutralizing antibodies. mechanisms has been much debated. standing of envelope function and evo- Interestingly, the development of resis- Douek presented data from acutely lution than vaccine design, because tance in the resurgent virus to the 2G12 infected macaques documenting SIV CD4-inducible neutralizing activity is monoclonal antibody was observed in 11 infection of 30% to 60% of memory only detected after the virus binds to of 13 patients. Overall, 7 of 14 patients CD4+ cells. Although this high level of CD4. Thus, the access of antibodies to had either a delayed or a decreased infection was most striking in the gut, it this binding site is stearically inhibited rebound in viremia after interruption of was also observed in peripheral blood following the interaction between HIV therapy.