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New Discoveries Energize the HIV Vaccine Field

Report from AIDS Vaccine 2008 Meeting

With help from the Global HIV Vaccine Enterprise, South African scientists hosted the AIDS Vaccine 2008 conference for the first time in Africa, the continent hardest hit by the HIV pandemic. The sudden halt of Merck’s Ad5-based HIV vaccine clinical trial in 2007 tilted the see-saw in favor of basic research, still leaving plenty of room for clinical testing of promising vaccines. Some of the exciting basic discoveries at this conference deepened our understanding of the natural immune responses to the virus, and how these responses might be exploited to guide future vaccine design

Potential for future use of B cells in fighting HIV

Matt Holl of Duke University School of Medicine found in mice B cells that bind to MPER, a region of the HIV envelope protein used by the virus for entry into cells, frequently populate the bone marrow, but rarely exist in the spleen. Tolerance mechanisms cause a loss of MPER-reactive B cells, and hence, MPER immunizations generate poor antibody responses in mice. Culturing the bone marrow B cells with a TLR4 ligand (LPS) expands the repertoire of cells that generate self-and MPER-reactive antibodies. When immuno-compromised mice lacking the recombination-activating (RAG) protein that makes them deficient in mature lymphocytes, are infused with cultured B cells, they respond to MPER immunization with 3-to 10-fold higher quantities of MPER-specific IgG antibodies compared to control mice. These experiments suggest that tolerance mechanisms delete B cells capable of producing rare broadly HIV-1 neutralizing antibodies, thereby serving to limit self-reactivity of B cells.

B cells use antigen-activated somatic hypermutation (SHM) of the immunoglobulin variable region genes to produce high-affinity antibodies of all isotypes. Dimiter Dimitrov of the National Cancer Institute, NIH analyzed mathematically the editing process to generate the repertoire of monoclonal antibodies against viruses. This analysis revealed that for SARS and Nipah viruses only limited somatic mutations from the germline sequences over a short period of time are needed to generate neutralizing antibodies. Based on the observation that all known broadly reactive neutralizing antibodies have exceptionally long, hypermutated CDR3 region, Dimitrov predicted that for HIV, significant diversification from the germline sequence was needed, and that it may take over three years to generate a broadly neutralizing antibody against HIV. Thus only through extensive mutation and affinity maturation can broadly neutralizing antibodies against HIV be generated. If this prediction is confirmed experimentally, it constitutes a major hurdle toward developing an HIV vaccine that can induce neutralizing antibodies. This problem could potentially be counteracted by identifying intermediates in the editing process and boosting their levels to promote production of neutralizing antibodies.

Neutralizing antibodies to thwart HIV

Dennis Burton of the Scripps Research Institute discussed how administering neutralizing antibodies can safeguard monkeys against infection with an HIV–SIV chimeric virus (SHIV). IgG1b12, a broadly neutralizing antibody competes for the same niche on the HIV shell glycoprotein, gp120 that serves as the initial contact point for CD4, thereby blocking viral entry into cells bearing CD4 on their surface. High concentration of b12 infused intravenously into monkeys prevents SHIV infection through the vaginal route (Nature 449: 101, 2007). Studies with another broadly neutralizing, 2G12 that binds to a dense cluster of carbohydrates on gp120, revealed that 2G12 protected monkeys at 100 fold lower concentration than b12, thus implying that the epitope targeted by 2G12 may be more beneficial or 2G12 is a more effective antibody. In addition, multiple low dose challenge experiments in monkeys to more closely mimic human HIV infection showed that b12 provided passive protection effectively at much lower concentrations that those employed in previous experiments.

Tony Moody of Duke University School of Medicine established a panel of b2-glycoprotein I independent anti-lipid monoclonal antibodies from auto-immune disease patients. These antibodies failed to neutralize HIV in the standardized TZM-bl reporter cell line assay. However, they neutralized virus in the PBMC assay, apparently through release of b-chemokines (MIP1a, MIP1b) by monocytes in the culture. Such chemokines interfere with virus entry through the CCR5 receptor. Furthermore, neutralization could be reverted by antibodies against MIP1a and MIP1b. These anti-lipid antibodies stick to the host target cell and not the virus to prevent infection. A vaccine that induces such antibodies may not be able to directly neutralize HIV but it may reduce virus spreading.

Gag targeted in HIV controllers

By unlocking the immune secrets of “elite controllers” who keep the virus at nearly undetectable levels (less than 50 copies/mL) for at least one year without resorting to anti-retroviral therapies, Bruce Walker of Harvard Medical School hopes to enlighten vaccinologists about the kinds of immune responses that an effective HIV vaccine must evoke. The convergence of three factors predispose these individuals to their “elite control” status: host genetics (ECs enriched in MHC class I alleles HLA-B*27, B*51, B*57) and immune responses (low levels of antibodies against the circulating virus, weaker CD8 T cell responses that are more focused on Gag), all of which collude to pressure the virus to mutate to become less fit. Substituting the wild-type virus’ gag-protease gene with the mutated sequences isolated from ECs’ viruses lowered the replication capacity of the reporter, thus accounting for the slow disease progression in these individuals (J. Virol. 83: 140, 2009).

Explaining the confounding results of the Step study

Susan Buchbinder of the San Francisco Department of Public Health showed that Merck’s Ad5 Gag/Pol/Nef candidate vaccine enhanced the risk of HIV incidence in two groups of men –those that were uncircumcised and those with high titers of antibodies against adenovirus type 5 (Ad5) (Lancet 372: 1881, 2008). Julie McElrath of the Fred Hutchinson Cancer Research Center explored the role of Ad5 antibodies and vaccine generated immune responses in the increased likelihood of HIV infection among uncircumcised, Ad5-positive men who received the vaccine over the placebo recipients in the STEP study. Both uninfected and infected men who received the vaccine generated similar frequency and magnitude of HIV-specific T cells (Lancet 372: 1894, 2008). Ad hoc analysis of the preliminary findings suggest that in Ad5-naïve individuals, the amount of HIV-specific IFNg secreting T cells might correlate inversely with viral load, and that this effect was more pronounced in vaccine recipients with “protective” HLA types lacking Ad5 antibodies. However it still remains unclear how the vaccine enhanced HIV infection among recipients.

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Last Updated January 05, 2009