Progress on the Induction of Neutralizing Antibodies Against HIV Type 1 (HIV-1)
Laboratory of Nucleic Acid Vaccines, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. BioDrugs
(Impact Factor: 2.99).
02/2009; 23(3):137-53. DOI: 10.2165/00063030-200923030-00001
Infection with HIV type 1 (HIV-1), the causative agent of AIDS, is one of the most catastrophic pandemics to affect human healthcare in the latter 20th century. The best hope of controlling this pandemic is the development of a successful prophylactic vaccine. However, to date, this goal has proven to be exceptionally elusive. The recent failure of an experimental vaccine in a phase IIb study, named the STEP trial, intended solely to elicit cell-mediated immune responses against HIV-1, has highlighted the need for a balanced immune response consisting of not only cellular immunity but also a broad and potent humoral antibody response that can prevent infection with HIV-1. This article reviews the efforts made up to this point to elicit such antibody responses, especially with regard to the use of a DNA prime-protein boost regimen, which has been proven to be a highly effective platform for the induction of neutralizing antibodies in both animal and early-phase human studies.
Available from: Nancy Haigwood
- "HIV Envelope evolves under immune pressure and escape mechanisms include increase in variable loop length, introduction of specific amino acid mutations and additions and/or shift of potential N-linked glycosylation sites . The current study identifies a previously unknown combination of four PNGS (located at positions 130, 139, 160 and 397) as a key motif affecting 2G12 neutralization resistance in Envelopes isolated from a SHIV-infected macaque. "
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ABSTRACT: HIV-1 Envelope (Env) protein is the sole target of neutralizing antibodies (NAbs) that arise during infection to neutralize autologous variants. Under this immune pressure, HIV escape variants are continuously selected and over the course of infection Env becomes more neutralization resistant. Many common alterations are known to affect sensitivity to NAbs, including residues encoding potential N-linked glycosylation sites (PNGS). Knowledge of Env motifs associated with neutralization resistance is valuable for the design of an effective Env-based vaccine so we characterized Envs isolated longitudinally from a SHIVSF162P4 infected macaque for sensitivity to neutralizing monoclonal antibodies (MAbs) B12, 2G12, 4E10 and 2F5. The early Env, isolated from plasma at day 56 after infection, was the most sensitive and the late Env, from day 670, was the most resistant to MAbs. We identified four PNGS in these Envs that accumulated over time at positions 130, 139, 160 and 397. We determined that removal of these PNGS significantly increased neutralization sensitivity to 2G12, and conversely, we identified mutations by in silico analyses that contributed resistance to 2G12 neutralization. In order to expand our understanding of these PNGS, we analyzed Envs from clade B HIV-infected human subjects and identified additional glycan and amino acid changes that could affect neutralization by 2G12 in a context-dependent manner. Taken together, these in vitro and in silico analyses of clade B Envs revealed that 2G12 resistance is achieved by previously unrecognized PNGS substitutions in a context-dependent manner and by subject-specific pathways.
Available from: Nancy Haigwood
- "The generation of potent, broad neutralizing antibodies (NAbs) effective against HIV-1 from diverse clades remains a key objective for HIV vaccines. Numerous Envelope (Env) immunization studies have resulted in NAbs of limited potency and breadth [reviewed in  ]   , and these observations are found both for subtype A and B Envs . The extreme variability of this protein renders empirical searches for an ideal Env immunogen virtually impossible; thus a bioinformatics-based approach may be an attractive alternative . "
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ABSTRACT: HIV-1 infection results in the development of a diverging quasispecies unique to each infected individual. Envelope (Env)-specific neutralizing antibodies (NAbs) typically develop over months to years after infection and initially are limited to the infecting virus. In some subjects, antibody responses develop that neutralize heterologous isolates (HNAbs), a phenomenon termed broadening of the NAb response. Studies of co-crystalized antibodies and proteins have facilitated the identification of some targets of broadly neutralizing monoclonal antibodies (NmAbs) capable of neutralizing many or most heterologous viruses; however, the ontogeny of these antibodies in vivo remains elusive. We hypothesize that Env protein escape variants stimulate broad NAb development in vivo and could generate such NAbs when used as immunogens. Here we test this hypothesis in rabbits using HIV Env vaccines featuring: (1) use of individual quasispecies env variants derived from an HIV-1 subtype A-infected subject exhibiting high levels of NAbs within the first year of infection that increased and broadened with time; (2) motif optimization of envs to enhance in vivo expression of DNA formulated as vaccines; and (3) a combined DNA plus protein boosting regimen. Vaccines consisted of multiple env variants delivered sequentially and a simpler regimen that utilized only the least and most divergent clones. The simpler regimen was as effective as the more complex approach in generating modest HNAbs and was more efficient when modified, motif-optimized DNA was used in combination with trimeric gp140 protein. This is a rationally designed strategy that facilitates future vaccine design by addressing the difficult problem of generating HNAbs to HIV by empirically testing the immunogenicity of naturally occurring quasispecies env variants.
Available from: Ted M Ross
- "Since the beginning of the VaxGen trials, HIV prophylaxis vaccines designed to elicit humoral response have increased in sophistication. Vaccine designs used to induce effective neutralizing antibodies is covered in a review by Vaine et al.(Vaine, Lu et al. 2009). Vaccine designs include use of envelopes with variable loops deleted, glycosylation mutated, eptitope grafting, envelope trimers and centralized sequences. "
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