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Development of Neutralization Breadth against Diverse HIV-1 by Increasing Ab-Ag Interface on V2.

ABSTRACT: Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV-1 can be highly informative for HIV-1 vaccine development. A lineage of J038 bnAbs is now obtained from a long-term SHIV-infected macaque. J038 neutralizes 54% of global circulating HIV-1 strains. Its binding induces a unique "up" conformation for one of the V2 loops in the trimeric envelope glycoprotein and is heavily dependent on glycan, which provides nearly half of the binding surface. Their unmutated common ancestor neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody-Env contact areas surrounding the core region contacted by germline-encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for elicitation and maturation of V2-targeting bnAbs.

SUBMITTER: Gao N

PROVIDER: S-EPMC9130890 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Development of Neutralization Breadth against Diverse HIV-1 by Increasing Ab-Ag Interface on V2.

Gao Nan N Gai Yanxin Y Meng Lina L Wang Chu C Wang Wei W Li Xiaojun X Gu Tiejun T Louder Mark K MK Doria-Rose Nicole A NA Wiehe Kevin K Nazzari Alexandra F AF Olia Adam S AS Gorman Jason J Rawi Reda R Wu Wenmin W Smith Clayton C Khant Htet H de Val Natalia N Yu Bin B Luo Junhong J Niu Haitao H Tsybovsky Yaroslav Y Liao Huaxin H Kepler Thomas B TB Kwong Peter D PD Mascola John R JR Qin Chuan C Zhou Tongqing T Yu Xianghui X Gao Feng F

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220323 15

Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV-1 can be highly informative for HIV-1 vaccine development. A lineage of J038 bnAbs is now obtained from a long-term SHIV-infected macaque. J038 neutralizes 54% of global circulating HIV-1 strains. Its binding induces a unique "up" conformation for one of the V2 loops in the trimeric envelope glycoprotein and is heavily dependent on glycan, which provides nearly half of the binding surface. Their unmutated co ...[more]

PMID: 35319830

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Project description:The goals of preclinical HIV vaccine studies in nonhuman primates are to develop and test different approaches for their ability to generate protective immunity. Here, we compared the impact of 7 different vaccine modalities, all expressing the HIV-1 1086.C clade C envelope (Env), on (i) the magnitude and durability of antigen-specific serum antibody responses and (ii) autologous and heterologous neutralizing antibody capacity. These vaccination regimens included immunization with different combinations of DNA, modified vaccinia virus Ankara (MVA), soluble gp140 protein, and different adjuvants. Serum samples collected from 130 immunized monkeys at two key time points were analyzed using the TZM-bl cell assay: at 2 weeks after the final immunization (week 40/41) and on the day of challenge (week 58). Key initial findings were that inclusion of a gp140 protein boost had a significant impact on the magnitude and durability of Env-specific IgG antibodies, and addition of 3M-052 adjuvant was associated with better neutralizing activity against the SHIV1157ipd3N4 challenge virus and a heterologous HIV-1 CRF01 Env, CNE8. We measured neutralization against a panel of 12 tier 2 Envs using a newly described computational tool to quantify serum neutralization potency by factoring in the predetermined neutralization tier of each reference Env. This analysis revealed modest neutralization breadth, with DNA/MVA immunization followed by gp140 protein boosts in 3M-052 adjuvant producing the best scores. This study highlights that protein-containing regimens provide a solid foundation for the further development of novel adjuvants and inclusion of trimeric Env immunogens that could eventually elicit a higher level of neutralizing antibody breadth.IMPORTANCE Despite much progress, we still do not have a clear understanding of how to elicit a protective neutralizing antibody response against HIV-1 through vaccination. There have been great strides in the development of envelope immunogens that mimic the virus particle, but less is known about how different vaccination modalities and adjuvants contribute to shaping the antibody response. We compared seven different vaccines that were administered to rhesus macaques and that delivered the same envelope protein through various modalities and with different adjuvants. The results demonstrate that some vaccine components are better than others at eliciting neutralizing antibodies with breadth.

Project description:UnlabelledThe isolation of broadly neutralizing HIV-1 monoclonal antibodies (MAbs) to distinct epitopes on the viral envelope glycoprotein (Env) provides the potential to use combinations of MAbs for prevention and treatment of HIV-1 infection. Since many of these MAbs have been isolated in the last few years, the potency and breadth of MAb combinations have not been well characterized. In two parallel experiments, we examined the in vitro neutralizing activities of double-, triple-, and quadruple-MAb combinations targeting four distinct epitopes, including the CD4-binding site, the V1V2-glycan region, the V3-glycan supersite, and the gp41 membrane-proximal external region (MPER), using a panel of 125 Env-pseudotyped viruses. All MAb combinations showed substantially improved neutralization breadth compared to the corresponding single MAbs, while the neutralization potency of individual MAbs was maintained. At a 50% inhibitory concentration (IC50) cutoff of 1 μg/ml per antibody, double-MAb combinations neutralized 89 to 98% of viruses, and triple combinations neutralized 98 to 100%. Overall, the improvement of neutralization breadth was closely predicted by an additive-effect model and explained by complementary neutralization profiles of antibodies recognizing distinct epitopes. Subtle but consistent favorable interactions were observed in some MAb combinations, whereas less favorable interactions were observed on a small subset of viruses that are highly sensitive to V3-glycan MAbs. These data demonstrate favorable in vitro combinations of broadly neutralizing HIV-1 MAbs and suggest that such combinations could have utility for HIV-1 prevention and treatment.ImportanceOver the last 5 years, numerous broadly reactive HIV-1-neutralizing MAbs have been isolated from B cells of HIV-1-infected donors. Each of these MAbs binds to one of the major vulnerable sites (epitopes) on the surface of the viral envelope glycoprotein. Since antibodies to distinct viral epitopes could theoretically act together to provide greater potency and breadth of virus neutralization, we tested physical mixtures of double, triple, and quadruple combinations of neutralizing MAbs targeting four major epitopes on HIV-1 Env. When tested together, antibody combinations showed substantially improved neutralization breadth compared to single MAbs. This improvement could be explained by the complementary neutralization profiles of individual MAbs. We further demonstrated that each antibody maintained its full neutralization potency when used in combination with other MAbs. These data provide a rationale for clinical use of antibody-based combinations for HIV-1 prevention and therapy.

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Development of Neutralization Breadth against Diverse HIV-1 by Increasing Ab-Ag Interface on V2.

Publications

Development of Neutralization Breadth against Diverse HIV-1 by Increasing Ab-Ag Interface on V2.

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