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Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition.

ABSTRACT: The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT₈₀) biomarker-which quantifies the neutralization potency of antibodies in an individual's serum against an HIV-1 isolate-can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT₈₀ of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT₈₀ <200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT₈₀ biomarker as a surrogate endpoint for evaluatinon of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines.

SUBMITTER: Gilbert PB

PROVIDER: S-EPMC9499869 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition.

Gilbert Peter B PB Huang Yunda Y deCamp Allan C AC Karuna Shelly S Zhang Yuanyuan Y Magaret Craig A CA Giorgi Elena E EE Korber Bette B Edlefsen Paul T PT Rossenkhan Raabya R Juraska Michal M Rudnicki Erika E Kochar Nidhi N Huang Ying Y Carpp Lindsay N LN Barouch Dan H DH Mkhize Nonhlanhla N NN Hermanus Tandile T Kgagudi Prudence P Bekker Valerie V Kaldine Haajira H Mapengo Rutendo E RE Eaton Amanda A Domin Elize E West Carley C Feng Wenhong W Tang Haili H Seaton Kelly E KE Heptinstall Jack J Brackett Caroline C Chiong Kelvin K Tomaras Georgia D GD Andrew Philip P Mayer Bryan T BT Reeves Daniel B DB Sobieszczyk Magdalena E ME Garrett Nigel N Sanchez Jorge J Gay Cynthia C Makhema Joseph J Williamson Carolyn C Mullins James I JI Hural John J Cohen Myron S MS Corey Lawrence L Montefiori David C DC Morris Lynn L

Nature medicine 20220822 9

The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT<sub>80</sub>) biomarker-which quantifies the neutralization potency of antibodies in an individual's serum against an HIV-1 isolate-can be used to predict HIV-1 prevention efficacy. Similar to the results of ...[more]

PMID: 35995954

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Project description:BackgroundHIV-1 typically develops resistance to any single antiretroviral agent. Combined anti-retroviral therapy to reduce drug-resistance development is necessary to control HIV-1 infection. Here, to assess the utility of a combination of antibody and fusion inhibitor treatments, we investigated the potency of monoclonal antibodies at neutralizing HIV-1 variants that are resistant to fusion inhibitors.ResultsMutations that confer resistance to four fusion inhibitors, enfuvirtide, C34, SC34, and SC34EK, were introduced into the envelope of HIV-1JR-FL, a CCR5-tropic tier 2 strain. Pseudoviruses with these mutations were prepared and used for the assessment of neutralization sensitivity to an array of antibodies. The resulting neutralization data indicate that the potencies of some antibodies, especially of those against the CD4 binding site, V3 loop, and membrane-proximal external region epitopes, were increased by the mutations in gp41 that conferred resistance to the fusion inhibitors. C34-, SC34-, and SC34EK-resistant mutants showed more sensitivity to monoclonal antibodies than enfuvirtide-resistant mutants. An analysis of C34-resistant mutations revealed that the I37K mutation in gp41 HR1 is a key mutation for C34 resistance, low infectivity, neutralization sensitivity, epitope exposure, and slow fusion kinetics. The N126K mutation in the gp41 HR2 domain contributed to C34 resistance and neutralization sensitivity to anti-CD4 binding site antibodies. In the absence of L204I, the effect of N126K was antagonistic to that of I37K. The results of a molecular dynamic simulation of the envelope trimer confirmation suggest that an I37K mutation induces the augmentation of structural fluctuations prominently in the interface between gp41 and gp120. Our observations indicate that the "conformational unmasking" of envelope glycoprotein by an I37K mutation is one of the mechanisms of neutralization sensitivity enhancement. Furthermore, the enhanced neutralization of C34-resistant mutants in vivo was shown by its high rate of neutralization by IgG from HIV patient samples.ConclusionsMutations in gp41 that confer fusion inhibitor resistance exert enhanced sensitivity to broad neutralizing antibodies (e.g., VRC01 and 10E8) and other conventional antibodies developed in HIV-1 infected patients. Therefore, next-generation fusion inhibitors and monoclonal antibodies could be a potential combination for future regimens of combined antiretroviral therapy.

Project description:HIV-1 envelope glycoprotein (Env) mediates virus attachment and entry into the host cells. Like other membrane-bound and secreted proteins, HIV-1 Env contains at its N terminus a signal peptide (SP) that directs the nascent Env to the endoplasmic reticulum (ER) where Env synthesis and post-translational modifications take place. SP is cleaved during Env biosynthesis but potentially influences the phenotypic traits of the Env protein. The Env SP sequences of HIV-1 isolates display high sequence variability, and the significance of such variability is unclear. We postulate that changes in the Env SP influence Env transport through the ER-Golgi secretory pathway and Env folding and/or glycosylation that impact on Env incorporation into virions, receptor binding and antibody recognition. We first evaluated the consequences of mutating the charged residues in the Env SP in the context of infectious molecular clone HIV-1 REJO.c/2864. Results show that three different mutations affecting histidine at position 12 affected Env incorporation into virions that correlated with reduction of virus infectivity and DC-SIGN-mediated virus capture and transmission. Mutations at positions 8, 12, and 15 also rendered the virus more resistant to neutralization by monoclonal antibodies against the Env V1V2 region. These mutations affected the oligosaccharide composition of N-glycans as shown by changes in Env reactivity with specific lectins and by mass spectrometry. Increased neutralization resistance and N-glycan composition changes were also observed when analogous mutations were introduced to another HIV-1 strain, JRFL. To the best of our knowledge, this is the first study showing that certain residues in the HIV-1 Env SP can affect virus neutralization sensitivity by modulating oligosaccharide moieties on the Env N-glycans. The HIV-1 Env SP sequences thus may be under selective pressure to balance virus infectiousness with virus resistance to the host antibody responses. (289 words).

Dataset Information

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition.

Publications

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition.

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