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Increased breadth of HIV-1 neutralization achieved by diverse antibody clones each with limited neutralization breadth.

ABSTRACT: Broadly neutralizing antibodies (bNAbs) are rarely elicited by current human immunodeficiency virus type 1 (HIV-1) vaccine designs, but the presence of bNAbs in naturally infected individuals may be associated with high plasma viral loads, suggesting that the magnitude, duration, and diversity of viral exposure may contribute to the development of bNAbs. Here, we report the isolation and characterization of a panel of human monoclonal antibodies (mAbs) from two subjects who developed broadly neutralizing autologous antibody responses during HIV-1 infection. In both subjects, we identified collections of mAbs that exhibited specificity only to a few autologous envelopes (Envs), with some mAbs exhibiting specificity only to a subset of Envs within the quasispecies of a particular sample at one time point. Neutralizing antibodies (NAbs) isolated from these subjects mapped mostly to epitopes in the Env V3 loop region and the CD4 binding site. None of the individual neutralizing mAbs recovered exhibited the cumulative breadth of neutralization present in the serum of the subjects. Surprisingly, however, the activity of polyclonal mixtures comprising individual mAbs that each possessed limited neutralizing activity, could achieve increased breadth of neutralizing activity against autologous isolates. While a single broadly neutralizing antibody targeting one epitope can mediate neutralization breadth, the findings presented here suggest that a cooperative polyclonal process mediated by diverse antibodies with more limited breadth targeting multiple epitopes also can achieve neutralization breadth against HIV-1.

SUBMITTER: Chukwuma VU

PROVIDER: S-EPMC6300260 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Increased breadth of HIV-1 neutralization achieved by diverse antibody clones each with limited neutralization breadth.

Chukwuma Valentine U VU Kose Nurgun N Sather D Noah DN Sapparapu Gopal G Falk Rachel R King Hannah H Singh Vidisha V Lampley Rebecca R Malherbe Delphine C DC Ditto Noah T NT Sullivan Jonathan T JT Barnes Trevor T Doranz Benjamin J BJ Labranche Celia C CC Montefiori David C DC Kalams Spyros A SA Haigwood Nancy L NL Crowe James E JE

PloS one 20181219 12

Broadly neutralizing antibodies (bNAbs) are rarely elicited by current human immunodeficiency virus type 1 (HIV-1) vaccine designs, but the presence of bNAbs in naturally infected individuals may be associated with high plasma viral loads, suggesting that the magnitude, duration, and diversity of viral exposure may contribute to the development of bNAbs. Here, we report the isolation and characterization of a panel of human monoclonal antibodies (mAbs) from two subjects who developed broadly neu ...[more]

PMID: 30566528

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Project description:UnlabelledAntigen-specific CD4(+) T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4(+) T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4(+) T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4(+) T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4(+) T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4(+) T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4(+) T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4(+) T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4(+) T cells and, to a lesser extent, gp41-specific CD4(+) T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies.ImportanceOne of the earliest discoveries related to CD4(+) T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4(+) T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4(+) T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4(+) T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4(+) T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag- and gp41-specific CD4(+) T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection.

Project description:BackgroundEarly events in HIV infection are still poorly understood; virus derived from acute infections, the transmitted/founders IMCs, could provide more reliable information as they represent strains that established HIV infection in vivo, and therefore are investigated to elucidate potentially shared biological features.MethodsThis study examined synergy in neutralization by six monoclonal antibodies targeting different domains in gp120 and gp41 and assayed in pairwise combination against 11 HIV-1 clade B strains, either Env pseudoviruses (PV, n = 5) or transmitted/founder infectious molecular clones (T/F IMCs, n = 6). Three of the early-infection env tested as PV were juxtaposed with T/F viruses derived from the same three patients, respectively.ResultsAll antibodies reaching IC50 were assayed pairwise (n = 50). T/F IMCs showed overall lower sensitivity to neutralization by single antibodies than PV, including within the three patient-matched pairs. Remarkably, combination index (CI) calculated using the Chow and Talalay method indicated synergy (CI < 0.9) in 42 data sets, and occurred in T/F IMC at similar proportions (15 of 17 antibody-T/F IMC combinations tested) as in pseudoviruses (27 of 33). CI values indicative of additivity and low-level antagonism were seen in 5 and 3 cases, respectively. Most pairs showed comparable synergic neutralizing effects on both virus groups, with the 4E10 + PG16 pair achieving the best synergic effects. Variability in neutralization was mostly observed on pseudovirus isolates, suggesting that factors other than virus isolation technology, such as env conformation, epitope accessibility and antibody concentration, are likely to affect polyclonal neutralization.ConclusionsThe findings from this study suggest that inhibitory activity of bNAbs can be further augmented through appropriate combination, even against viruses representing circulating strains, which are likely to exhibit a less sensitive Tier 2 neutralization phenotype. This notion has important implications for the design and development of anti-Env bNAb-inducing vaccines and polyclonal sera for passive immunization.

Dataset Information

Increased breadth of HIV-1 neutralization achieved by diverse antibody clones each with limited neutralization breadth.

Publications

Increased breadth of HIV-1 neutralization achieved by diverse antibody clones each with limited neutralization breadth.

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