Limited Neutralizing Antibody Specificities Drive Neutralization Escape in Early HIV-1 Subtype C Infection
Open Access
- 18 September 2009
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 5 (9), e1000598
- https://doi.org/10.1371/journal.ppat.1000598
Abstract
We previously showed that HIV-1 subtype C viruses elicit potent but highly type-specific neutralizing antibodies (nAb) within the first year of infection. In order to determine the specificity and evolution of these autologous nAbs, we examined neutralization escape in four individuals whose responses against the earliest envelope differed in magnitude and potency. Neutralization escape occurred in all participants, with later viruses showing decreased sensitivity to contemporaneous sera, although they retained sensitivity to new nAb responses. Early nAb responses were very restricted, occurring sequentially and targeting only two regions of the envelope. In V1V2, limited amino acid changes often involving indels or glycans, mediated partial or complete escape, with nAbs targeting the V1V2 region directly in 2 cases. The alpha-2 helix of C3 was also a nAb target, with neutralization escape associated with changes to positively charged residues. In one individual, relatively high titers of anti-C3 nAbs were required to drive genetic escape, taking up to 7 weeks for the resistant variant to predominate. Thereafter titers waned but were still measurable. Development of this single anti-C3 nAb specificity was associated with a 7-fold drop in HIV-1 viral load and a 4-fold rebound as the escape mutation emerged. Overall, our data suggest the development of a very limited number of neutralizing antibody specificities during the early stages of HIV-1 subtype C infection, with temporal fluctuations in specificities as escape occurs. While the mechanism of neutralization escape appears to vary between individuals, the involvement of limited regions suggests there might be common vulnerabilities in the HIV-1 subtype C transmitted envelope. Most HIV-1 infected individuals develop neutralizing antibodies against their own virus, termed an autologous neutralizing response. It is known that this response exerts pressure on the envelope of HIV, the target of such antibodies, resulting in neutralization escape. Here we have identified the targets of these antibodies and the precise genetic basis of neutralization escape in 4 individuals infected with HIV-1 subtype C. We show that V1V2 is commonly involved in escape, and that the C3 region is also a target in some cases. The latter observation confirms this region is exposed in subtype C, unlike subtype B. We show that neutralization escape is conferred by a few amino acid mutations, some of which are outside the antibody target site. Moreover, escape from these limited specificities even within a single individual occurs via a variety of different pathways involving substitutions, indels and glycan shifts. The finding in 2 individuals that an anti-C3 response developed first, followed by an anti-V1V2 response, suggests there may be specific regions of envelope particularly vulnerable to antibody neutralization. Overall, we propose a mechanistic explanation for how HIV-1 epitopes drive sequential waves of neutralization escape in early subtype C infection.Keywords
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