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.
Highlights
Neutralizing antibody responses which target the Env of HIV-1 and block viral entry develop in most HIV-1 infected individuals, reaching detectable levels within a few months of infection when measured against the autologous Env [1,2,3,4]
We show that neutralization escape is conferred by a few amino acid mutations, some of which are outside the antibody target site
We propose a mechanistic explanation for how HIV-1 epitopes drive sequential waves of neutralization escape in early subtype C infection
Summary
Neutralizing antibody (nAb) responses which target the Env of HIV-1 and block viral entry develop in most HIV-1 infected individuals, reaching detectable levels within a few months of infection when measured against the autologous Env [1,2,3,4]. Even in virus controllers with relatively low levels of antigenic stimulation of B cells, continuous viral selection and escape from autologous nAbs occurs [16]. The dynamic nature of the autologous neutralizing response is exemplified by the fact that escape variants are sensitive to de novo nAb responses generated to new variants. It seems likely that early nAbs will wane as escape occurs, when the antigen responsible for elicitation of such responses is replaced by escape variants, which would presumably no longer stimulate existing antigen-specific B cells
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