Abstract
Identifying the targets of broadly neutralizing antibodies to HIV-1 and understanding how these antibodies develop remain important goals in the quest to rationally develop an HIV-1 vaccine. We previously identified a participant in the CAPRISA Acute Infection Cohort (CAP257) whose plasma neutralized 84% of heterologous viruses. In this study we showed that breadth in CAP257 was largely due to the sequential, transient appearance of three distinct broadly neutralizing antibody specificities spanning the first 4.5 years of infection. The first specificity targeted an epitope in the V2 region of gp120 that was also recognized by strain-specific antibodies 7 weeks earlier. Specificity for the autologous virus was determined largely by a rare N167 antigenic variant of V2, with viral escape to the more common D167 immunotype coinciding with the development of the first wave of broadly neutralizing antibodies. Escape from these broadly neutralizing V2 antibodies through deletion of the glycan at N160 was associated with exposure of an epitope in the CD4 binding site that became the target for a second wave of broadly neutralizing antibodies. Neutralization by these CD4 binding site antibodies was almost entirely dependent on the glycan at position N276. Early viral escape mutations in the CD4 binding site drove an increase in wave two neutralization breadth, as this second wave of heterologous neutralization matured to recognize multiple immunotypes within this site. The third wave targeted a quaternary epitope that did not overlap any of the four known sites of vulnerability on the HIV-1 envelope and remains undefined. Altogether this study showed that the human immune system is capable of generating multiple broadly neutralizing antibodies in response to a constantly evolving viral population that exposes new targets as a consequence of escape from earlier neutralizing antibodies.
Highlights
Neutralizing antibodies are the principal correlate of protection for most preventative vaccines
We show how escape from the first wave of antibodies targeting V2 exposed a second site that was the stimulus for a new wave of glycan dependent broadly neutralizing antibodies against the CD4 binding site
We document a third wave of neutralization that targets an undefined epitope that did not appear to overlap with the four known sites of vulnerability on the HIV-1 envelope
Summary
Neutralizing antibodies are the principal correlate of protection for most preventative vaccines. Designing suitable vaccine immunogens to elicit these types of antibodies has been relatively simple for conserved pathogens such as smallpox and other DNA viruses. For more diverse pathogens like HIV-1, the neutralizing antibodies elicited by vaccination or during natural infection are largely strain-specific and would not be protective against globally circulating viral variants [1,2,3,4,5]. The HIV-1 envelope glycoprotein spikes mediate viral entry and are the sole targets for neutralizing antibodies. All HIV-1 infected individuals develop strain-specific neutralizing antibodies which target these sequence variable regions, but only a quarter develop broadly neutralizing antibodies [7,8,9,10,11], which will likely be needed
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