Abstract
Objective:Development of immunogens that elicit an anti-HIV-1 broadly neutralizing antibody (bnAb) response will be a key step in the development of an effective HIV-1 vaccine. Although HIV-1 bnAb epitopes have been identified and mechanisms of action studied, current HIV-1 envelope-based immunogens do not elicit HIV-1 bnAbs in humans or animal models. A better understanding of how HIV-1 bnAbs arise during infection and the clinical factors associated with bnAb development may be critical for HIV-1 immunogen design efforts.Design and methods:Longitudinal plasma samples from the treatment-naive control arm of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) primary HIV-1 infection cohort were used in an HIV-1 pseudotype neutralization assay to measure the neutralization breadth, potency and specificity of bnAb responses over time.Results:In the SPARTAC cohort, development of plasma neutralization breadth and potency correlates with duration of HIV infection and high viral loads, and typically takes 3–4 years to arise. bnAb activity was mostly directed to one or two bnAb epitopes per donor and more than 60% of donors with the highest plasma neutralization having bnAbs targeted towards glycan-dependent epitopes.Conclusion:This study highlights the SPARTAC cohort as an important resource for more in-depth analysis of bnAb developmental pathways.
Highlights
A key goal in HIV-1 vaccine development is the elicitation of antibodies that potently neutralize a broad range of HIV-1 strains [1]
Neutralizing antibody responses in the participants randomized to the Short Pulse AntiRetroviral Therapy at Seroconversion cohort control arm Fifty individuals from the SPARTAC trial control arm were selected based on availability of biobanked plasma samples (Fig. 1a)
Similar to other HIV-1 cohort studies [36,40,42,43], plasma neutralization correlated with both duration of HIV-1 infection and viral load, suggesting that both extended levels of antigenic stimulation through chronic infection and high levels of viral antigen are required for the extensive somatic hypermutation that is a characteristic of many HIV-1 broadly neutralizing antibodies (bnAbs)
Summary
A key goal in HIV-1 vaccine development is the elicitation of antibodies that potently neutralize a broad range of HIV-1 strains [1]. Such antibodies, termed broadly neutralizing antibodies (bnAbs), typically develop 2–3 years after infection in 10–30% of HIV-infected individuals [2,3,4,5,6], in rare occasions can be detected within the first year of infection [7]. BnAbs are thought to arise following multiple rounds of viral escape and antibody somatic hypermutation where the immune response is progressively targeted towards the most conserved regions of HIV-1 Env [24,25]. Understanding how bnAbs arise during natural infection, and the clinical and virological correlates relating to their elicitation, may be critical for the development of immunogens capable of eliciting protective bnAbs through vaccination
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