SIV infection duration largely determines broadening of neutralizing antibody response in macaques
Fan Wu, Ilnour Ourmanov, Andrea Kirmaier, Sivan Leviyang, Celia LaBranche, Jinghe Huang, Sonya Whitted, Kenta Matsuda, David Montefiori, Vanessa M. Hirsch
Fan Wu, Ilnour Ourmanov, Andrea Kirmaier, Sivan Leviyang, Celia LaBranche, Jinghe Huang, Sonya Whitted, Kenta Matsuda, David Montefiori, Vanessa M. Hirsch
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Research Article AIDS/HIV Virology

SIV infection duration largely determines broadening of neutralizing antibody response in macaques

Abstract

The development of broadly neutralizing antibodies (BNAbs) in HIV infection is a result of long-term coevolutionary interaction between viruses and antibodies. Understanding how this interaction promotes the increase of neutralization breadth during infection will improve the way in which AIDS vaccine strategies are designed. In this paper, we used SIV-infected rhesus macaques as a model to study the development of neutralization breadth by infecting rhesus macaques with longitudinal NAb escape variants and evaluating the kinetics of NAb response and viral evolution. We found that the infected macaques developed a stepwise NAb response against escape variants and increased neutralization breadth during the course of infection. Furthermore, the increase of neutralization breadth correlated with the duration of infection but was independent of properties of the inoculum, viral loads, or viral diversity during infection. These results imply that the duration of infection was the main factor driving the development of BNAbs. These data suggest the importance of novel immunization strategies to induce effective NAb response against HIV infection by mimicking long-term infection.

Authors

Fan Wu, Ilnour Ourmanov, Andrea Kirmaier, Sivan Leviyang, Celia LaBranche, Jinghe Huang, Sonya Whitted, Kenta Matsuda, David Montefiori, Vanessa M. Hirsch

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Figure 4

Statistical analysis of factors associated with the increase of neutralization breadth during infection.

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Statistical analysis of factors associated with the increase of neutrali...
(A–C) Macaques divided into 3 groups based on the inoculated viruses and the kinetics of NAb titers against SIVsmE660-FL14 tier 1 (A), H807-16w-6 tier 2 (B), and H807-24w-4 tier 3 (C) are shown as the geometric mean with 95% CI (n = 6 for each group). The different inoculated viruses did not make a significant difference on NAb titers against tier 1 (P = 0.3353, A), tier 2 (P = 0.9261, B), or tier 3 (P = 0.7609, C) viruses, whereas infection time made a significant difference on NAb titers against all 3 viruses (P < 0.001, repeated-measures 2-way ANOVA). To analyze the effect of viral loads on NAb titers, macaques were divided into suppressors or nonsuppressors based on the plasma viremia at the chronic phase of infection. Macaques Rh844, Rh845, Rh847, Rh852, Rh853, and Rh854, whose plasma viremia was below 104 copies, were designated as suppressors (n = 6), and the other macaques, whose plasma viremia was above 104 copies, were designated as nonsuppressors (n = 12). (D–F) The kinetics of NAb titers against SIVsmE660-FL14 tier 1 (D), H807-16w-6 tier 2 (E), and H807-24w-4 tier 3 (F) in suppressors and nonsuppressors are shown as geometric mean with 95% CI. The different plasma viremia did not make a significant difference on NAb titers against tier 1 (P = 0.0762, D), tier 2 (P = 0.2614, E), or tier 3 (P = 0.9592, F) viruses, whereas infection time made a significant difference on NAb titers against all 3 viruses (P < 0.01, repeated-measures 2-way ANOVA).