Assessing the impact of autologous neutralizing antibodies on viral rebound in postnatally SHIV-infected ART-treated infant rhesus macaques

Abstract

While the benefits of early antiretroviral therapy (ART) initiation in perinatally infected infants are well documented, early ART initiation is not always possible in postnatal pediatric HIV infections, which account for the majority of pediatric HIV cases worldwide. The timing of onset of ART initiation is likely to affect the size of the latent viral reservoir established, as well as the development of adaptive immune responses, such as the generation of neutralizing antibody responses against the virus. How these parameters impact the ability of infants to control viremia and the time to viral rebound after ART interruption is unclear. To gain insight into the dynamics, we utilized mathematical models to investigate the effect of time of ART initiation via latent reservoir size and autologous virus neutralizing antibody responses in delaying viral rebound when treatment is interrupted. We used an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model that mimics breast milk HIV transmission in human infants. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT and either given ART at 4-7 days post-infection (early ART condition), at 2 weeks post-infection (intermediate ART condition), or at 8 weeks post-infection (late ART condition). These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. We develop a stochastic mathematical model to investigate the joint effect of latent reservoir size, the autologous neutralizing antibody potency, and CD4+ T cell levels on the time to viral rebound and control of post-rebound viral loads. We find that the latent reservoir size is an important determinant in explaining time to viral rebound by affecting the growth rate of the virus. The presence of neutralizing antibodies also can delay rebound, but we find this effect for high potency antibody responses only.

Assessing the impact of autologous neutralizing antibodies on rebound dynamics in postnatally SHIV-infected ART-treated infant rhesus macaques

“…The start of exponential viral growth designates viral rebound time. Our finding is consistent with the central hypothesis that the activation of latently infected cells drives viral rebound [ 57 – 60 ], as well as with previous modeling results of the same dataset [ 61 ]. The latent reservoir size is also associated with changes in immune-related parameters consistent with stronger immune responses, both cellular and humoral.…”

Comparative Analysis of Within-Host Dynamics of Acute Infection and Viral Rebound Dynamics in Postnatally SHIV-Infected ART-Treated Infant Rhesus Macaques

“…Out of the 13 models selected, three of them predict that the mean value for the onset of exponential viral growth ( t start ) is slower during rebound compared to acute infection (Fig 5). This observation is expected, since the development of immune responses during rebound can reduce viremia, thus delaying rebound [71]. However, for the remaining 10 selected models, such a difference in mean values is not predicted.…”