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[Preprint]. 2023 Sep 14:2023.07.22.550159.
doi: 10.1101/2023.07.22.550159.

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

Ellie Mainou  1 , Stella J Berendam  2 , Veronica Obregon-Perko  3 , Emilie A Uffman  4 , Caroline T Phan  4 , George M Shaw  5 , Katherine J Bar  5 , Mithra R Kumar  6 , Emily J Fray  7 , Janet M Siliciano  8 , Robert F Siliciano  8 , Guido Silvestri  9 , Sallie R Permar  10 , Genevieve G Fouda  10 , Janice McCarthy  11 , Ann Chahroudi  12 , Jessica M Conway  13 , Cliburn Chan  11
Affiliations

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

Ellie Mainou et al. bioRxiv. .

Update in

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.

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Figures

Figure 1:
Figure 1:. Model schematic.
We assume that following ATI, latent cell activations are followed by chains of infection that may die out, i.e., go extinct, with probability q, or successfully re-establish high viral loads associated with chronic infection, with probability 1−q. In the latter case, we further assume a delay τ between activation and the time when plasma viral load crosses the detection threshold.
Figure 2:
Figure 2:
Null model predictions on time to viral rebound for subjects (grey shaded area) and the average time to viral rebound (thick, solid line), for a) the late treatment group, b) the intermediate treatment group, c) the early treatment group and d) all treatment groups combined. For the null model, we do not incorporate information on the latent reservoir size and the strength of neutralizing antibodies on the cumulative probability of rebound, PVR.
Figure 3:
Figure 3:
Best model predictions on time to viral rebound for subjects (grey shaded area) and the average time to viral rebound (thick, solid line), for a) the late treatment group, b) the intermediate treatment group, c) the early treatment group and d) all treatment groups combined.
Figure 4:
Figure 4:
Increase in median time to viral rebound through an intervention that elevates the antibody neutralization strength by 10% and 50% (A) or decreases the latent reservoir size by 1 or 2 logs (B).
See this image and copyright information in PMC

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