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

Viral dynamics of acute HIV infection and HIV rebound following suspension of antiretroviral therapy may be qualitatively similar but must differ given, for one, the development of adaptive immune responses. Understanding the differences between acute HIV infection and viral rebound dynamics in pediatric populations may provide insights into the mechanisms of viral control with potential implications for vaccine design and the development of effective targeted therapeutics for infants and children. Mathematical models have been a crucial tool to elucidate the complex processes driving viral infections within the host. Traditionally, acute HIV infection has been modeled with the standard model of viral dynamics, initially developed to explore viral decay during treatment, while viral rebound has necessitated extensions of that standard model to incorporate explicit immune responses. Previous efforts to fit these models to viral load data have underscored differences between the two infection stages, such as increased viral clearance rate and increased death rate of infected cells during rebound. However, these findings have been predicated on viral load measurements from disparate adult individuals. In this study, we aim to bridge this gap, in infants, by comparing the dynamics of acute infection and viral rebound within the same individuals by leveraging an infant non-human primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Ten infant Rhesus macaques (RMs) orally challenged with SHIV.C.CH505.375H.dCT were given ART at 8 weeks post-infection. These infants were monitored for up to 60 weeks post-infection to ensure full suppression, then underwent analytic treatment interruption (ATI), resulting in viral rebound. We use the HIV standard viral dynamics model fit to viral load measurements in a nonlinear mixed effects framework to identify primary mechanisms distinguishing acute and rebound infection dynamics. We find that the primary difference between acute infection and viral rebound is the increased death rate of infected cells during the rebound phase. These findings allow us to formulate hypotheses about the effects of adaptive immune responses. Specifically, we propose that delayed viral rebound is characterized by a stronger CD8+ T-cell response. Our analysis provides evidence to support this notion and helps elucidate the observed outcomes.