Breastfeeding transmission accounts for the majority of new pediatric infections and commits infants to lifelong ART, as interruption is typically followed by return of replication and repopulation of reservoirs. A better understanding of the anatomic origin and kinetics of viral rebound during analytical treatment interruption (ATI) could inform the development of alternatives to ART-based strategies to achieve long-term viral remission in the pediatric population.
At 4 wks old, 10 rhesus macaques were orally-administered SHIV.CH505.375H.dCT and placed on daily ART at 8 wpi. ART was interrupted after 1 yr in a subset of animals (n=6) to assess viral rebound. Blood and tissue were collected throughout the study for flow cytometry and viral measurements. For whole-body ImmunoPET, macaques were infused with 68Ga-labeled PGT145 F(ab) and imaged by PET/CT. Scans were done once on long-term ART and twice weekly following ATI.
Median viral loads at peak infection and just prior to ART were 5×105 and 1×105 copies/mL, respectively. During ATI, rebound viremia was detected within 10-24 d, with variable peak viral loads that reached levels seen at ART initiation. Post-treatment control within 4 wks of rebound was seen in 1/2 Mamu A01+ macaques. Various parameters were evaluated for their ability to predict time to viral rebound. In our model, we did not see an association between PD-1 expression on CD4+ T cells and time to rebound, as previously reported for HIV-1 infection. SHIV-DNA and -RNA persistence in blood, lymph node, and colorectal CD4+ T cells was also evaluated. Just prior to ATI, the highest levels of SHIV-RNA were found in the colorectal compartment, suggesting this region could be an early site of viral reactivation following ART interruption. Indeed, longitudinal imaging of SHIV Env expressing cells in tissues by ImmunoPET before and immediately following ATI showed an expansion of infected cells in the GI tract prior to SHIV RNA reaching detectable levels in the plasma. A similar trend was observed in the lungs, where tissue-resident macrophages have been found to be the principal target cells of infection.
This work provides novel insight into the kinetics, anatomic origin, and predictors of viral rebound in a pre-clinical NHP model of pediatric HIV infection. Our preliminary data implicates the GI tract as a key site to be studied for the development of remission strategies and one to be monitored in HIV-infected children being considered for ATI.