Methods: In this pilot study to establish the model, 4 infant rhesus macaques (RM) were orally infected with SIVmac251 at 19-20 wks of age and treated with a potent ART regimen including an integrase inhibitor and two reverse transcriptase inhibitors initiated at 35 d post-infection. SIV RNA and DNA levels were measured by real-time PCR and immunological parameters by flow cytometry. RM infants were euthanized and necropsied on ART for a comprehensive cellular and anatomic analysis of virus persistence.
Results: Consistent with prior reports in HIV/SIV-infected infants, plasma SIV RNA levels peaked at 106-107copies/ml and did not exhibit the typical post-peak decline seen in adults. After ART initiation, SIV RNA levels declined 2-3 logs in the first 2 wks, reaching undetectable level at 4-20 wks of therapy. ART was well tolerated by infant RM, with blood counts and renal function tests remaining in a normal range. Importantly, infants demonstrated steady weight gain following ART initiation. The frequency of memory CD4+ T-cell subsets that serve as HIV/SIV reservoirs was significantly different in infant compared to adult RM. The majority of CD4+ T cells displayed a naïve phenotype in infants, and we found that the total estimated circulating number of CD4+ T memory stem cells, central memory T-cells, transitional memory T-cells and effector memory T-cells in the body was lower than in adults. These data suggest a smaller potential reservoir of CD4+ memory T cells in infants, especially if ART is started very early.
Conclusion: This study establishes a novel model of pediatric SIV infection under ART, providing an in vivo platform to study SIV reservoirs in infancy. As the developing immune system of infants differs from that of adults, strategies to cure HIV infection in children will benefit from research conducted in ART-treated SIV-infected infant RM.
E. Cartwright, None
B. Lawson, None
M. Paiardini, None
J. Cohen, None
F. Amblard, None
R. Schinazi, None
R. Geleziunas, Gilead: Employee , Salary
J. Hesselgesser, Gilead: Employee , Salary
B. Li, Gilead: Employee , Salary
J. Hattersley, Gilead: Employee , Salary
G. Silvestri, None
A. Chahroudi, PHS Grant UL1TR000454 from the Clinical and Translational Science Award Program, National Institutes of Health, National Center for Advancing Translational Sciences: Grant Investigator , Grant recipient
Emory+Children’s Pediatric Center Seed Grant Program: Grant Investigator , Grant recipient