Despite remarkable advances in the prevention of mother to child transmission (MTCT) in developed countries, the number of pediatric HIV-1 infections continues to increase worldwide. Although the reasons are unknown, children infected with HIV often have higher viral loads and progress to AIDS faster than HIV-infected adults. Understanding the mechanisms by which this occurs would increase our understanding of HIV pathogenesis in both children and adults, and improve prevention and therapeutic strategies for AIDS. We hypothesize that the CD4+ T cell loss that occurs in pediatric SIV infection is attributed to direct cell lysis, mediated by high levels of viral replication specifically within activated, CCR5+CD4+ T cells residing in mucosal tissues. Moreover, we hypothesize that neonates have much higher basal regenerative rates of these cells, resulting in a more rapid and persistent turnover of these specific cell subsets in mucosal tissues, which may disguise the level of CD4 T cell loss in infected neonates when examining CD4+ T cells in blood alone. Finally, we hypothesize that neonatal SIV infection may be prevented, or ameliorated by treatment with CCR5 inhibitors which prevent viral entry into CCR5+CD4+ T cell subsets, thus preventing the loss of, and preserving the effector function of, this important regulatory cell subset.
The specific aims are to:
Specific Aim 1. Examine the rates of T cell turnover in mucosal and peripheral lymphoid tissues in pediatric SIV infection by; quantifying BrdU incorporation and Ki-67 expression in well-defined CD4+ and CD8+ T cell subsets in primary, secondary, and mucosal lymphoid tissues;
Specific Aim 2. Define the mechanism(s) of CD4+ T cell loss in pediatric SIV infection by; examining the relative contributions of CTL-mediated killing, bystander apoptosis, and direct viral lysis to the overall loss of CD4+ T cell subsets in both peripheral and mucosal tissues, and;
Specific Aim 3. Determine if SIV infection of pediatric macaques may be prevented, or ameliorated by blocking CCR5 expression in vivo; Neonates will be treated with a new and novel CCR5 fusion inhibitor, which may prove to prevent SIV infection, and/or reduce viral loads in SIV-infected neonates.
