This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.
The aim of this pilot study is to establish a GBV-C and SIV coinfection rhesus macaque model for studying the GBV-C and HIV interactions and mechanisms of the potential benefit of GBV-C to slow progression of AIDS. Five Chinese-origin rhesus macaques (Ch Rh) were used in this study. Each animal was inoculated by intravenous route with 10 ml of blood from a human donor containing GBV-C. However, monkeys were not infected with GBV-C, but T cell turnover was studied after SIVmac239 inoculation. BrdU was injected intravenously with 60 mg/kg per animal before SIV inoculation, at week 2 and week 26 post infection. T Lymphocytes were assessed prospectively by multiparameter flow cytometric analysis with intracellular staining for BrdU and Ki67 antigen along with surface T cell subset phenotyping markers in peripheral blood before BrdU injection, 24hrs, 48hrs and 72hrs after BrdU injection. The average peak PVL was 107 copies/ml at week 2. One animal had a viral load that decreased to 300 copies/ml at week 26 after the peak viremia (LTNP virus controller). The set points of PVL in the other animals were 106 copies/ml (progressors). Comparison of the dynamics of T cells between the controller and progressors showed that while the controller had similar percentage of CD4+ T cells as the other animals, it had 75% of memory CD4+ T cells (CD4+CD95+), the others had an average 58.8% (ranged from 46% ~ 67%). All animals had similar levels of effector memory (CD28-CD95+) CD4+ T cells (average of 6.5%), but the controller had relatively high central memory (CD28+CD95+) CD4+ T cells before infection (controller vs progressor: 67.8% vs 51.1%). Memory CD4+ T cells rapidly decreased from 58.8% to 30.6% (week 2 p.i.) to 36% (week 26 p.i.) in progressors, and from 75% to 46.8% to 60.8% of the controller. The central memory cells from 51% to 24.6% to 36.5% of progressors and 68% to 41% to 60% of controller. Memory CD4+ CCR5+T cells also slightly decreased at week 2 p.i. in all animals, and maintained the low levels in progressors but increased to 1.5 fold higher in the controller at week 26 p.i.. Proliferation of memory CD4+ T cells were two- to five-fold increase at week 2 and week 26 p.i.. The portion of Ki67+BrdU+ of CD8+ T cells increased 15-fold in progressors and 20-fold in the controller at week 2 p.i, and continued to be 7-fold in progressors and 10-fold in the controller at week 26 after infection, most of these increased cells were memory CD8+ T cells. NK+ proliferation significantly increased during the acute phase compared to baseline before infection, however, the animal that had the lowest viral load had lowest NK+ proliferation. In conclusion, memory CD4+ T cell restoration, especially central memory CD4+ T cells restoration, correlated with virus suppression. Massive proliferation of CD8+ T cells were induced during SIVmac infection. A cause and effect relationship will require further study.
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