RESUMO
Allogeneic transplantation (allo-HCT) has led to the cure of HIV in one individual, raising the question of whether transplantation can eradicate the HIV reservoir. To test this, we here present a model of allo-HCT in SHIV-infected, cART-suppressed nonhuman primates. We infect rhesus macaques with SHIV-1157ipd3N4, suppress them with cART, then transplant them using MHC-haploidentical allogeneic donors during continuous cART. Transplant results in ~100% myeloid donor chimerism, and up to 100% T-cell chimerism. Between 9 and 47 days post-transplant, terminal analysis shows that while cell-associated SHIV DNA levels are reduced in the blood and in lymphoid organs post-transplant, the SHIV reservoir persists in multiple organs, including the brain. Sorting of donor-vs.-recipient cells reveals that this reservoir resides in recipient cells. Moreover, tetramer analysis indicates a lack of virus-specific donor immunity post-transplant during continuous cART. These results suggest that early post-transplant, allo-HCT is insufficient for recipient reservoir eradication despite high-level donor chimerism and GVHD.
Assuntos
Reservatórios de Doenças/virologia , Transplante de Células-Tronco Hematopoéticas , Complexo Principal de Histocompatibilidade , Vírus da Imunodeficiência Símia/fisiologia , Transplante Haploidêntico , Animais , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD8-Positivos/imunologia , DNA Viral/metabolismo , Macaca mulatta , RNA Viral/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Transplante HomólogoRESUMO
BACKGROUND: Nonhuman primates (NHPs) are an important model organism for studies of HIV pathogenesis and preclinical evaluation of anti-HIV therapies. The successful translation of NHP-derived data to clinically relevant anti-HIV studies will require better understanding of the viral strains and NHP species used and their responses to existing antiretroviral therapies (ART). METHODS: Five pigtailed macaques (Macaca nemestrina) were productively infected with the SIV/HIV chimeric virus SHIV-1157 ipd3N4 following intravenous challenge. After 8 or 27 weeks, ART (PMPA, FTC, raltegravir) was initiated. Viral load, T-cell counts, and production of SHIV-specific antibodies were monitored throughout the course of infection and ART. RESULTS: ART led to a rapid and sustained decrease in plasma viral load. Suppression of plasma viremia by ART was independent of the timing of initiation during chronic infection. CONCLUSIONS: We present a new NHP model of HIV infection on antiretroviral therapy, which should prove applicable to multiple clinically relevant anti-HIV approaches.
