Abstract
Despite many advances in AIDS research, a cure for HIV infection remains elusive. Here, we performed autologous hematopoietic stem cell transplantation (HSCT) in three Simian/Human Immunodeficiency Virus (SHIV)-infected, antiretroviral therapy (ART)-treated rhesus macaques (RMs) using HSCs collected prior to infection and compared them to three SHIV-infected, ART-treated, untransplanted control animals to assess the effect of conditioning and autologous HSCT on viral persistence. As expected, ART drastically reduced virus replication, below 100 SHIV-RNA copies per ml of plasma in all animals. After several weeks on ART, experimental RMs received myeloablative total body irradiation (1080 cGy), which resulted in the depletion of 94–99% of circulating CD4+ T-cells, and low to undetectable SHIV-DNA levels in peripheral blood mononuclear cells. Following HSC infusion and successful engraftment, ART was interrupted (40–75 days post-transplant). Despite the observed dramatic reduction of the peripheral blood viral reservoir, rapid rebound of plasma viremia was observed in two out of three transplanted RMs. In the third transplanted animal, plasma SHIV-RNA and SHIV DNA in bulk PBMCs remained undetectable at week two post-ART interruption. No further time-points could be assessed as this animal was euthanized for clinical reasons; however, SHIV-DNA could be detected in this animal at necropsy in sorted circulating CD4+ T-cells, spleen and lymph nodes but not in the gastro-intestinal tract or tonsils. Furthermore, SIV DNA levels post-ART interruption were equivalent in several tissues in transplanted and control animals. While persistence of virus reservoir was observed despite myeloablation and HSCT in the setting of short term ART, this experiment demonstrates that autologous HSCT can be successfully performed in SIV-infected ART-treated RMs offering a new experimental in vivo platform to test innovative interventions aimed at curing HIV infection in humans.
Highlights
The introduction of antiretroviral therapy (ART) has dramatically reduced the morbidity and mortality associated with HIV infection and AIDS
While antiretroviral therapy (ART) can reduce HIV replication, it does not eradicate the virus from an infected individual
Replication-competent viruses persist on ART and our incomplete understanding of these viral reservoirs greatly complicates the generation of a cure for HIV
Summary
The introduction of antiretroviral therapy (ART) has dramatically reduced the morbidity and mortality associated with HIV infection and AIDS. Many studies indicate that the key obstacle to cure HIV infection is the presence of a persistent reservoir of latently infected cells that are not eliminated by ART [1,2]. Several biological aspects of this virus reservoir, including its exact cellular and anatomic origin as well as the mechanisms responsible for its establishment and persistence under ART remain poorly understood. This limited knowledge represents a fundamental barrier to a cure for HIV infection, and novel therapeutic strategies aimed at eliminating the reservoir will likely not be developed until we overcome this barrier
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