“…Nonetheless, as shown in Fig. 5 , low-level SHIV RNA expression was detected in selected sites in individual animals, consistent with prior findings from our group and others 17 , 36 – 39 . Fig.…”
Section: Resultssupporting
confidence: 91%
“…3a . Recipient animals underwent pre-transplant conditioning using total body irradiation (TBI) as we have previously described (1040 cGy, delivered in 4 divided doses given over 2 days) 17 , 29 . GVHD prophylaxis included sirolimus (with a target serum level of 5–15 ng/mL), tacrolimus (0.025 mg/kg twice daily, target serum level of 5–10 ng/mL), and mycophenolate mofetil (15 mg/kg twice daily).…”
Section: Resultsmentioning
confidence: 99%
“…We have previously shown in nonhuman primate (NHP) modeling experiments that transplantation with unmodified autologous hematopoietic stem cells (HSCs) is insufficient to achieve cART-free virus remission 16 , 17 . We first used simian/human immunodeficiency virus carrying an HIV-1 reverse transcriptase (RT-SHIV) to infect rhesus macaques, followed by suppressive cART 16 .…”
Section: Introductionmentioning
confidence: 99%
“…In the third animal, although viremia remained stably suppressed in peripheral blood at necropsy, tissue-associated viral DNA was later recovered. More recently, 100% of pigtail macaques infected with an HIV-enveloped SHIV, SHIV-1157ipd3N4 (SHIV-C) also rebounded following autologous transplantation 17 . Interestingly, we found that transplanted animals displayed a significant increase in plasma and tissue viral rebound relative to controls, suggesting that the non-specific impact of the myeloablative conditioning regimen on virus-specific immune cells may offset its benefit in killing virus-infected cells.…”
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.
“…Nonetheless, as shown in Fig. 5 , low-level SHIV RNA expression was detected in selected sites in individual animals, consistent with prior findings from our group and others 17 , 36 – 39 . Fig.…”
Section: Resultssupporting
confidence: 91%
“…3a . Recipient animals underwent pre-transplant conditioning using total body irradiation (TBI) as we have previously described (1040 cGy, delivered in 4 divided doses given over 2 days) 17 , 29 . GVHD prophylaxis included sirolimus (with a target serum level of 5–15 ng/mL), tacrolimus (0.025 mg/kg twice daily, target serum level of 5–10 ng/mL), and mycophenolate mofetil (15 mg/kg twice daily).…”
Section: Resultsmentioning
confidence: 99%
“…We have previously shown in nonhuman primate (NHP) modeling experiments that transplantation with unmodified autologous hematopoietic stem cells (HSCs) is insufficient to achieve cART-free virus remission 16 , 17 . We first used simian/human immunodeficiency virus carrying an HIV-1 reverse transcriptase (RT-SHIV) to infect rhesus macaques, followed by suppressive cART 16 .…”
Section: Introductionmentioning
confidence: 99%
“…In the third animal, although viremia remained stably suppressed in peripheral blood at necropsy, tissue-associated viral DNA was later recovered. More recently, 100% of pigtail macaques infected with an HIV-enveloped SHIV, SHIV-1157ipd3N4 (SHIV-C) also rebounded following autologous transplantation 17 . Interestingly, we found that transplanted animals displayed a significant increase in plasma and tissue viral rebound relative to controls, suggesting that the non-specific impact of the myeloablative conditioning regimen on virus-specific immune cells may offset its benefit in killing virus-infected cells.…”
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.
“…Here, we showed that autologous HSCT results in a relative loss of immunity, captured most precisely in our model by a higher estimated clearance rate of the cytolytic immune response, leading to a higher viral load set point and more rapid progression to AIDS. Our prediction that the anti-SHIV cytolytic response is less durable following HSCT is consistent with the finding of disrupted CD8 ϩ and CD4 ϩ T cell homeostasis and with the increased exhaustion markers noted in the same cohort of macaques used in the present study (38).…”
Primary HIV-1 infection induces a virus-specific adaptive/cytolytic immune response that impacts the plasma viral load set point and the rate of progression to AIDS. Combination antiretroviral therapy (cART) suppresses plasma viremia to undetectable levels that rebound upon cART treatment interruption. Following cART withdrawal, the memory component of the virus-specific adaptive immune response may improve viral control compared to primary infection. Here, using primary infection and treatment interruption data from macaques infected with simian/human immunodeficiency virus (SHIV), we observe a lower peak viral load but an unchanged viral set point during viral rebound. The addition of an autologous stem cell transplant before cART withdrawal alters viral dynamics: we found a higher rebound set point but similar peak viral loads compared to the primary infection. Mathematical modeling of the data that accounts for fundamental immune parameters achieves excellent fit to heterogeneous viral loads. Analysis of model output suggests that the rapid memory immune response following treatment interruption does not ultimately lead to better viral containment. Transplantation decreases the durability of the adaptive immune response following cART withdrawal and viral rebound. Our model's results highlight the impact of the endogenous adaptive immune response during primary SHIV infection. Moreover, because we capture adaptive immune memory and the impact of transplantation, this model will provide insight into further studies of cure strategies inspired by the Berlin patient. HIV patients who interrupt combination antiretroviral therapy (cART) eventually experience viral rebound, the return of viral loads to pretreatment levels. However, the "Berlin patient" remained free of HIV rebound over a decade after stopping cART. His cure is attributed to leukemia treatment that included an HIV-resistant stem cell transplant. Inspired by this case, we studied the impact of stem cell transplantation in a macaque simian/HIV (SHIV) system. Using a mechanistic mathematical model, we found that while primary infection generates an adaptive immune memory response, stem cell transplantation disrupts this learned immunity. The results have implications for HIV cure regimens based on stem cell transplantation.
As the HIV pandemic rapidly spread worldwide in the 1980s and 1990s, a new approach to treat cancer, genetic diseases, and infectious diseases was also emerging. Cell and gene therapy strategies are connected with human pathologies at a fundamental level, by delivering DNA and RNA molecules that could correct and/or ameliorate the underlying genetic factors of any illness. The history of HIV gene therapy is especially intriguing, in that the virus that was targeted was soon co-opted to become part of the targeting strategy. Today, HIV-based lentiviral vectors, along with many other gene delivery strategies, have been used to evaluate HIV cure approaches in cell culture, small and large animal models, and in patients. Here, we trace HIV cell and gene therapy from the earliest clinical trials, using genetically unmodified cell products from the patient or from matched donors, through current state-of-the-art strategies. These include engineering HIV-specific immunity in T-cells, gene editing approaches to render all blood cells in the body HIV-resistant, and most importantly, combination therapies that draw from both of these respective "offensive" and "defensive" approaches. It is widely agreed upon that combinatorial approaches are the most promising route to functional cure/remission of HIV infection. This chapter outlines cell and gene therapy strategies that are poised to play an essential role in eradicating HIV-infected cells in vivo.
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