Robust suppression of env‐<scp>SHIV</scp> viremia in <i><scp>M</scp>acaca nemestrina</i> by 3‐drug <scp>ART</scp> is independent of timing of initiation during chronic infection

Peterson, Christopher W.; Younan, Patrick; Polacino, Patricia; Maurice, Nicholas J.; Miller, Hannah W.; Prlic, Martin; Jerome, Keith R.; Woolfrey, Ann E.; Hu, Shiu Lok; Kiem, Hans Peter

doi:10.1111/jmp.12060

Cited by 16 publications

(30 citation statements)

References 56 publications

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“…infection in pigtail macaques, and can be suppressed by cART (11,12). Pathogenicity in this species is consistent with available information for the closely related rhesus macaque (Macaca mulatta) (13,14).…”

Section: Introductionsupporting

confidence: 86%

“…The experimental design of this study is shown in Figure 1A, and time points are listed in Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.91230DS1. All animals underwent intravenous challenge with SHIV-1157ipd3N4 (SHIV-C), and cART was applied 6 months after infection as previously described (11). Peak viral loads (VLs) ranged between 10 5 and 10 7 copies/ml plasma, and VL set points ranged between 10 2 and 10 5 copies/ml ( Figure 1B) (18).…”

Section: Resultsmentioning

confidence: 99%

“…Intravenous inoculation with 9500 TCID50 SHIV-1157ipd3N4 (provided by Ruth Ruprecht, Texas Biomedical Research Institute), administration of cART (tenofovir [PMPA], emtricitabine [FTC], and raltegravir), and measurement of plasma VLs and absolute CD4 + and CD8 + T cell counts were conducted as described previously (11,14,58). PMPA and FTC were gifts of Gilead Sciences, and raltegravir was a gift of Merck.…”

Section: Methodsmentioning

confidence: 99%

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Loss of immune homeostasis dictates SHIV rebound after stem-cell transplantation

Peterson¹,

Benne²,

Polacino³

et al. 2017

JCI Insight

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Section: Introductionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Loss of immune homeostasis dictates SHIV rebound after stem-cell transplantation

Peterson¹,

Benne²,

Polacino³

et al. 2017

JCI Insight

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“…Tissue harvest and blood and serum collection were performed prior to and following SHIV challenge. Antiretroviral drugs were administered as previously described 44. …”

mentioning

confidence: 99%

Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates

Younan

Peterson

Polacino³

et al. 2015

Molecular Therapy

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Recent studies have demonstrated that genetically modified hematopoietic stem cells (HSCs) can reduce HIV viremia. We have developed an HIV/AIDS-patient model in Simian/human immunodeficiency virus (SHIV)-infected pigtailed macaques that are stably suppressed on antiretroviral therapy (ART: raltegravir, emtricitabine and tenofovir). Following SHIV infection and ART, animals undergo autologous HSC transplantation (HSCT) with lentivirally transduced cluster of differentiation (CD)34(+) cells expressing the mC46 anti-HIV fusion protein. We show that SHIV(+), ART-treated animals had very low gene marking levels after HSCT. Pretransduction CD34(+) cells contained detectable levels of all three ART drugs, likely contributing to the low gene transfer efficiency. Following HSCT recovery and the cessation of ART, plasma viremia rebounded, indicating that myeloablative total body irradiation cannot completely eliminate viral reservoirs after autologous HSCT. The kinetics of recovery following autologous HSCT in SHIV(+), ART-treated macaques paralleled those observed following transplantation of control animals. However, T-cell subset analyses demonstrated a high percentage of C-C chemokine receptor 5 (CCR5)-expressing CD4(+) T-cells after HSCT. These data suggest that an extended ART interruption time may be required for more efficient lentiviral transduction. To avoid complications associated with ART interruption in the context of high percentages of CD4(+)CCR5(+)T-cells after HSCT, the use of vector systems not impaired by the presence of residual ART may also be beneficial.

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“…Pigtailed macaques were challenged with SHIV1157ipd3N4, observed off therapy for 25 weeks, and treated with cART for 55 weeks (29). At 80 weeks postinfection, cART was withdrawn (analytic treatment interruption [ATI]).…”

Section: Resultsmentioning

confidence: 99%

Autologous Stem Cell Transplantation Disrupts Adaptive Immune Responses during Rebound Simian/Human Immunodeficiency Virus Viremia

Reeves

Peterson

Kiem

et al. 2017

J Virol

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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.

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Robust suppression of env‐SHIV viremia in Macaca nemestrina by 3‐drug ART is independent of timing of initiation during chronic infection

Cited by 16 publications

References 56 publications

Loss of immune homeostasis dictates SHIV rebound after stem-cell transplantation

Loss of immune homeostasis dictates SHIV rebound after stem-cell transplantation

Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates

Autologous Stem Cell Transplantation Disrupts Adaptive Immune Responses during Rebound Simian/Human Immunodeficiency Virus Viremia

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