Animal models to achieve an HIV cure

Kumar, Nitasha; Chahroudi, Ann; Silvestri, Guido

doi:10.1097/coh.0000000000000290

Cited by 46 publications

(43 citation statements)

References 84 publications

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“…Asian NHPs, namely rhesus (Macaca mulatta), pigtailed (Macaca nemestrina), and cynomolgus (Macaca fascicaluris) macaques, have become the most commonly used and widely accepted animal models for HIV-1 infection [16][17][18]. Additionally, neurodevelopment is similar between infant humans and macaques, making them suitable for studies of neurologic disease [19][20][21].…”

Section: Sivs and Shivs In Hiv Researchmentioning

confidence: 99%

The Brain Retains: Nonhuman Primate Models for Pediatric HIV-1 in the CNS

2020

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Purpose of Review Perinatal HIV-1 infection is associated with an increased risk for neurologic impairments. With limited access to clinical specimens, animal models could advance our understanding of pediatric central nervous system (CNS) disease and viral persistence. Here, we summarize current findings on HIV-1 CNS infection from nonhuman primate (NHP) models and discuss their implications for improving pediatric clinical outcomes. Recent Findings SIV/SHIV can be found in the CNS of infant macaques within 48 h of challenge. Recent studies show an impermeable BBB during SIV infection, suggesting neuroinvasion in post-partum infection is likely not wholly attributed to barrier dysfunction. Histopathological findings reveal dramatic reductions in hippocampal neuronal populations and myelination in infected infant macaques, providing a link for cognitive impairments seen in pediatric cases. Evidence from humans and NHPs support the CNS as a functional latent reservoir, harbored in myeloid cells that may require unique eradication strategies. Summary Studies in NHP models are uncovering early events, causes, and therapeutic targets of CNS disease as well as highlighting the importance of age-specific studies that capture the distinct features of pediatric HIV-1 infection.

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Section: Sivs and Shivs In Hiv Researchmentioning

confidence: 99%

The Brain Retains: Nonhuman Primate Models for Pediatric HIV-1 in the CNS

2020

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“…To address these potential limitations of previous studies in humans, we used the model of SIV infection of rhesus macaques (RMs), which is very well established and robust and features a number of important similarities with HIV infection in terms of early acute infection events, viral and CD4 ϩ T cell dynamics, establishment of reservoirs, and events associated with late disease progression (23,24). Importantly, the RM model of SIV infection has recently been sufficiently validated for studies of virus eradication and/or functional cure by developing an optimized ART regimen that fully and consistently suppresses virus replication in SIV-infected RMs (25)(26)(27).…”

Section: Importancementioning

confidence: 99%

Short-Term Pegylated Interferon α2a Treatment Does Not Significantly Reduce the Viral Reservoir of Simian Immunodeficiency Virus-Infected, Antiretroviral Therapy-Treated Rhesus Macaques

Palesch

Bosinger

Mavigner

et al. 2018

J Virol

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The major obstacle to human immunodeficiency type 1 (HIV-1) eradication is a reservoir of latently infected cells that persists despite long-term antiretroviral therapy (ART) and causes rapid viral rebound if treatment is interrupted. Type I interferons are immunomodulatory cytokines that induce antiviral factors and have been evaluated for the treatment of HIV-infected individuals, resulting in moderate reduction of viremia and inconclusive data about their effect on reservoir size. Here, we assessed the potential of pegylated IFN-α2a (pIFN-α2a) to reduce the viral reservoir in simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques (RMs). We found that pIFN-α2a treatment of animals in which virus replication is effectively suppressed with ART is safe and well tolerated, as no major clinical side effects were observed. By monitoring the cellular immune response during this intervention, we established that pIFN-α2a administration is not associated with either CD4 T cell depletion or increased immune activation. Importantly, we found that interferon-stimulated genes (ISGs) were significantly upregulated in IFN-treated RMs compared to control animals, confirming that pIFN-α2a is bioactive To evaluate the effect of pIFN-α2a administration on the viral reservoir in CD4 T cells, we performed cell-associated proviral SIV DNA measurements in multiple tissues and assessed levels of replication-competent virus by a quantitative viral outgrowth assay (QVOA). These analyses failed to reveal any significant difference in reservoir size between IFN-treated and control animals. In summary, our data suggest that short-term type I interferon treatment in combination with suppressive ART is not sufficient to induce a significant reduction of the viral reservoir in SIV-infected RMs. The potential of type I interferons to reduce the viral reservoir has been recently studied in clinical trials in HIV-infected humans. However, given the lack of mechanistic data and the potential for safety concerns, a more comprehensive testing of IFN treatment in SIV-infected RMs is critical to provide rationale for further development of this intervention in humans. Utilizing the SIV/RM model in which virus replication is suppressed with ART, we addressed experimental limitations of previous human studies, in particular the lack of a control group and specimen sampling limited to blood. Here, we show by rigorous testing of blood and lymphoid tissues that virus replication and reservoir size were not significantly affected by pIFN-α2a treatment in SIV-infected, ART-treated RMs. This suggests that intensified and/or prolonged IFN treatment regimens, possibly in combination with other antilatency agents, are necessary to effectively purge the HIV/SIV reservoir under ART.

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“…SIV infection in macaques comprehensively reproduces the immunodeficiency symptoms observed in HIV-infected humans, with infection of CD4+T cells and monocytes in blood, and of macrophages in tissues such as lymph nodes, bowel, brain, lung, spleen, and heart (81, 82). Antiretroviral drugs have been shown to fully suppress SIV replication in blood (82) and, in limited studies, CSF (83–85) to levels comparable to those in ART-suppressed HIV-infected individuals.…”

Section: Siv Macaque Modelsmentioning

confidence: 99%

“…Antiretroviral drugs have been shown to fully suppress SIV replication in blood (82) and, in limited studies, CSF (83–85) to levels comparable to those in ART-suppressed HIV-infected individuals. SIV-infected macaques carry latently infected CD4+T cells that harbor replication competent virus, as shown by quantitative viral outgrowth assays (QVOA) (86) and by the rapid rebound of SIV in plasma when ART is discontinued (87).…”

Section: Siv Macaque Modelsmentioning

confidence: 99%

SIV Latency in Macrophages in the CNS

Gama

Abreu

Shirk

et al. 2018

Current Topics in Microbiology and Immunology

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Lentiviruses infect myeloid cells, leading to acute infection followed by persistent/latent infections not cleared by the host immune system. HIV and SIV are lentiviruses that infect CD4+ lymphocytes in addition to myeloid cells in blood and tissues. HIV infection of myeloid cells in brain, lung, and heart causes tissue-specific diseases that are mostly observed during severe immunosuppression, when the number of circulating CD4+ T cells declines to exceeding low levels. Antiretroviral therapy (ART) controls viral replication but does not successfully eliminate latent virus, which leads to viral rebound once ART is interrupted. HIV latency in CD4+ lymphocytes is the main focus of research and concern when HIV eradication efforts are considered. However, myeloid cells in tissues are long-lived and have not been routinely examined as a potential reservoir. Based on a quantitative viral outgrowth assay (QVOA) designed to evaluate latently infected CD4+ lymphocytes, a similar protocol was developed for the assessment of latently infected myeloid cells in blood and tissues. Using an SIV ART model, it was demonstrated that myeloid cells in blood and brain harbor latent SIV that can be reactivated and produce infectious virus in vitro, demonstrating that myeloid cells have the potential to be an additional latent reservoir of HIV that should be considered during HIV eradication strategies.

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Animal models to achieve an HIV cure

Cited by 46 publications

References 84 publications

The Brain Retains: Nonhuman Primate Models for Pediatric HIV-1 in the CNS

The Brain Retains: Nonhuman Primate Models for Pediatric HIV-1 in the CNS

Short-Term Pegylated Interferon α2a Treatment Does Not Significantly Reduce the Viral Reservoir of Simian Immunodeficiency Virus-Infected, Antiretroviral Therapy-Treated Rhesus Macaques

SIV Latency in Macrophages in the CNS

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