Nonhuman Primate Models for Studies of AIDS Virus Persistence During Suppressive Combination Antiretroviral Therapy

Prete, Gregory Q. Del; Lifson, Jeffrey D.

doi:10.1007/82_2017_73

Cited by 14 publications

(21 citation statements)

References 217 publications

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“…The virulence of lentiviral infections of nonhuman primates (NHPs) can vary widely, ranging from nonpathogenic to highly pathogenic, depending on the NHP species [1][2][3]. For instance, SIV infection is pathogenic in Asian NHPs, such as rhesus (RMs), pigtailed (PTMs) and cynomolgus macaques [1,2] and, in the absence of antiretroviral therapy (ART), progresses to AIDS; therefore, macaques have been extensively employed as models of HIV/AIDS in humans [4][5][6][7]. Conversely, SIV infections are nonpathogenic in African NHPs, such as African green monkeys (AGMs), sooty mangabeys (SMs) and mandrills (MNDs) [2,8,9].…”

Section: Introductionmentioning

confidence: 99%

African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity

Raehtz

Barrenäs

et al. 2020

PLoS Pathog

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Unlike HIV infection, SIV infection is generally nonpathogenic in natural hosts, such as African green monkeys (AGMs), despite lifelong high viral replication. Lack of disease progression was reportedly based on the ability of SIV-infected AGMs to prevent gut dysfunction, avoiding microbial translocation and the associated systemic immune activation and chronic inflammation. Yet, the maintenance of gut integrity has never been documented, and the mechanism(s) by which gut integrity is preserved are unknown. We sought to investigate the early events of SIV infection in AGMs, specifically examining the impact of SIVsab infection on the gut mucosa. Twenty-nine adult male AGMs were intrarectally infected with SIV-sab92018 and serially sacrificed at well-defined stages of SIV infection, preramp-up (1-3 days post-infection (dpi)), ramp-up (4-6 dpi), peak viremia (9-12 dpi), and early chronic SIV infection (46-55 dpi), to assess the levels of immune activation, apoptosis, epithelial damage and microbial translocation in the GI tract and peripheral lymph nodes. Tissue viral loads, plasma cytokines and plasma markers of gut dysfunction were also measured

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Section: Introductionmentioning

confidence: 99%

African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity

Raehtz

Barrenäs

et al. 2020

PLoS Pathog

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“…For those reasons, animal models of HIV infection have been developed. All the available animal models have limitations, which must be addressed to validate their relevance for asking specific research questions [16].…”

Section: Introductionmentioning

confidence: 99%

Clonal expansion of SIV-infected cells in macaques on antiretroviral therapy is similar to that of HIV-infected cells in humans

et al. 2019

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Clonal expansion of HIV infected cells plays an important role in the formation and persistence of the reservoir that allows the virus to persist, in DNA form, despite effective antiretroviral therapy. We used integration site analysis to ask if there is a similar clonal expansion of SIV infected cells in macaques. We show that the distribution of HIV and SIV integration sites in vitro is similar and that both viruses preferentially integrate in many of the same genes. We obtained approximately 8000 integration sites from blood samples taken from SIV-infected macaques prior to the initiation of ART, and from blood, spleen, and lymph node samples taken at necropsy. Seven clones were identified in the pre-ART samples; one persisted for a year on ART. An additional 100 clones were found only in on-ART samples; a number of these clones were found in more than one tissue. The timing and extent of clonal expansion of SIV-infected cells in macaques and HIV-infected cells in humans is quite similar. This suggests that SIV-infected macaques represent a useful model of the clonal expansion of HIV infected cells in humans that can be used to evaluate strategies intended to control or eradicate the viral reservoir.

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“…Simian immunodeficiency virus (SIV)-infected nonhuman primates (NHPs) are similar in their pathophysiology and viral dynamics to humans infected with HIV-1 (26)(27)(28)(29)(30) and therefore make ideal models for testing novel intervention strategies. Similarly to HIV-1 in humans, cART regimens can suppress SIV replication in rhesus macaques to levels not detectable with routine assays (Ͻ30 viral RNA copies/ml plasma), but virus persists and rebound viremia typically occurs upon treatment interruption even when cART treatment is started early and continues for a prolonged period (30,31).…”

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confidence: 99%

Evaluating the Intactness of Persistent Viral Genomes in Simian Immunodeficiency Virus-Infected Rhesus Macaques after Initiating Antiretroviral Therapy within One Year of Infection

Long

Fennessey

Newman

et al. 2019

J Virol

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The major obstacle to more-definitive treatment for HIV infection is the early establishment of virus that persists despite long-term combination antiretroviral therapy (cART) and can cause recrudescent viremia if cART is interrupted. Previous studies of HIV DNA that persists despite cART indicated that only a small fraction of persistent viral sequences was intact. Experimental simian immunodeficiency virus (SIV) infections of nonhuman primates (NHPs) are essential models for testing interventions designed to reduce the viral reservoir. We studied the viral genomic integrity of virus that persists during cART under conditions typical of many NHP reservoir studies, specifically with cART started within 1 year postinfection and continued for at least 9 months. The fraction of persistent DNA in SIV-infected NHPs starting cART during acute or chronic infection was assessed with a multiamplicon, real-time PCR assay designed to analyze locations that are regularly spaced across the viral genome to maximize coverage (collectively referred to as “tile assay”) combined with near-full-length (nFL) single-genome sequencing. The tile assay is used to rapidly screen for major deletions, with nFL sequence analysis used to identify additional potentially inactivating mutations. Peripheral blood mononuclear cells (PBMC) from animals started on cART within 1 month of infection, sampled at least 9 months after cART initiation, contained at least 80% intact genomes, whereas those from animals started on cART 1 year postinfection and treated for 1 year contained intact genomes only 47% of the time. The most common defect identified was large deletions, with the remaining defects caused by APOBEC-mediated mutations, frameshift mutations, and inactivating point mutations. Overall, this approach can be used to assess the intactness of persistent viral DNA in NHPs. IMPORTANCE Molecularly defining the viral reservoir that persists despite antiretroviral therapy and that can lead to rebound viremia if antiviral therapy is removed is critical for testing interventions aimed at reducing this reservoir. In HIV infection in humans with delayed treatment initiation and extended treatment duration, persistent viral DNA has been shown to be dominated by nonfunctional genomes. Using multiple real-time PCR assays across the genome combined with near-full-genome sequencing, we defined SIV genetic integrity after 9 to 18 months of combination antiretroviral therapy in rhesus macaques starting therapy within 1 year of infection. In the animals starting therapy within a month of infection, the vast majority of persistent DNA was intact and presumptively functional. Starting therapy within 1 year increased the nonintact fraction of persistent viral DNA. The approach described here allows rapid screening of viral intactness and is a valuable tool for assessing the efficacy of novel reservoir-reducing interventions.

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Nonhuman Primate Models for Studies of AIDS Virus Persistence During Suppressive Combination Antiretroviral Therapy

Cited by 14 publications

References 217 publications

African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity

African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity

Clonal expansion of SIV-infected cells in macaques on antiretroviral therapy is similar to that of HIV-infected cells in humans

Evaluating the Intactness of Persistent Viral Genomes in Simian Immunodeficiency Virus-Infected Rhesus Macaques after Initiating Antiretroviral Therapy within One Year of Infection

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