The SIV Envelope Glycoprotein, Viral Tropism, and Pathogenesis: Novel Insights from Nonhuman Primate Models of AIDS

Swanstrom, Adrienne E.; Prete, Gregory Q. Del; Deléage, Claire; Elser, Samra E.; Lackner, Andrew A.; Hoxie, James A.

doi:10.2174/1570162x15666171124123116

Cited by 12 publications

(8 citation statements)

References 123 publications

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“…Non-human primate (NHP) models involving macaques infected with simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) allow investigation of viral persistence and cure strategies (Borducchi et al, 2016;Cartwright et al, 2016;Del Prete et al, 2014b, 2016aDel Prete and Lifson, 2017;Dinoso et al, 2009;Kumar et al, 2016;Mavigner et al, 2014;McGary et al, 2017;Okoye et al, 2018;Shen et al, 2003;Swanstrom et al, 2018;Whitney et al, 2014). ART suppresses SIV replication (Del Prete et al, 2016b) but is not curative because SIV also establishes a latent reservoir in resting CD4 + T cells (Dinoso et al, 2009;Shen et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The Landscape of Persistent Viral Genomes in ART-Treated SIV, SHIV, and HIV-2 Infections

Bender

Simonetti

Kumar

et al. 2019

Cell Host & Microbe

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113

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Section: Introductionmentioning

confidence: 99%

The Landscape of Persistent Viral Genomes in ART-Treated SIV, SHIV, and HIV-2 Infections

Bender

Simonetti

Kumar

et al. 2019

Cell Host & Microbe

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113

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“…During their pathogenesis, lentiviruses such as HIV type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV) infect both dividing CD4 1 T cells and terminally differentiated/nondividing myeloid cells such as macrophages and microglia (1)(2)(3)(4). Although sharing a selective cellular tropism, cell-dependent replication kinetics differ among the viruses because HIV-1 replication kinetics are delayed in nondividing cell populations (5).…”

mentioning

confidence: 99%

Enhanced enzyme kinetics of reverse transcriptase variants cloned from animals infected with SIVmac239 lacking viral protein X

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Kim

Schinazi

et al. 2020

Journal of Biological Chemistry

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HIV Type 1 (HIV-1) and simian immunodeficiency virus (SIV) display differential replication kinetics in macrophages. This is because high expression levels of the active host deoxynucleotide triphosphohydrolase sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) depletes intracellular dNTPs, which restricts HIV-1 reverse transcription, and results in a restrictive infection in this myeloid cell type. Some SIVs overcome SAMHD1 restriction using viral protein X (Vpx), a viral accessory protein that induces proteasomal degradation of SAMHD1, increasing cellular dNTP concentrations and enabling efficient proviral DNA synthesis. We previously reported that SAMHD1 non-counteracting lentiviruses may have evolved to harbor reverse transcriptase (RT) proteins that efficiently polymerize DNA, even at low dNTP concentrations, to circumvent SAMHD1 restriction. Here we investigated whether RTs from SIVmac239 virus lacking a Vpx protein evolve during the course of in vivo infection to more efficiently synthesize DNA at the low dNTP concentrations found in macrophages. Sequence analysis of RTs cloned from Vpx (+) and Vpx (-) SIVmac239 infected animals revealed that Vpx (-) RTs contained more extensive mutations than Vpx (+) RTs. While the amino acid substitutions were dispersed indiscriminately across the protein, steady state and pre-steady state analysis demonstrated that selected SIVmac239 Vpx (-) RTs are characterized by higher catalytic efficiency and incorporation efficiency values than RTs cloned from SIVmac239 Vpx (+) infections. Overall, this study supports the possibility that the loss of Vpx may generate in vivo SIVmac239 RT variants that can counteract the limited availability of dNTP substrate in macrophages.

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“…Although myeloid lineage cells also represent a potentially infectable CD4 + cell type that may be resistant to antibody-mediated depletion, and indeed we observed no evidence of depletion of monocytes in blood following anti-CD4 administration, during early SIV and HIV infection the overwhelming majority of infected cells are T cells (45,(52)(53)(54)(55)(56). This is particularly true for SIVmac239, a strictly T cell tropic virus that only infects substantial numbers of macrophages in a subset of animals late in infection in association with progression to clinical disease (57). Thus, infected macrophages are unlikely to have contributed appreciably to the overall viral reservoirs established within our study animals.…”

Section: Discussionmentioning

confidence: 62%

Antibody-mediated depletion of viral reservoirs is limited in SIV-infected macaques treated early with antiretroviral therapy

Swanstrom¹,

Immonen²,

Oswald³

et al. 2021

Journal of Clinical Investigation

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The effectiveness of virus-specific strategies, including administered HIV-specific mAbs, to target cells that persistently harbor latent, rebound competent HIV genomes during combination antiretroviral therapy (cART) has been limited by inefficient induction of viral protein expression.To examine antibody-mediated viral reservoir targeting without a need for viral induction, we used an anti-CD4 mAb to deplete both infected and uninfected CD4 + T cells. Ten rhesus macaques infected with barcoded SIVmac239M received cART for 93 weeks starting 4 days post-infection.During cART, five animals received 5-6 anti-CD4 antibody administrations and CD4 + T cell

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The SIV Envelope Glycoprotein, Viral Tropism, and Pathogenesis: Novel Insights from Nonhuman Primate Models of AIDS

Abstract: Collectively, these findings have yielded novel insights into the critical role of the viral Env and tropism as a driver of pathogenesis and host control and have helped to identify new areas for targeted interventions in therapy and prevention of HIV-1 infection.

Cited by 12 publications

References 123 publications

The Landscape of Persistent Viral Genomes in ART-Treated SIV, SHIV, and HIV-2 Infections

The Landscape of Persistent Viral Genomes in ART-Treated SIV, SHIV, and HIV-2 Infections

Enhanced enzyme kinetics of reverse transcriptase variants cloned from animals infected with SIVmac239 lacking viral protein X

Antibody-mediated depletion of viral reservoirs is limited in SIV-infected macaques treated early with antiretroviral therapy

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