Enhanced Antiretroviral Therapy in Rhesus Macaques Improves RT-SHIV Viral Decay Kinetics

North, Thomas W.; Villalobos, Andradi; Hurwitz, Selwyn J.; Deere, Jesse D.; Higgins, Joanne; Chatterjee, Payel; Tao, Sijia; Kauffman, Robert C.; Luciw, Paul A.; Kohler, James J.; Schinazi, Raymond F.

doi:10.1128/aac.02522-14

Cited by 10 publications

(5 citation statements)

References 42 publications

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“…Nevertheless, all four animal studies also showed that the dominant antiviral effect of the antibodies tested was virus neutralization that prevented new rounds of infection. We are able to reach these quantitative conclusions because prior studies of HIV-1 dynamics in infected humanized mice ( 18 , 45 ) and SIV or SHIV dynamics on infected rhesus macaques ( 46 – 48 ) have been found to be similar to that reported for HIV-1 dynamics in patients.…”

Section: Discussionsupporting

confidence: 62%

Quantifying the contribution of Fc-mediated effector functions to the antiviral activity of anti–HIV-1 IgG1 antibodies in vivo

Wang

Gajjar

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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In combating viral infections, the Fab portion of an antibody could mediate virus neutralization, whereas Fc engagement of Fc-γ receptors (FcγRs) could mediate an array of effector functions. Evidence abounds that effector functions are important in controlling infections by influenza, Ebola, or HIV-1 in animal models. However, the relative contribution of virus neutralization versus effector functions to the overall antiviral activity of an antibody remains unknown. To address this fundamental question in immunology, we utilized our knowledge of HIV-1 dynamics to compare the kinetics of the viral load decline (ΔVL) in infected animals given a wild-type (WT) anti–HIV-1 immunoglobulin G1 (IgG1) versus those given a Fc-Null variant of the same antibody. In three independent experiments in HIV-1–infected humanized mice and one pivotal experiment in simian–human immunodeficiency virus (SHIV)-infected rhesus macaques, an earlier and sharper decline in viral load was consistently detected for the WT antibody. Quantifications of the observed differences indicate that Fc-mediated effector functions accounted for 25–45% of the total antiviral activity in these separate experiments. In this study, Fc-mediated effector functions have been quantified in vivo relative to the contribution of virus neutralization mediated by the Fab.

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Section: Discussionsupporting

confidence: 62%

Quantifying the contribution of Fc-mediated effector functions to the antiviral activity of anti–HIV-1 IgG1 antibodies in vivo

Wang

Gajjar

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…However, non-human primate models used to evaluate anti-HIV-1 RT inhibitor efficacy often employ SIV encoding HIV-1 RT in lieu of SIV RT; HIV-1 RT is substituted in place of SIV RT given the differences between these enzymes and NNRTI efficacy (Ambrose et al, 2004, 2014; Balzarini et al, 1995; North et al, 2014; Wang et al, 2014; Witvrouw et al, 2004). Although the importance of substituting HIV-1 RT in lieu of SIV RT in this context is recognized, the relationship between Vpx and evaluation of NRTI efficacy in the context of RT-SHIV constructs, to our knowledge, has not been addressed prior to this report.…”

Section: Discussionmentioning

confidence: 99%

Differential regulatory activities of viral protein X for anti-viral efficacy of nucleos(t)ide reverse transcriptase inhibitors in monocyte-derived macrophages and activated CD4+ T cells

et al. 2015

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Vpx encoded by HIV-2 and SIVsm enhances retroviral reverse transcription in macrophages in vitro by mediating the degradation of the host SAMHD1 protein that hydrolyzes dNTPs and by elevating cellular dNTP levels. Here we employed RT-SHIV constructs (SIV encoding HIV-1 RT) to investigate the contribution of Vpx to the potency of NRTIs, which compete against dNTPs, in monocyte-derived macrophages (MDMs) and activated CD4+ T cells. Relative to HIV-1, both SIV and RT-SHIV exhibited reduced sensitivities to AZT, 3TC and TDF in MDMs but not in activated CD4+ T cells. However, when SIV and RT-SHIV constructs not coding for Vpx were utilized, we observed greater sensitivities to all NRTIs tested using activated CD4+ T cells relative to the Vpx-coding counterparts. This latter phenomenon was observed for AZT only when using MDMs. Our data suggest that Vpx in RT-SHIVs may underestimate the antiviral efficacy of NRTIs in a cell type dependent manner.

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“…It was highly expected that these SHIVs are very useful to study the basic virus property in vivo, the effect of antiviral drugs in vivo, the emergence of drug-resistance variants, and/or the host immunological responses associated with the concerned viral proteins. In fact, a large number of scientific reports on SHIV-RTs have been published (for example, see references [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59]). More impressively, SHIV-Env constructs have played a critical role in the HIV-1/AIDS research activity as fully revealed by selected, only a small portion of scientific articles published so far .…”

Section: Siv/shiv Clones and Nonhuman Primate Modelsmentioning

confidence: 99%

HIV-1 replication and pathogenicity: lessons from macaque-tropic HIV-1 derivatives

Koma,

Doi,

Quoc Le

et al. 2023

Viral Replication Cycle - From Pathogenesis and Immune Response to Diagnosis and Therapy

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Human immunodeficiency virus type 1 (HIV-1) is tropic for humans and replicates in virtually none of the other animal species. While various animal models to mimic the conflict between HIV-1 and human hosts have been proposed, nonhuman primates (NHPs) are thought to be most suitable from a purely scientific point of view for the HIV-1/AIDS model studies. Because NHPs are resistant to HIV-1, remodeling the HIV-1 genome is required to validate the productive infection of NHPs. Two types have been reported as retrofitted viruses, that is, SHIVs and HIV-1 derivatives. SHIVs are SIVs (simian immunodeficiency viruses) that carry a small portion of the HIV-1 genome, whereas HIV-1 derivatives are HIV-1 with a minimal sequence/genome modification. SHIVs have been successfully used for studies specifically targeting HIV-1 Pol-RT (reverse transcriptase) and Env proteins. HIV-1 derivatives can induce AIDS in NHPs under certain conditions. More importantly, HIV-1 derivatives contribute to elucidating the HIV-1 adaptation and virus-host interaction through analyzing the process of acquiring replication capacity and pathogenicity in restrictive hosts distinct from natural hosts. In this chapter, we summarize NHP model studies on HIV-1/AIDS using SIV, SHIV, or HIV-1 derivatives and discuss the significance of HIV-1 derivatives toward understanding the HIV-1 biology.

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Enhanced Antiretroviral Therapy in Rhesus Macaques Improves RT-SHIV Viral Decay Kinetics

Cited by 10 publications

References 42 publications

Quantifying the contribution of Fc-mediated effector functions to the antiviral activity of anti–HIV-1 IgG1 antibodies in vivo

Quantifying the contribution of Fc-mediated effector functions to the antiviral activity of anti–HIV-1 IgG1 antibodies in vivo

Differential regulatory activities of viral protein X for anti-viral efficacy of nucleos(t)ide reverse transcriptase inhibitors in monocyte-derived macrophages and activated CD4+ T cells

HIV-1 replication and pathogenicity: lessons from macaque-tropic HIV-1 derivatives

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