Vpr Is a VIP: HIV Vpr and Infected Macrophages Promote Viral Pathogenesis

Lubow, Jay; Collins, Kathleen L.

doi:10.3390/v12080809

Cited by 12 publications

(9 citation statements)

References 201 publications

(264 reference statements)

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“…While host restriction factors in human cells help impede SIV replication, they allow HIV replication and the reverse is true in simian cells (24)(25)(26). Many of the accessory proteins in HIV such as Vif, Vpx, Vpr, Vpu, and Nef are all well-known for their ability to counteract human host restriction factors (19,(27)(28)(29)(30)(31)(32). Thus, counteracting restriction factors successfully is a key aspect for cross species viral transmissions.…”

Section: Introductionmentioning

confidence: 99%

In vivo Infection Dynamics and Human Adaptive Changes of SIVsm-Derived Viral Siblings SIVmac239, SIVB670, and SIVhu in Humanized Mice as a Paralog of HIV-2 Genesis

et al. 2021

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Simian immunodeficiency virus native to sooty mangabeys (SIVsm) is believed to have given rise to HIV-2 through cross-species transmission and evolution in the human. SIVmac239 and SIVB670, pathogenic to macaques, and SIVhu, isolated from an accidental human infection, also have origins in SIVsm. With their common ancestral lineage as that of HIV-2 from the progenitor SIVsm, but with different passage history in different hosts, they provide a unique opportunity to evaluate cross-species transmission to a new host and their adaptation/evolution both in terms of potential genetic and phenotypic changes. Using humanized mice with a transplanted human system, we evaluated in vivo replication kinetics, CD4+ T cell dynamics and genetic adaptive changes during serial passage with a goal to understand their evolution under human selective immune pressure. All the three viruses readily infected hu-mice causing chronic viremia. While SIVmac and SIVB670 caused CD4+ T cell depletion during sequential passaging, SIVhu with a deletion in nef gene was found to be less pathogenic. Deep sequencing of the genomes of these viruses isolated at different times revealed numerous adaptive mutations of significance that increased in frequency during sequential passages. The ability of these viruses to infect and replicate in humanized mice provides a new small animal model to study SIVs in vivo in addition to more expensive macaques. Since SIVmac and related viruses have been indispensable in many areas of HIV pathogenesis, therapeutics and cure research, availability of this small animal hu-mouse model that is susceptible to both SIV and HIV viruses is likely to open novel avenues of investigation for comparative studies using the same host.

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Section: Introductionmentioning

confidence: 99%

In vivo Infection Dynamics and Human Adaptive Changes of SIVsm-Derived Viral Siblings SIVmac239, SIVB670, and SIVhu in Humanized Mice as a Paralog of HIV-2 Genesis

et al. 2021

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“…However, it remains to be discovered how deletion-induced upregulation of Vpr expression is linked to efficient viral replication in CMs TC . It has been reported that Vpr targets multiple host factors for degradation [49], including proteins that regulate viral gene expression and virion production in macrophages [45,[50][51][52][53]. We tested the effects of WT and ∆15 viruses on G2/M cell cycle arrest in cell cultures, but no significant difference in the magnitude of cell arrest was observed (Fig.…”

Section: Discussionmentioning

confidence: 99%

Development of a novel Macaque-Tropic HIV-1 adapted to cynomolgus macaques

Ode

Saito

Washizaki

et al. 2022

Journal of General Virology

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Macaque-tropic HIV-1 (HIV-1mt) variants have been developed to establish preferable primate models that are advantageous in understanding HIV-1 infection pathogenesis and in assessing the preclinical efficacy of novel prevention/treatment strategies. We previously reported that a CXCR4-tropic HIV-1mt, MN4Rh-3, efficiently replicates in peripheral blood mononuclear cells (PBMCs) of cynomolgus macaques homozygous for TRIMCyp (CMsTC). However, the CMsTC challenged with MN4Rh-3 displayed low viral loads during the acute infection phase and subsequently exhibited short-term viremia. These virological phenotypes in vivo differed from those observed in most HIV-1-infected people. Therefore, further development of the HIV-1mt variant was needed. In this study, we first reconstructed the MN4Rh-3 clone to produce a CCR5-tropic HIV-1mt, AS38. In addition, serial in vivo passages allowed us to produce a highly adapted AS38-derived virus that exhibits high viral loads (up to approximately 106 copies ml−1) during the acute infection phase and prolonged periods of persistent viremia (lasting approximately 16 weeks postinfection) upon infection of CMsTC. Whole-genome sequencing of the viral genomes demonstrated that the emergence of a unique 15-nt deletion within the vif gene was associated with in vivo adaptation. The deletion resulted in a significant increase in Vpr protein expression but did not affect Vif-mediated antagonism of antiretroviral APOBEC3s, suggesting that Vpr is important for HIV-1mt adaptation to CMsTC. In summary, we developed a novel CCR5-tropic HIV-1mt that can induce high peak viral loads and long-term viremia and exhibits increased Vpr expression in CMsTC.

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“…Macrophages are an early cellular target for the HIV-1 infection, and the transmission between humans is caused by the macrophage-tropic virus rather than the CD4+ T cell-tropic virus [38]. In addition, macrophage-tropic HIV-1 is detected during rebound viremia after the discontinuation of ART [39]. Consequently, new and specific therapeutic targets, such as macrophage-targeting treatments, are required for the radical cure of HIV infection [38].…”

Section: Introductionmentioning

confidence: 99%

A Novel Class of HIV-1 Inhibitors Targeting the Vpr-Induced G2-Arrest in Macrophages by New Yeast- and Cell-Based High-Throughput Screening

Sato

Murakami

Matsuura

et al. 2022

Viruses

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The human immunodeficiency virus type 1 (HIV-1) accessory protein, Vpr, arrests the cell cycle of the G2 phase, and this Vpr-mediated G2 arrest is implicated in an efficient HIV-1 spread in monocyte-derived macrophages. Here, we screened new candidates for Vpr-targeting HIV-1 inhibitors by using fission yeast- and mammalian cell-based high-throughput screening. First, fission yeast strains expressing the HIV-1 Vpr protein were generated and then treated for 48 h with 20 μM of a synthetic library, including 140,000 chemical compounds. We identified 268 compounds that recovered the growth of Vpr-overexpressing yeast. The selected compounds were then tested in mammalian cells, and those displaying high cytotoxicity were excluded from further cell cycle analysis and imaging-based screening. A flow cytometry analysis confirmed that seven compounds recovered from the Vpr-induced G2 arrest. The cell toxicity and inhibitory effect of HIV-1 replication in human monocyte-derived macrophages (MDM) were examined, and three independent structural compounds, VTD227, VTD232, and VTD263, were able to inhibit HIV-1 replication in MDM. Furthermore, we showed that VTD227, but not VTD232 and VTD263, can directly bind to Vpr. Our results indicate that three new compounds and their derivatives represent new drugs targeting HIV-1 replication and can be potentially used in clinics to improve the current antiretroviral therapy.

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Vpr Is a VIP: HIV Vpr and Infected Macrophages Promote Viral Pathogenesis

Cited by 12 publications

References 201 publications

In vivo Infection Dynamics and Human Adaptive Changes of SIVsm-Derived Viral Siblings SIVmac239, SIVB670, and SIVhu in Humanized Mice as a Paralog of HIV-2 Genesis

In vivo Infection Dynamics and Human Adaptive Changes of SIVsm-Derived Viral Siblings SIVmac239, SIVB670, and SIVhu in Humanized Mice as a Paralog of HIV-2 Genesis

Development of a novel Macaque-Tropic HIV-1 adapted to cynomolgus macaques

A Novel Class of HIV-1 Inhibitors Targeting the Vpr-Induced G2-Arrest in Macrophages by New Yeast- and Cell-Based High-Throughput Screening

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