scholarly journals Cell Type-Dependent Escape of Capsid Inhibitors by Simian Immunodeficiency Virus SIVcpz

2020 ◽  
Vol 94 (23) ◽  
Author(s):  
Augustin Penda Twizerimana ◽  
Rachel Scheck ◽  
Daniel Becker ◽  
Zeli Zhang ◽  
Marianne Wammers ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Simian Immunodeficiency Virus ◽  
Pan Troglodytes ◽  
Hela Cells ◽  
Cyclophilin A ◽  
Human Pbmcs ◽  
Cell Type ◽  
Content Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Pandemic human immunodeficiency virus type 1 (HIV-1) is the result of the zoonotic transmission of simian immunodeficiency virus (SIV) from the chimpanzee subspecies Pan troglodytes troglodytes (SIVcpzPtt). The related subspecies Pan troglodytes schweinfurthii is the host of a similar virus, SIVcpzPts, which did not spread to humans. We tested these viruses with small-molecule capsid inhibitors (PF57, PF74, and GS-CA1) that interact with a binding groove in the capsid that is also used by CPSF6. While HIV-1 was sensitive to capsid inhibitors in cell lines, human macrophages, and peripheral blood mononuclear cells (PBMCs), SIVcpzPtt was resistant in rhesus FRhL-2 cells and human PBMCs but was sensitive to PF74 in human HOS and HeLa cells. SIVcpzPts was insensitive to PF74 in FRhL-2 cells, HeLa cells, PBMCs, and macrophages but was inhibited by PF74 in HOS cells. A truncated version of CPSF6 (CPSF6-358) inhibited SIVcpzPtt and HIV-1, while in contrast, SIVcpzPts was resistant to CPSF6-358. Homology modeling of HIV-1, SIVcpzPtt, and SIVcpzPts capsids and binding energy estimates suggest that these three viruses bind similarly to the host proteins cyclophilin A (CYPA) and CPSF6 as well as the capsid inhibitor PF74. Cyclosporine treatment, mutation of the CYPA-binding loop in the capsid, or CYPA knockout eliminated the resistance of SIVcpzPts to PF74 in HeLa cells. These experiments revealed that the antiviral capacity of PF74 is controlled by CYPA in a virus- and cell type-specific manner. Our data indicate that SIVcpz viruses can use infection pathways that escape the antiviral activity of PF74. We further suggest that the antiviral activity of PF74 capsid inhibitors depends on cellular cofactors. IMPORTANCE HIV-1 originated from SIVcpzPtt but not from the related virus SIVcpzPts, and thus, it is important to describe molecular infection by SIVcpzPts in human cells to understand the zoonosis of SIVs. Pharmacological HIV-1 capsid inhibitors (e.g., PF74) bind a capsid groove that is also a binding site for the cellular protein CPSF6. SIVcpzPts was resistant to PF74 in HeLa cells but sensitive in HOS cells, thus indicating cell line-specific resistance. Both SIVcpz viruses showed resistance to PF74 in human PBMCs. Modulating the presence of cyclophilin A or its binding to capsid in HeLa cells overcame SIVcpzPts resistance to PF74. These results indicate that early cytoplasmic infection events of SIVcpzPts may differ between cell types and affect, in an unknown manner, the antiviral activity of capsid inhibitors. Thus, capsid inhibitors depend on the activity or interaction of currently uncharacterized cellular factors.

scholarly journals CD4-Independent, CCR5-Dependent Simian Immunodeficiency Virus Infection and Chemotaxis of Human Cells

2000 ◽  
Vol 74 (15) ◽  
pp. 6720-6724 ◽  
Author(s):  
Sujatha Iyengar ◽  
David H. Schwartz ◽  
Janice E. Clements ◽  
James E. K. Hildreth
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Selective Advantage ◽  
Human Pbmcs ◽  
Macrophage Infection ◽  
Independent Manner ◽  
Peripheral Blood Mononuclear ◽  
New Host ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Most simian immunodeficiency virus (SIV), human immunodeficiency virus type 2 (HIV-2), and HIV-1 infection of host peripheral blood mononuclear cells (PBMCs) is CD4 dependent. In some cases, X4 HIV-1 chemotaxis is CD4 independent, and cross-species transmission might be facilitated by CD4-independent entry, which has been demonstrated for some SIV strains in CD4− non-T cells. As expected for CCR5-dependent virus, SIV required CD4 on rhesus and pigtail macaque PBMCs for infection and chemotaxis. However, SIV induced the chemotaxis of human PBMCs in a CD4-independent manner. Furthermore, in contrast to the results of studies using transfected human cell lines, SIV did not require CD4 binding to productively infect primary human PBMCs. CD4-independent lymphocyte and macrophage infection may facilitate cross-species transmission, while reacquisition of CD4 dependence may confer a selective advantage for the virus within new host species.

scholarly journals Differential Sensitivity of “Old” versus “New” APOBEC3G to Human Immunodeficiency Virus Type 1 Vif

2008 ◽  
Vol 83 (2) ◽  
pp. 1156-1160 ◽  
Author(s):  
Ritu Goila-Gaur ◽  
Mohammad A. Khan ◽  
Eri Miyagi ◽  
Klaus Strebel
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Hela Cells ◽  
Relative Sensitivity ◽  
Differential Sensitivity ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT HIV-1 Vif counteracts the antiviral activity of APOBEC3G by inhibiting its encapsidation into virions. Here, we compared the relative sensitivity to Vif of APOBEC3G in stable HeLa cells containing APOBEC3G (HeLa-A3G cells) versus that of newly synthesized APOBEC3G. We observed that newly synthesized APOBEC3G was more sensitive to degradation than preexisting APOBEC3G. Nevertheless, preexisting and transiently expressed APOBEC3G were packaged with similar efficiencies into vif-deficient human immunodeficiency virus type 1 (HIV-1) virions, and Vif inhibited the encapsidation of both forms of APOBEC3G into HIV particles equally well. Our results suggest that HIV-1 Vif preferentially induces degradation of newly synthesized APOBEC3G but indiscriminately inhibits encapsidation of “old” and “new” APOBEC3G.

scholarly journals Chimeric Human Immunodeficiency Virus Type 1 (HIV-1) Virions Containing HIV-2 or Simian Immunodeficiency Virus Nef Are Resistant to Cyclosporine Treatment

2004 ◽  
Vol 78 (4) ◽  
pp. 1843-1850 ◽  
Author(s):  
Mahfuz Khan ◽  
Lingling Jin ◽  
Ming Bo Huang ◽  
Lesa Miles ◽  
Vincent C. Bond ◽  
...  
Keyword(s):  
Amino Acids ◽  
Human Immunodeficiency Virus ◽  
Simian Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cyclophilin A ◽  
C Terminus ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The viral protein Nef and the cellular factor cyclophilin A are both required for full infectivity of human immunodeficiency virus type 1 (HIV-1) virions. In contrast, HIV-2 and simian immunodeficiency virus (SIV) do not incorporate cyclophilin A into virions or need it for full infectivity. Since Nef and cyclophilin A appear to act in similar ways on postentry events, we determined whether chimeric HIV-1 virions that contained either HIV-2 or SIV Nef would have a direct effect on cyclophilin A dependence. Our results show that chimeric HIV-1 virions containing either HIV-2 or SIV Nef are resistant to treatment by cyclosporine and enhance the infectivity of virions with mutations in the cyclophilin A binding loop of Gag. Amino acids at the C terminus of HIV-2 and SIV are necessary for inducing cyclosporine resistance. However, transferring these amino acids to the C terminus of HIV-1 Nef is insufficient to induce cyclosporine resistance in HIV-1. These results suggest that HIV-2 and SIV Nef are able to compensate for the need for cyclophilin A for full infectivity and that amino acids present at the C termini of these proteins are important for this function.

scholarly journals Cyclophilin A-Independent Replication of a Human Immunodeficiency Virus Type 1 Isolate Carrying a Small Portion of the Simian Immunodeficiency Virus SIVMACgag Capsid Region

2001 ◽  
Vol 75 (21) ◽  
pp. 10527-10531 ◽  
Author(s):  
Mikako Fujita ◽  
Akiko Yoshida ◽  
Maki Miyaura ◽  
Akiko Sakurai ◽  
Hirofumi Akari ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Simian Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Human Cell ◽  
Cyclophilin A ◽  
Chimeric Virus ◽  
Immunodeficiency Virus ◽  
Independent Replication ◽  
Hiv 1

ABSTRACT Hybrid viruses between human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus strain mac (SIVMAC) are invaluable to various fields of HIV-1 research. To date, however, no replication-competent HIV-1 strain containing the gagcapsid (CA) region of SIVMAC has been reported. To obtain the viable gag gene chimeric virus in an HIV-1 background, seven HIV-1 strains carrying a part of SIVMAC CA or a small deletion in the CA region were constructed and examined for their biological and biochemical characteristics. While all the recombinants and mutants were found to express Gag and to produce progeny virions on transfection, only one chimeric virus, which has 18 bp of SIVgag CA sequence in place of the region encoding the HIV-1 CA cyclophilin A (CyPA)-binding loop, was infectious for human cell lines. Although this chimeric virus was unable to grow in monkey lymphocytic cells like wild-type (wt) HIV-1 did, it grew much better than wt virus in the presence of cyclosporin A in a human cell line which supports HIV-1 replication in a CyPA-dependent manner. These results indicate that the transfer of a small portion of the SIVMAC CA region to HIV-1 could confer the CyPA-independent replication potential of SIVMAC on the virus.

scholarly journals Cyclophilin A and TRIM5α Independently Regulate Human Immunodeficiency Virus Type 1 Infectivity in Human Cells

2006 ◽  
Vol 80 (6) ◽  
pp. 2855-2862 ◽  
Author(s):  
Elena Sokolskaja ◽  
Lionel Berthoux ◽  
Jeremy Luban
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Leukemia Virus ◽  
Cyclophilin A ◽  
Human Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Cyclophilin A (CypA), a cytoplasmic, human immunodeficiency virus type 1 (HIV-1) CA-binding protein, acts after virion membrane fusion with human cells to increase HIV-1 infectivity. HIV-1 CA is similarly greeted by CypA soon after entry into rhesus macaque or African green monkey cells, where, paradoxically, the interaction decreases HIV-1 infectivity by facilitating TRIM5α-mediated restriction. These observations conjure a model in which CA recognition by the human TRIM5α orthologue is precluded by CypA. Consistent with the model, selection of a human cell line for decreased restriction of the TRIM5α-sensitive, N-tropic murine leukemia virus (N-MLV) rendered HIV-1 transduction of these cells independent of CypA. Additionally, HIV-1 virus-like particles (VLPs) saturate N-MLV restriction activity, particularly when the CA-CypA interaction is disrupted. Here the effects of CypA and TRIM5α on HIV-1 restriction were examined directly. RNA interference was used to show that endogenous human TRIM5α does indeed restrict HIV-1, but the magnitude of this antiviral activity was not altered by disruption of the CA-CypA interaction or by elimination of CypA protein. Conversely, the stimulatory effect of CypA on HIV-1 infectivity was completely independent of human TRIM5α. Together with previous reports, these data suggest that CypA protects HIV-1 from an unknown antiviral activity in human cells. Additionally, target cell permissivity increased after loading with heterologous VLPs, consistent with a common saturable target that is epistatic to both TRIM5α and the putative CypA-regulated restriction factor.

scholarly journals Amplification of a Complete Simian Immunodeficiency Virus Genome from Fecal RNA of a Wild Chimpanzee

2003 ◽  
Vol 77 (3) ◽  
pp. 2233-2242 ◽  
Author(s):  
Mario L. Santiago ◽  
Frederic Bibollet-Ruche ◽  
Elizabeth Bailes ◽  
Shadrack Kamenya ◽  
Martin N. Muller ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Pan Troglodytes ◽  
Current Knowledge ◽  
Extended Period ◽  
Amino Acid Sequences ◽  
Primate Species ◽  
Wild Chimpanzee ◽  
West Central ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Current knowledge of the genetic diversity of simian immunodeficiency virus (SIVcpz) infection of wild chimpanzees (Pan troglodytes) is incomplete since few isolates, mostly from captive apes from Cameroon and Gabon, have been characterized; yet this information is critical for understanding the origins of human immunodeficiency virus type 1 (HIV-1) and the circumstances leading to the HIV-1 pandemic. Here, we report the first full-length SIVcpz sequence (TAN1) from a wild chimpanzee (Pan troglodytes schweinfurthii) from Gombe National Park (Tanzania), which was obtained noninvasively by amplification of virion RNA from fecal samples collected under field conditions. Using reverse transcription-PCR and a combination of generic and strain-specific primers, we amplified 13 subgenomic fragments which together spanned the entire TAN1 genome (9,326 bp). Distance and phylogenetic tree analyses identified TAN1 unambiguously as a member of the HIV-1/SIVcpz group of viruses but also revealed an extraordinary degree of divergence from all previously characterized SIVcpz and HIV-1 strains. In Gag, Pol, and Env proteins, TAN1 differed from west-central African SIVcpz and HIV-1 strains on average by 36, 30, and 51% of amino acid sequences, respectively, approaching distance values typically found for SIVs from different primate species. The closest relative was SIVcpzANT, also from a P. t. schweinfurthii ape, which differed by 30, 25, and 44%, respectively, in these same protein sequences but clustered with TAN1 in all major coding regions in a statistically highly significant manner. These data indicate that east African chimpanzees, like those from west-central Africa, are naturally infected by SIVcpz but that their viruses comprise a second, divergent SIVcpz lineage which appears to have evolved in relative isolation for an extended period of time. Our data also demonstrate that noninvasive molecular epidemiological studies of SIVcpz in wild chimpanzees are feasible and that such an approach may prove essential for unraveling the evolutionary history of SIVcpz/HIV-1 as well as that of other pathogens naturally infecting wild primate populations.

scholarly journals Kinetics of Antiviral Activity and Intracellular Pharmacokinetics of Human Immunodeficiency Virus Type 1 Protease Inhibitors in Tissue Culture

1999 ◽  
Vol 43 (11) ◽  
pp. 2629-2634 ◽  
Author(s):  
Michelina Nascimbeni ◽  
Claire Lamotte ◽  
Gilles Peytavin ◽  
Robert Farinotti ◽  
François Clavel
Keyword(s):  
Human Immunodeficiency Virus ◽  
Tissue Culture ◽  
Antiviral Activity ◽  
Protease Inhibitors ◽  
Hela Cells ◽  
Immunodeficiency Virus ◽  
Antiviral Activities ◽  
Kinetics Of ◽  
Hiv 1

ABSTRACT We have examined the kinetics of the inhibition of human immunodeficiency virus type 1 (HIV-1) particle infectivity by protease inhibitors (PIs) in cell culture, using either transfected HeLa cells or infected peripheral blood mononuclear cells (PBMCs) as producers of infectious virions. Both the kinetics of the initiation of antiviral activity after addition of the PIs to these cultures and the kinetics of restoration of virion infectivity after removal of the PIs from the treated cultures were examined. We found that the kinetics of initiation of particle infectivity inhibition produced by a high extracellular concentration (5 μM) of the inhibitors were similar for all five inhibitors tested: loss of particle infectivity was perceptible as early as 1 h after the initiation of PI treatment and increased gradually thereafter. By contrast, the durability of this antiviral effect following removal of the drug from the culture varied dramatically according to the drug studied. In transfected HeLa cells, saquinavir and nelfinavir exerted the most prolonged inhibition, with the half-lives of their antiviral activities being greater than 24 h, while ritonavir exerted an intermediate length of inhibition (18 h) and indinavir and amprenavir exerted a reproducibly shorter length of inhibition (5 h). For all five tested PIs, these kinetics were significantly faster in PBMCs than in HeLa cells. The striking differences in antiviral kinetics observed among the different PIs appear mostly due to differences in their intracellular concentrations and/or rates of cellular clearance. Our observations, although limited to tissue culture conditions, may help delineate the cellular parameters of the antiviral activities of HIV-1 PIs and further optimize the efficiencies of these antiretrovirals in vivo.

scholarly journals Cyclophilin A Renders Human Immunodeficiency Virus Type 1 Sensitive to Old World Monkey but Not Human TRIM5α Antiviral Activity

2006 ◽  
Vol 80 (10) ◽  
pp. 4683-4690 ◽  
Author(s):  
Zuzana Keckesova ◽  
Laura M. J. Ylinen ◽  
Greg J. Towers
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Cyclosporine A ◽  
World Monkey ◽  
Cyclophilin A ◽  
Old World ◽  
Old World Monkey ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT TRIM5α is an important mediator of antiretroviral innate immunity influencing species-specific retroviral replication. Here we investigate the role of the peptidyl prolyl isomerase enzyme cyclophilin A in TRIM5α antiviral activity. Cyclophilin A is recruited into nascent human immunodeficiency virus type 1 (HIV-1) virions as well as incoming HIV-1 capsids, where it isomerizes an exposed proline residue. Here we show that cyclophilin A renders HIV-1 sensitive to restriction by TRIM5α in cells from Old World monkeys, African green monkey and rhesus macaque. Inhibition of cyclophilin A activity with cyclosporine A, or reducing cyclophilin A expression with small interfering RNA, rescues TRIM5α-restricted HIV-1 infectivity. The effect of cyclosporine A on HIV-1 infectivity is dependent on TRIM5α expression, and expression of simian TRIM5α in permissive feline cells renders them able to restrict HIV-1 in a cyclosporine A-sensitive way. We use an HIV-1 cyclophilin A binding mutant (CA G89V) to show that cyclophilin A has different roles in restriction by Old World monkey TRIM5α and owl monkey TRIM-Cyp. TRIM-Cyp, but not TRIM5α, recruits its tripartite motif to HIV-1 capsid via cyclophilin A and, therefore, HIV-1 G89V is insensitive to TRIM-Cyp but sensitive to TRIM5α. We propose that cyclophilin A isomerization of a proline residue in the TRIM5α sensitivity determinant of the HIV-1 capsid sensitizes it to restriction by Old World monkey TRIM5α. In humans, where HIV-1 has adapted to bypass TRIM5α activity, the effects of cyclosporine A are independent of TRIM5α. We speculate that cyclophilin A alters HIV-1 sensitivity to a TRIM5α-independent innate immune pathway in human cells.

scholarly journals Cyclophilin A-Dependent Restriction of Human Immunodeficiency Virus Type 1 Capsid Mutants for Infection of Nondividing Cells

2008 ◽  
Vol 82 (24) ◽  
pp. 12001-12008 ◽  
Author(s):  
Mingli Qi ◽  
Ruifeng Yang ◽  
Christopher Aiken
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Hela Cells ◽  
Cyclophilin A ◽  
Cell Protein ◽  
Target Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Among retroviruses, lentiviruses are unusual in their ability to efficiently infect both dividing and nondividing cells, such as activated T cells and macrophages, respectively. Recent studies implicate the viral capsid protein (CA) as a key determinant of cell-cycle-independent infection by human immunodeficiency virus type 1 (HIV-1). We investigated the effects of the host cell protein cyclophilin A (CypA), which binds to HIV-1 CA, on HIV-1 infection of nondividing cells. The HIV-1 CA mutants A92E, T54A, and R132K were impaired for infection of aphidicolin-arrested HeLa cells, but not HOS cells. The mutants synthesized normal quantities of two-long-terminal-repeat circles in arrested HeLa cells, indicating that the mutant preintegration complexes can enter the nuclei of both dividing and nondividing cells. The impaired infectivity of the CA mutants on both dividing and nondividing HeLa cells was relieved by either pharmacological or genetic disruption of the CypA-CA interaction or by RNA interference-mediated depletion of CypA expression in target cells. A second-site suppressor of the CypA-restricted phenotype also restored the ability of CypA-restricted HIV-1 mutants to infect growth-arrested HeLa cells. These results indicate that CypA-restricted mutants are specifically impaired at a step between nuclear import and integration in nondividing HeLa cells. This study reveals a novel target cell-specific restriction of HIV-1 CA mutants in nondividing cells that is dependent on CypA-CA interactions.

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