scholarly journals Modulation of HIV-1 infectivity and cyclophilin A-dependence by Gag sequence and target cell type

Retrovirology ◽  
2009 ◽  
Vol 6 (1) ◽  
pp. 21 ◽  
Author(s):  
Saori Matsuoka ◽  
Elisabeth Dam ◽  
Denise Lecossier ◽  
François Clavel ◽  
Allan J Hance
Keyword(s):  
Target Cell ◽  
Cyclophilin A ◽  
Cell Type ◽  
Hiv 1

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 Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Melissa Kane ◽  
Stephanie V Rebensburg ◽  
Matthew A Takata ◽  
Trinity M Zang ◽  
Masahiro Yamashita ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nuclear Dna ◽  
Cyclophilin A ◽  
Nuclear Pore ◽  
Dependent Manner ◽  
Cell Type ◽  
Antiviral Protein ◽  
Interphase Cells ◽  
A Cell ◽  
Hiv 1

HIV-1 accesses the nuclear DNA of interphase cells via a poorly defined process involving functional interactions between the capsid protein (CA) and nucleoporins (Nups). Here, we show that HIV-1 CA can bind multiple Nups, and that both natural and manipulated variation in Nup levels impacts HIV-1 infection in a manner that is strikingly dependent on cell-type, cell-cycle, and cyclophilin A (CypA). We also show that Nups mediate the function of the antiviral protein MX2, and that MX2 can variably inhibit non-viral NLS function. Remarkably, both enhancing and inhibiting effects of cyclophilin A and MX2 on various HIV-1 CA mutants could be induced or abolished by manipulating levels of the Nup93 subcomplex, the Nup62 subcomplex, NUP88, NUP214, RANBP2, or NUP153. Our findings suggest that several Nup-dependent ‘pathways’ are variably exploited by HIV-1 to target host DNA in a cell-type, cell-cycle, CypA and CA-sequence dependent manner, and are differentially inhibited by MX2.

scholarly journals Effect of induced dNTP pool imbalance on HIV-1 reverse transcription in macrophages

Retrovirology ◽  
2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Caitlin Shepard ◽  
Joella Xu ◽  
Jessica Holler ◽  
Dong-Hyun Kim ◽  
Louis M. Mansky ◽  
...  
Keyword(s):  
Target Cell ◽  
Copy Number ◽  
Transduction Efficiency ◽  
Cell Type ◽  
Single Cycle ◽  
Dntp Pool ◽  
Sam Domain ◽  
Primary Monocyte ◽  
Viral Mutant ◽  
Hiv 1

Abstract Background Terminally differentiated/nondividing macrophages, a key target cell type of HIV-1, harbor extremely low dNTP concentrations established by a host dNTP triphosphohydrolase, SAM domain and HD domain containing protein 1 (SAMHD1). We tested whether the induction of dNTP pool imbalance can affect HIV-1 replication in macrophages. For this test, we induced a large dNTP pool imbalance by treating human primary monocyte derived macrophages with either one or three of the four deoxynucleosides (dNs), which are phosphorylated to dNTPs in cells, to establish two different dNTP imbalance conditions in macrophages. Results The transduction efficiency and 2-LTR circle copy number of HIV-1 GFP vector were greatly diminished in human primary macrophages treated with the biased dN treatments, compared to the untreated macrophages. We also observed the induced dNTP bias blocked the production of infectious dual tropic HIV-1 89.6 in macrophages. Moreover, biochemical DNA synthesis by HIV-1 reverse transcriptase was significantly inhibited by the induced dNTP pool imbalance. Third, the induced dNTP bias increased the viral mutant rate by approximately 20–30% per a single cycle infection. Finally, unlike HIV-1, the single dN treatment did not significantly affect the transduction of SIVmac239-based GFP vector encoding Vpx in macrophages. This is likely due to Vpx, which can elevate all four dNTP levels even with the single dN treatment. Conclusion Collectively, these data suggest that the elevated dNTP pool imbalance can induce kinetic block and mutation synthesis of HIV-1 in macrophages.

scholarly journals Target Cell Cyclophilin A Modulates Human Immunodeficiency Virus Type 1 Infectivity

2004 ◽  
Vol 78 (23) ◽  
pp. 12800-12808 ◽  
Author(s):  
Elena Sokolskaja ◽  
David M. Sayah ◽  
Jeremy Luban
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Target Cell ◽  
Cyclophilin A ◽  
Immunodeficiency Virus ◽  
Producer Cell ◽  
Hiv 1

ABSTRACT The peptidyl-prolyl isomerase cyclophilin A (CypA) increases the kinetics by which human immunodeficiency virus type 1 (HIV-1) spreads in tissue culture. This was conclusively demonstrated by gene targeting in human CD4+ T cells, but the role of CypA in HIV-1 replication remains unknown. Though CypA binds to mature HIV-1 capsid protein (CA), it is also incorporated into nascent HIV-1 virions via interaction with the CA domain of the Gag polyprotein. These findings raised the possibility that CypA might act at multiple steps of the retroviral life cycle. Disruption of the CA-CypA interaction, either by the competitive inhibitor cyclosporine (CsA) or by mutation of CA residue G89 or P90, suggested that producer cell CypA was required for full virion infectivity. However, recent studies indicate that CypA within the target cell regulates HIV-1 infectivity by modulating Ref1- or Lv1-mediated restriction. To examine the relative contribution to HIV-1 replication of producer cell CypA and target cell CypA, we exploited multiple tools that disrupt the HIV-1 CA-CypA interaction. These tools included the drugs CsA, MeIle4-CsA, and Sanglifehrin; CA mutants exhibiting decreased affinity for CypA or altered CypA dependence; HeLa cells with CypA knockdown by RNA interference; and Jurkat T cells homozygous for a deletion of the gene encoding CypA. Our results clearly demonstrate that target cell CypA, and not producer cell CypA, is important for HIV-1 CA-mediated function. Inhibition of HIV-1 infectivity resulting from virion production in the presence of CsA occurs independently of the CA-CypA interaction or even of CypA.

scholarly journals Target Cell Type-Dependent Modulation of Human Immunodeficiency Virus Type 1 Capsid Disassembly by Cyclophilin A

2009 ◽  
Vol 83 (21) ◽  
pp. 10951-10962 ◽  
Author(s):  
Yuan Li ◽  
Alak Kanti Kar ◽  
Joseph Sodroski
Keyword(s):  
Human Immunodeficiency Virus ◽  
Target Cell ◽  
Cyclophilin A ◽  
Target Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Capsid Disassembly ◽  
Ca Protein

ABSTRACT The binding of cyclophilin A (CypA) to the human immunodeficiency virus type 1 (HIV-1) capsid protein (CA protein) is required soon after virus entry into natural target cells. In Jurkat T lymphocytes, disrupting CypA-CA interaction either by cyclosporine (Cs) treatment or by alteration (e.g., P90A) of the CA inhibits HIV-1 infection. In HeLa cells, however, treatment with Cs or Cs analogues minimally inhibits the early phase of HIV-1 infection but selects for a Cs-dependent virus with a change (A92E) in CA. To understand these phenomena, we examined the effects of the P90A and A92E changes in the HIV-1 CA protein on the stability of capsid complexes assembled in vitro and on capsid disassembly in the cytosol of virus-exposed target cells. The A92E change impaired CA-CA interactions in vitro and decreased the amount of particulate capsids in the cytosol of HeLa target cells. Reducing the binding of CypA to the A92E mutant capsid, either by Cs treatment or by an additional P90A change in the CA protein, increased the amount of particulate capsids and viral infectivity in HeLa cells. In contrast, reduction of the binding of CypA to HIV-1 capsids in Jurkat T lymphocytes resulted in a decrease in the amount of particulate capsids and infectivity. Thus, depending on the capsid and the target cell, CypA-CA binding either stabilized or destabilized the capsid, indicating that CypA modulates HIV-1 capsid disassembly. In both cell types examined, decreased stability of the capsid was associated with a decrease in the efficiency of HIV-1 infection.

scholarly journals Novel Cell type-specific aptamer-siRNA delivery system for HIV-1 therapy

2007 ◽  
Author(s):  
Jiehua Zhou ◽  
Haitang Li ◽  
Shirley Li ◽  
John Zaia ◽  
John Rossi
Keyword(s):  
Delivery System ◽  
Sirna Delivery ◽  
Cell Type ◽  
Cell Type Specific ◽  
Hiv 1 ◽  
Sirna Delivery System

scholarly journals Retinal cell type expression specificity of HIV-1-derived gene transfer vectors upon subretinal injection in the adult rat: influence of pseudotyping and promoter

2005 ◽  
Vol 7 (10) ◽  
pp. 1367-1374 ◽  
Author(s):  
Alexis-Pierre Bemelmans ◽  
Sébastien Bonnel ◽  
Leïla Houhou ◽  
Noëlle Dufour ◽  
Emeline Nandrot ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Retinal Cell ◽  
Cell Type ◽  
Adult Rat ◽  
Transfer Vectors ◽  
Hiv 1 ◽  
Subretinal Injection

scholarly journals The Cysteine Residues of HIV-1 Capsid Regulate Oligomerization and Cyclophilin A-Induced Changes

2005 ◽  
Vol 88 (3) ◽  
pp. 2078-2088 ◽  
Author(s):  
Marjorie Bon Homme ◽  
Carol Carter ◽  
Suzanne Scarlata
Keyword(s):  
Cyclophilin A ◽  
Cysteine Residues ◽  
Induced Changes ◽  
Hiv 1

scholarly journals Functional Mapping of Regions Involved in the Negative Imprinting of Virion Particle Infectivity and in Target Cell Protection by Interferon-Induced Transmembrane Protein 3 against HIV-1

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Romain Appourchaux ◽  
Mathilde Delpeuch ◽  
Li Zhong ◽  
Julien Burlaud-Gaillard ◽  
Kevin Tartour ◽  
...  
Keyword(s):  
Target Cell ◽  
Transmembrane Protein ◽  
Regulatory Role ◽  
Target Cells ◽  
Restriction Factors ◽  
Cell Protection ◽  
Differential Behavior ◽  
Antiviral Activities ◽  
Divergent Behavior ◽  
Hiv 1

ABSTRACT The interferon-induced transmembrane proteins (IFITMs) are a family of highly related antiviral factors that affect numerous viruses at two steps: in target cells by sequestering incoming viruses in endosomes and in producing cells by leading to the production of virions that package IFITMs and exhibit decreased infectivity. While most studies have focused on the former, little is known about the regulation of the negative imprinting of virion particle infectivity by IFITMs and about its relationship with target cell protection. Using a panel of IFITM3 mutants against HIV-1, we have explored these issues as well as others related to the biology of IFITM3, in particular virion packaging, stability, the relation to CD63/multivesicular bodies (MVBs), the modulation of cholesterol levels, and the relationship between negative imprinting of virions and target cell protection. The results that we have obtained exclude a role for cholesterol and indicate that CD63 accumulation does not directly relate to an antiviral behavior. We have defined regions that modulate the two antiviral properties of IFITM3 as well as novel domains that modulate protein stability and that, in so doing, influence the extent of its packaging into virions. The results that we have obtained, however, indicate that, even in the context of an IFITM-susceptible virus, IFITM3 packaging is not sufficient for negative imprinting. Finally, while most mutations concomitantly affect target cell protection and negative imprinting, a region in the C-terminal domain (CTD) exhibits a differential behavior, potentially highlighting the regulatory role that this domain may play in the two antiviral activities of IFITM3. IMPORTANCE IFITM proteins have been associated with the sequestration of incoming virions in endosomes (target cell protection) and with the production of virion particles that incorporate IFITMs and exhibit decreased infectivity (negative imprinting of virion infectivity). How the latter is regulated and whether these two antiviral properties are related remain unknown. By examining the behavior of a large panel of IFITM3 mutants against HIV-1, we determined that IFITM3 mutants are essentially packaged into virions proportionally to their intracellular levels of expression. However, even in the context of an IFITM-susceptible virus, IFITM3 packaging is not sufficient for the antiviral effects. Most mutations were found to concomitantly affect both antiviral properties of IFITM3, but one CTD mutant exhibited a divergent behavior, possibly highlighting a novel regulatory role for this domain. These findings thus advance our comprehension of how this class of broad antiviral restriction factors acts.

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