Influence of gag on Human Immunodeficiency Virus Type 1 Species-Specific Tropism

ABSTRACT The narrow host range of human immunodeficiency virus type 1 (HIV-1) is due in part to dominant acting restriction factors in humans (Ref1) and monkeys (Lv1). Here we show that gag encodes determinants of species-specific lentiviral infection, related in part to such restriction factors. Interaction between capsid and host cyclophilin A (CypA) protects HIV-1 from restriction in human cells but is essential for maximal restriction in simian cells. We show that sequence variation between HIV-1 isolates leads to variation in sensitivity to restriction factors in human and simian cells. We present further evidence for the importance of target cell CypA over CypA packaged in virions, specifically in the context of gp160 pseudotyped HIV-1 vectors. We also show that sensitivity to restriction is controlled by an H87Q mutation in the capsid, implicated in the immune control of HIV-1, possibly linking immune and innate control of HIV-1 infection.

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Binding and Susceptibility to Postentry Restriction Factors in Monkey Cells Are Specified by Distinct Regions of the Human Immunodeficiency Virus Type 1 Capsid

Journal of Virology ◽

10.1128/jvi.78.10.5423-5437.2004 ◽

2004 ◽

Vol 78 (10) ◽

pp. 5423-5437 ◽

Cited By ~ 96

Author(s):

Christopher M. Owens ◽

Byeongwoon Song ◽

Michel J. Perron ◽

Peter C. Yang ◽

Matthew Stremlau ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Cyclophilin A ◽

New World Monkeys ◽

Restriction Factors ◽

Factor Binding ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT In cells of Old World and some New World monkeys, dominant factors restrict human immunodeficiency virus type 1 (HIV-1) infections after virus entry. The simian immunodeficiency virus SIVmac is less susceptible to these restrictions, a property that is determined largely by the viral capsid protein. For this study, we altered exposed amino acid residues on the surface of the HIV-1 capsid, changing them to the corresponding residues found on the SIVmac capsid. We identified two distinct pathways of escape from early, postentry restriction in monkey cells. One set of mutants that were altered near the base of the cyclophilin A-binding loop of the N-terminal capsid domain or in the interdomain linker exhibited a decreased ability to bind the restricting factor(s). Consistent with the location of this putative factor-binding site, cyclophilin A and the restricting factor(s) cooperated to achieve the postentry block. A second set of mutants that were altered in the ridge formed by helices 3 and 6 of the N-terminal capsid domain efficiently bound the restricting factor(s) but were resistant to the consequences of factor binding. These results imply that binding of the simian restricting factor(s) is not sufficient to mediate the postentry block to HIV-1 and that SIVmac capsids escape the block by decreases in both factor binding and susceptibility to the effects of the factor(s).

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Human immunodeficiency virus type 1 Vif supports efficient primate lentivirus replication in rhesus monkey cells

Journal of General Virology ◽

10.1099/vir.0.19449-0 ◽

2003 ◽

Vol 84 (12) ◽

pp. 3227-3231 ◽

Cited By ~ 2

Author(s):

Sujata Kar ◽

Phoebe Cummings ◽

Louis Alexander

Keyword(s):

Human Immunodeficiency Virus ◽

Rhesus Monkey ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Rhesus Monkeys ◽

Specific Activity ◽

Immunodeficiency Virus ◽

Species Specific ◽

Hiv 1

Human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) Vif share limited homology and display species-specific activity, leading to speculation that Vif sequences could determine the block in HIV-1 replication in rhesus monkeys. To address this issue, we engineered a novel SIV recombinant in which HIV-1 vif replaced SIV vif in a SIVmac239 background. Insertion of HIV-1 vif into the SIV vif locus did not produce a replication-competent virus. Therefore, we inserted HIV-1 vif sequences into the SIV nef locus, which produced a recombinant that, in the absence of SIV vif sequences, replicated similarly to wild-type SIVmac239 in rhesus monkey PBMC. From these studies we conclude that the HIV-1 replication block in rhesus monkeys is almost certainly not Vif determined. These studies also suggest that SHIV/NVif or derivative sequences could be utilized for structure/function studies of HIV-1 Vif in experimentally infected rhesus monkeys.

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Species-Specific Tropism Determinants in the Human Immunodeficiency Virus Type 1 Capsid

Journal of Virology ◽

10.1128/jvi.78.11.6005-6012.2004 ◽

2004 ◽

Vol 78 (11) ◽

pp. 6005-6012 ◽

Cited By ~ 98

Author(s):

Theodora Hatziioannou ◽

Simone Cowan ◽

Uta K. von Schwedler ◽

Wesley I. Sundquist ◽

Paul D. Bieniasz

Keyword(s):

Human Immunodeficiency Virus ◽

Binding Site ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Restriction Factors ◽

Immunodeficiency Virus ◽

Variable Loops ◽

Hiv 1 ◽

Cypa Binding

ABSTRACT Retroviral tropism is determined in part by cellular restriction factors that block infection by targeting the incoming viral capsid. Indeed, human immunodeficiency virus type 1 (HIV-1) infection of many nonhuman primate cells is inhibited by one such factor, termed Lv1. In contrast, a restriction factor in humans, termed Ref1, does not inhibit HIV-1 infection unless nonnatural mutations are introduced into the HIV-1 capsid protein (CA). Here, we examined the infectivity of a panel of mutant HIV-1 strains carrying substitutions in the N-terminal CA domain in cells that exhibit restriction attributable to Lv1 or Ref1. Manipulation of HIV-1 CA could alter HIV-1 tropism, and several mutations were identified that increased or decreased HIV-1 infectivity in a target-cell-specific manner. Many residues that affected HIV-1 tropism were located in the three variable loops that lie on the outer surface of the modeled HIV-1 conical capsid. Some tropism determinants, including the CypA binding site, coincided with residues whose mutation conferred on HIV-1 CA the ability to saturate Ref1 in human cells. Notably, a mutation that reverses the infectivity defect in human cells induced by CypA binding site mutation inhibits recognition by Ref1. Overall, these findings demonstrate that exposed variable loops in CA and a partial CypA “coat” can modulate restriction and HIV-1 tropism and suggest a model in which the exposed surface of the incoming retroviral capsid is the target for inhibition by host cell-specific restriction factors.

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Heat Shock Perturbs TRIM5α Restriction of Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.00962-07 ◽

2007 ◽

Vol 82 (5) ◽

pp. 2575-2579 ◽

Cited By ~ 1

Author(s):

Jenny L. Anderson ◽

Edward M. Campbell ◽

Anna Figueiredo ◽

Thomas J. Hope

Keyword(s):

Human Immunodeficiency Virus ◽

Heat Shock ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Proteasome Inhibitors ◽

Target Cells ◽

Restriction Factors ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT TRIM5α restriction factors protect target cells from retroviruses by blocking infection prior to the accumulation of viral reverse transcription (RT) products. Here, we demonstrate that heat shock perturbed owl monkey TRIMCyp and rhesus TRIM5α-mediated restriction of human immunodeficiency virus type 1 (HIV-1) late RT products and 2-long terminal repeat circles. Heat shock partially rescued HIV-1 infection from TRIMCyp restriction, and this rescue became more profound when combined with the presence of the proteasome inhibitor MG132. This indicates that viral RT products rescued from restriction by either heat shock treatment or the presence of MG132 are on a productive pathway, supporting a model in which TRIM5α proteins restrict retroviruses in multiple phases that are differentially sensitive to heat shock and proteasome inhibitors.

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