Macaque-tropic human immunodeficiency virus type 1: breaking out of the host restriction factors

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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Structural Requirements for Recognition of the Human Immunodeficiency Virus Type 1 Core during Host Restriction in Owl Monkey Cells

Journal of Virology ◽

10.1128/jvi.79.2.869-875.2005 ◽

2005 ◽

Vol 79 (2) ◽

pp. 869-875 ◽

Cited By ~ 63

Author(s):

Brett M. Forshey ◽

Jiong Shi ◽

Christopher Aiken

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Target Cells ◽

Host Restriction ◽

Amino Terminal ◽

Immunodeficiency Virus ◽

Owl Monkey ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection of simian cells is restricted at an early postentry step by host factors whose mechanism of action is unclear. These factors target the viral capsid protein (CA) and attenuate reverse transcription, suggesting that they bind to the HIV-1 core and interfere with its uncoating. To identify the relevant binding determinants in the capsid, we tested the capacity of viruses containing Gag cleavage site mutations and amino acid substitutions in CA to inhibit restriction of a wild type HIV-1 reporter virus in owl monkey cells. The results demonstrated that a stable, polymeric capsid and a correctly folded amino-terminal CA subunit interface are essential for saturation of host restriction in target cells by HIV-1 cores. We conclude that the owl monkey cellular restriction machinery recognizes a polymeric array of CA molecules, most likely via direct engagement of the HIV-1 capsid in target cells prior to uncoating.

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

Journal of Virology ◽

10.1128/jvi.78.21.11816-11822.2004 ◽

2004 ◽

Vol 78 (21) ◽

pp. 11816-11822 ◽

Cited By ~ 69

Author(s):

Yasuhiro Ikeda ◽

Laura M. J. Ylinen ◽

Maria Kahar-Bador ◽

Greg J. Towers

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Restriction Factors ◽

Narrow Host Range ◽

Immunodeficiency Virus ◽

Lentiviral Infection ◽

Species Specific ◽

Hiv 1

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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Restriction of Human Immunodeficiency Virus Type 1 by TRIM-CypA Occurs with Rapid Kinetics and Independently of Cytoplasmic Bodies, Ubiquitin, and Proteasome Activity

Journal of Virology ◽

10.1128/jvi.79.24.15567-15572.2005 ◽

2005 ◽

Vol 79 (24) ◽

pp. 15567-15572 ◽

Cited By ~ 118

Author(s):

David Perez-Caballero ◽

Theodora Hatziioannou ◽

Fengwen Zhang ◽

Simone Cowan ◽

Paul D. Bieniasz

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Ubiquitin Proteasome System ◽

Restriction Factors ◽

Cytoplasmic Bodies ◽

Immunodeficiency Virus ◽

Modular Domain ◽

Rapid Kinetics

ABSTRACT TRIM-CypA is an owl monkey-specific variant of the retrovirus restriction factor TRIM5α. Here, we exploit its modular domain organization and cyclosporine sensitivity to probe the kinetics and mechanism of TRIM5-mediated restriction. Time of addition/withdrawal experiments reveal that inhibition of incoming human immunodeficiency virus type 1 capsids by TRIM-CypA occurs within minutes of their delivery to the target cell cytoplasm. However, while TRIM-CypA restriction is partly dependent on a RING domain, restriction occurs independently of the ubiquitin/proteasome system. Moreover, tagged TRIM-CypA proteins can be fully active as restriction factors without forming cytoplasmic bodies.

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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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Distinct Domains within APOBEC3G and APOBEC3F Interact with Separate Regions of Human Immunodeficiency Virus Type 1 Vif

Journal of Virology ◽

10.1128/jvi.01621-08 ◽

2008 ◽

Vol 83 (4) ◽

pp. 1992-2003 ◽

Cited By ~ 80

Author(s):

Rebecca A. Russell ◽

Jessica Smith ◽

Rebekah Barr ◽

Darshana Bhattacharyya ◽

Vinay K. Pathak

Keyword(s):

Amino Acids ◽

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Defense Mechanism ◽

Antiviral Drug ◽

Host Restriction ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human APOBEC3G (A3G) and APOBEC3F (A3F) inhibit the replication of Vif-deficient human immunodeficiency virus type 1 (HIV-1). HIV-1 Vif overcomes these host restriction factors by binding to them and inducing their degradation. Thus, the Vif-A3G and Vif-A3F interactions are attractive targets for antiviral drug development, as inhibiting these interactions could allow the host defense mechanism to control HIV-1 replication. Recently, it has been reported that amino acids 105 to 156 of A3G are involved in the interaction with Vif; however, to date, the region of A3F involved in Vif binding has not been identified. Using our previously reported Vif mutants that are capable of binding to only A3G (3G binder) or only A3F (3F binder), in conjunction with a series of A3G-A3F chimeras, we have now mapped the APOBEC3-Vif interaction domains. We found that the A3G domain that interacts with the Vif YRHHY region is located between amino acids 126 and 132 of A3G, which is consistent with the conclusions reported in previous studies. The A3F domain that interacts with the Vif DRMR region did not occur in the homologous domain but instead was located between amino acids 283 and 300 of A3F. These studies are the first to identify the A3F domain that interacts with the Vif DRMR region and show that distinct domains of A3G and A3F interact with different Vif regions. Pharmacological inhibition of either or both of these Vif-A3 interactions should prevent the degradation of the APOBEC3 proteins and could be used as a therapy against HIV-1.

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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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