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

2005 ◽  
Vol 79 (24) ◽  
pp. 15567-15572 ◽  
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.

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

2004 ◽  
Vol 78 (10) ◽  
pp. 5423-5437 ◽  
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).

scholarly journals Ubiquitination of the Human Immunodeficiency Virus Type 1 Env Glycoprotein

2000 ◽  
Vol 74 (11) ◽  
pp. 5373-5376 ◽  
Author(s):  
Andreas Bültmann ◽  
Josef Eberle ◽  
Jürgen Haas
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Ubiquitin Proteasome System ◽  
Immunodeficiency Virus ◽  
Ubiquitin Proteasome ◽  
Infected Cells ◽  
Hiv 1 ◽  
Env Glycoprotein

ABSTRACT Expression of the human immunodeficiency virus type 1 (HIV-1) Env glycoprotein is stringently regulated in infected cells. The majority of the glycoprotein does not reach the cell surface but rather is retained in the endoplasmic reticulum or a cis-Golgi compartment and subsequently degraded. We here report that Env of various HIV-1 isolates is ubiquitinated at the extracellular domain of gp41 and that Env expression could be increased by lactacystin, a specific proteasome inhibitor, suggesting that the ubiquitin/proteasome system is involved in control of expression and degradation.

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

2004 ◽  
Vol 78 (21) ◽  
pp. 11816-11822 ◽  
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.

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

2004 ◽  
Vol 78 (11) ◽  
pp. 6005-6012 ◽  
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.

scholarly journals Heat Shock Perturbs TRIM5α Restriction of Human Immunodeficiency Virus Type 1

2007 ◽  
Vol 82 (5) ◽  
pp. 2575-2579 ◽  
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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