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Journal of Virology, June 2004, p. 6005-6012, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.6005-6012.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Theodora Hatziioannou,1 Simone Cowan,1 Uta K. von Schwedler,2 Wesley I. Sundquist,2 and Paul D. Bieniasz1*

Aaron Diamond AIDS Research Center and the Rockefeller University, New York, New York 10016,1 Department of Biochemistry, University of Utah, Salt Lake City, Utah 841322

Received 14 November 2003/ Accepted 24 January 2004

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.

* Corresponding author. Mailing address: AIDS Research Center, 455 First Ave., New York, NY 10021. Phone: (212) 448-5070. Fax: (212) 725-1126. E-mail: pbienias{at}adarc.org.

Journal of Virology, June 2004, p. 6005-6012, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.6005-6012.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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