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Journal of Virology, November 2004, p. 11739-11750, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11739-11750.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Lv1 Inhibition of Human Immunodeficiency Virus Type 1 Is Counteracted by Factors That Stimulate Synthesis or Nuclear Translocation of Viral cDNA

Lionel Berthoux,1 Sarah Sebastian,1 Elena Sokolskaja,1 and Jeremy Luban1,2*

Departments of Microbiology,1 Medicine, Columbia University, New York, New York2

Received 25 February 2004/ Accepted 16 July 2004

Human immunodeficiency virus type 1 (HIV-1) cDNA synthesis is inhibited in cells from some nonhuman primates by an activity called Lv1. Sensitivity to restriction by Lv1 maps to a region of the HIV-1 CA required for interaction with the cellular protein cyclophilin A. A similar antiviral activity in mammalian cells, Ref1, inhibits reverse transcription of murine leukemia virus (MLV), but only with viral strains bearing N-tropic CA. Disruption of the HIV-1 CA-cyclophilin A interaction inhibits Lv1 restriction in some cells and, paradoxically, seems to render HIV-1 sensitive to Ref1. Lv1 and Ref1 activities are overcome by high-titer infection and are saturable with nonreplicating, virus-like particles encoded by susceptible viruses. Two compounds that disrupt mitochondrial membrane potential, As2O3 and m-Cl-CCP, reduce Ref1 activity. Here we show that these drugs, as well as a third compound with similar effects on mitochondria, PK11195, attenuate Lv1 activity in rhesus macaque and African green monkey cells. Effects of PK11195 and virus-like particles on HIV-1 infectivity in these cells were largely redundant, each associated with increased HIV-1 cDNA. Comparison of acutely infected macaque and human cells suggested that, in addition to effects on cDNA synthesis, Lv1 inhibits the accumulation of nuclear forms of HIV-1 cDNA. Disruption of the HIV-1 CA-cyclophilin A interaction caused a minimal increase in total viral cDNA but increased the proportion of viral cDNA in the nucleus. Consistent with a model in which Lv1 inhibits both synthesis and nuclear translocation of HIV-1 cDNA, complete suppression of macaque or African green monkey Lv1 was achieved by the additive effect of factors that stimulate both processes.

* Corresponding author. Mailing address: Microbiology Department, Columbia University, 701 W. 168th St., New York, NY 10032. Phone: (212) 305-8710. Fax: (212) 305-0333. E-mail: jl45{at}columbia.edu.

Journal of Virology, November 2004, p. 11739-11750, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11739-11750.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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