Lv1 inhibition of human immunodeficiency virus type 1 is counteracted by factors that stimulate synthesis or nuclear translocation of viral cDNA.
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, As(2)O(3) 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.
Berthoux
Lionel
L
Department of Microbiology Department, Columbia University, 701 W. 168th St., New York, NY 10032, USA.
Sebastian
Sarah
S
Sokolskaja
Elena
E
Luban
Jeremy
J
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002522:Chlorocebus aethiops; D021984:Cyclophilin A / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism*; D004279:DNA, Viral / Q000378:metabolism*; D015683:Gene Products, gag / Q000502:physiology; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008253:Macaca mulatta; D008928:Mitochondria / Q000187:drug effects; D014771:Virion / Q000502:physiology; D014779:Virus Replication
D018076:DNA, Complementary; D004279:DNA, Viral; D015683:Gene Products, gag; D007546:Isoquinolines; D016572:Cyclosporine; D021984:Cyclophilin A; C037850:PK 11195