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.
Department of Microbiology Department, Columbia University, 701 W. 168th St., New York, NY 10032, USA.
Lionel
L
Berthoux
Sarah
S
Sebastian
Elena
E
Sokolskaja
Jeremy
J
Luban
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