Lv1 inhibition of human immunodeficiency virus type 1 is counteracted by factors that stimulate synthesis or nuclear translocation of viral cDNA

L Berthoux, S Sebastian, E Sokolskaja… - Journal of virology, 2004 - Am Soc Microbiol
L Berthoux, S Sebastian, E Sokolskaja, J Luban
Journal of virology, 2004Am Soc Microbiol
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 …
Abstract
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.
American Society for Microbiology