Mechanisms involved in stimulation of human immunodeficiency virus type 1 replication by aminooxypentane RANTES

Aminooxypentane (AOP)-RANTES is a potent inhibitor of nonsyncytium-inducing (NSI), CCR5-tropic (R5) human immunodeficiency virus type 1 (HIV-1) isolat es. Although classical chemotactic responses are not induced in primary leu kocytes by AOP-RANTES, recent studies suggest that a remnant of cell signal ing occurs upon binding of receptor to this compound. We have detected a br eakthrough of NSI/R5 replication from the inhibitory effects of high AOP-RA NTES concentrations (< 100 nM). A stimulation of different primary syncytiu m-inducing (SI), CXCR4-tropic (X4) HIV-1 isolates was also observed in the presence of AOP-RANTES. This stimulation was also observed after 110 h in P CR and RT-PCR for minus-strand strong-stop DNA and unspliced and multiply s pliced RNA, respectively. However, there was significant variability betwee n different SI/X4 or NSI/R5 HIV-1 isolates with regard to this AOP-RANTES-m ediated stimulation or breakthrough, respectively. To further define the me chanism(s) responsible for this AOP-RANTES effect, we performed detailed re troviral replication studies with an NSI/R5 (B-92BR021) and SI/X4 (D-92UG02 1) HIV-1 isolate in the presence of the drug. Treatment of peripheral blood mononuclear cells with 125 nM AOP-RANTES and virus did not alter corecepto r expression, HIV-1 entry, reverse transcription, or mRNA transcription fro m the long terminal repeat, but it did result in increased HIV-1 integratio n. This AOP-RANTES-mediated increase in HIV-1 integration was diminished by treatment with pertussis toxin. Phosphorylation of the mitogen-activated p rotein kinase (MAPK) isoforms, extracellular signal-regulated kinase 1 (ERK 1) and ERK2, was increased in a CD4(+) CCR5(+) U87 cell line treated with A OP-RANTES or with an NSI/R5 HIV-1 isolate. These findings suggest that AOP- RANTES may induce a MAPK/ERK signal transduction pathway upon binding to a G-protein-coupled receptor. MAPK/ERK1 and -2 appear to phosphorylate the HI V-1 preintegration complex, a step necessary for nuclear translocation and successful integration.