Mechanisms Involved in Stimulation of Human Immunodeficiency Virus Type 1 Replication by Aminooxypentane RANTES

doi:10.1128/JVI.75.18.8624-8638.2001

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Journal of Virology, September 2001, p. 8624-8638, Vol. 75, No. 18
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.18.8624-8638.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Mechanisms Involved in Stimulation of Human Immunodeficiency Virus Type 1 Replication by Aminooxypentane RANTES

Andre J. Marozsan,¹^,² Vincent S. Torre,¹ Michael Johnson,¹ Sarah C. Ball,¹ Janet V. Cross,³ Dennis J. Templeton,³ Miguel E. Quiñones-Mateu,¹^, Robin E. Offord,⁴ and Eric J. Arts¹^,²^,^*

Division of Infectious Diseases, Department of Medicine,¹ Department of Pharmacology,² and Department of Pathology,³ Case Western Reserve University, Cleveland, Ohio 44106, and Department of Medical Biochemistry, University of Geneva, Geneva, Switzerland⁴

Received 12 April 2001/Accepted 19 June 2001

Aminooxypentane (AOP)-RANTES is a potent inhibitor of nonsyncytium-inducing (NSI), CCR5-tropic (R5) human immunodeficiencyvirus type 1 (HIV-1) isolates. Although classical chemotacticresponses are not induced in primary leukocytes by AOP-RANTES,recent studies suggest that a remnant of cell signaling occursupon binding of receptor to this compound. We have detected abreakthrough of NSI/R5 replication from the inhibitory effectsof high AOP-RANTES concentrations (<100 nM). A stimulation ofdifferent primary syncytium-inducing (SI), CXCR4-tropic (X4) HIV-1isolates was also observed in the presence of AOP-RANTES. Thisstimulation was also observed after 110 h in PCR and RT-PCR forminus-strand strong-stop DNA and unspliced and multiply splicedRNA, respectively. However, there was significant variabilitybetween different SI/X4 or NSI/R5 HIV-1 isolates with regard tothis AOP-RANTES-mediated stimulation or breakthrough, respectively.To further define the mechanism(s) responsible for this AOP-RANTESeffect, we performed detailed retroviral replication studies withan NSI/R5 (B-92BR021) and SI/X4 (D-92UG021) HIV-1 isolate in thepresence of the drug. Treatment of peripheral blood mononuclearcells with 125 nM AOP-RANTES and virus did not alter coreceptorexpression, HIV-1 entry, reverse transcription, or mRNA transcriptionfrom the long terminal repeat, but it did result in increasedHIV-1 integration. This AOP-RANTES-mediated increase in HIV-1integration was diminished by treatment with pertussis toxin.Phosphorylation of the mitogen-activated protein kinase (MAPK)isoforms, extracellular signal-regulated kinase 1 (ERK1) and ERK2,was increased in a CD4⁺ CCR5⁺ U87 cell line treated with AOP-RANTES or with an NSI/R5 HIV-1isolate. These findings suggest that AOP-RANTES may induce a MAPK/ERKsignal transduction pathway upon binding to a G-protein-coupledreceptor. MAPK/ERK1 and -2 appear to phosphorylate the HIV-1 preintegrationcomplex, a step necessary for nuclear translocation and successfulintegration.

^* Corresponding author. Mailing address: Division of Infectious Diseases, BRB 1029, Case Western Reserve University, 10900 EuclidAve., Cleveland, OH 44106. Phone: (216) 368-8904. Fax: (216) 368-2034.E-mail: eja3{at}po.cwru.edu.

Present address: Department of Virology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH44195.

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