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Journal of Virology, September 2001, p. 8624-8638, Vol. 75, No. 18
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 immunodeficiency virus type 1 (HIV-1) isolates. Although classical chemotactic responses
are not induced in primary leukocytes by AOP-RANTES, recent studies
suggest that a remnant of cell signaling occurs upon binding of
receptor to this compound. We have detected a breakthrough of NSI/R5
replication from the inhibitory effects of high AOP-RANTES
concentrations (<100 nM). A stimulation of different primary
syncytium-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 PCR and RT-PCR for minus-strand
strong-stop DNA and unspliced and multiply spliced RNA, respectively.
However, there was significant variability between different SI/X4 or
NSI/R5 HIV-1 isolates with regard to this AOP-RANTES-mediated
stimulation or breakthrough, respectively. To further define the
mechanism(s) responsible for this AOP-RANTES effect, we performed
detailed retroviral replication studies with an NSI/R5 (B-92BR021) and
SI/X4 (D-92UG021) 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 coreceptor expression, HIV-1 entry, reverse
transcription, or mRNA transcription from the long terminal repeat, but
it did result in increased HIV-1 integration. This AOP-RANTES-mediated
increase in HIV-1 integration 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-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 HIV-1
preintegration complex, a step necessary for nuclear translocation and
successful integration.
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
*
Corresponding author. Mailing address: Division of
Infectious Diseases, BRB 1029, Case Western Reserve University, 10900 Euclid Ave., 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, OH 44195.
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.
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