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Published online before print August 24, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0606376

Received for publication June 7, 2006.
Revised July 21, 2006.
Accepted for publication July 26, 2006.

Article

Mechanisms underlying activity of antiretroviral drugs in HIV-1-infected macrophages: new therapeutic strategies

Stefano Aquaro ^*@, Valentina Svicher ^*, Dominique Schols , Michela Pollicita ^*, Andrea Antinori , Jan Balzarini , and Carlo Federico Perno ^*

*Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," Italy; Department of Pharmaco-Biology, University of Calabria, Rende (CS), Italy; Rega Institute for Medical Research, Catholic University of Leuven, Belgium; and National Institute for Infectious Diseases "L. Spallanzani," Rome, Italy

^@ To whom correspondence should be addressed. E-mail: aquaro{at}uniroma2.it.

	Abstract

Monocyte-derived macrophages (M/M) are considered the second cellular target of HIV-1 and a crucial virus reservoir. M/M are widely distributed in all tissues and organs, including the CNS, where they represent the most common HIV-infected cells. Differently from activated CD4+ T lymphocytes, M/M are resistant to the cytopathic effect of HIV and survive HIV infection for a long time. Moreover, HIV-1 replication in M/M is a key pathogenetic event during the course of HIV-1 infection. Overall findings strongly support the clinical relevance of anti-HIV drugs in M/M. Nucleoside RT inhibitors (NRTIs) are more active against HIV in M/M than in CD4+ T lymphocytes. Their activity is further boosted by the presence of an additional monophosphate group (i.e., a phosphonate group, as in the case of Tenofovir), thus overcoming the bottleneck of the low phosphorylation ability of M/M. In contrast, the antiviral activity of non-NRTIs (not affecting the DNA chain elongation) in M/M is similar to that in CD4+ T lymphocytes. Protease inhibitors are the only clinically approved drugs acting at a late stage of the HIV lifecycle. They are able to interfere with HIV replication in HIV-1 chronically infected M/M, even if at concentrations greater than those observed in HIV-1 chronically infected CD4+ T lymphocytes. Finally, several new drugs have been shown to interfere efficiently with HIV replication in M/M, including entry inhibitors. A better understanding of the activity of the anti-HIV drugs in M/M may represent a key element for the design of effective anti-HIV chemotherapy.

Key Words: anti-HIV drugs • protease • reverse transcriptase • gp41 • CCR5 coreceptor

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