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Mechanisms underlying activity of antiretroviral drugs in HIV‐1‐infected macrophages: new therapeutic strategies
Author(s) -
Aquaro Stefano,
Svicher Valentina,
Schols Dominique,
Pollicita Michela,
Antinori Andrea,
Balzarini Jan,
Perno Carlo Federico
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0606376
Subject(s) - biology , human immunodeficiency virus (hiv) , antiretroviral therapy , immunology , virology , macrophage , pharmacology , viral load , in vitro , biochemistry
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.