title: Mechanisms underlying activity of antiretroviral drugs in HIV-1-infected macrophages: new therapeutic strategies.
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.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Rome, Rome, Italy. aquaro@uniroma2.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Aquaro
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Michela
authors.initials: M
authors.lastname: Pollicita
authors.forename: Andrea
authors.initials: A
authors.lastname: Antinori
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000821:virology; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents