Macrophages (M/M) are identified as the second cellular target of HIV and a crucial virus reservoir. M/M are persistently infected cells and not susceptible to the HIV cytophatic effects typical of infected CD4+ T-lymphocytes. HIV replication in M/M is a crucial pathogenetic event during the whole course of the disease. Moreover, the dynamics of HIV-1 replication and cumulative virus production is quite different in M/M and CD4+ T-lymphocytes in the presence or in the absence of antiviral drugs. Thus, for their unique cellular characteristics, the activity of anti-HIV compounds could be different in M/M than in CD4+ T-lymphocytes. Indeed, nucleoside analogues inhibitors of HIV-reverse transcriptase (NRTIs) show potent antiviral activity in macrophages, although the limited penetration of these compounds in sequestered body compartments and the scarce phosphorylation ability of macrophages, suggest that a phosphate group linked to NRTIs may confer a greater anti-HIV activity in such cells. The antiviral activity of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in macrophages is similar to that found in CD4-lymphocytes. Interestingly, protease inhibitors (PIs), acting at post-integrational stages of virus replication, are the only drugs able to interfere with virus production and release from macrophages with established and persistent HIV infection. For these reasons, a careful analysis of the distribution of antiviral drugs, and the assessment of their activity in cells of macrophage lineage, represent key factors in the development of therapeutic strategies aimed to the treatment of the HIV-infected patients.
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