Premium
Inhibition of replication of HIV in primary monocyte/macrophages by different antiviral drugs and comparative efficacy in lymphocytes
Author(s) -
Aquaro Stefano,
Perno CarloFederico,
Balestra Emanuela,
Balzarini Jan,
Cenci Alessandra,
Francesconi Mauro,
Panti Stefania,
Serra Franca,
Villani Nicoletta,
Caliò Raffaele
Publication year - 1997
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 - 10.1002/jlb.62.1.138
Subject(s) - biology , nucleoside , reverse transcriptase , viral replication , monocyte , virus , virology , nucleoside reverse transcriptase inhibitor , interferon , microbiology and biotechnology , rna , biochemistry , immunology , viral load , gene , antiretroviral therapy
Several anti‐HIV drugs acting on different steps of virus replication were tested in our experimental model of primary monocyte/macrophages; the results were compared with the activity found in lymphocytes. Nucleoside analogues (AZT, ddl, ddC, d4T, PMEA, 3TC etc.) show greater activity in macrophages (M/M) than in lymphocytes. In particular, the EC50 of AZT, ddC, and ddI in M/M is 2‐ to 100‐fold lower than that found in lymphocytes. This greater efficacy of nucleoside analogues in M/M depends on the enhancement of their chain‐terminating activity by the low levels of endogenous deoxynucleoside‐triphosphates (dNTP) usually found in resting cells such as M/M. Non‐nucleoside reverse transcriptase inhibitors (NNRTI) do not act as chain terminators (thus their antiviral effect is not related to the intracellular concentrations of dNTP); as a consequence the activity of TSAO, HEPT, TIBO, and other NNRTI tested in M/M is similar to that found in lymphocytes. Regarding inhibitors of binding and fusion of HIV, we found that their anti‐HIV activity is markedly decreased (or even nullified) when M/M are treated with cytokine activators of M/M function and enhancers of HIV replication. More relevant from a clinical standpoint, protease inhibitors are able to inhibit HIV replication in chronically infected macrophages cells carrying the proviral genome already integrated in the host genome). All other inhibitors of late stage of virus life cycle tested (antisense‐rev, anti‐tat, interferon‐α and ‐γ, phosphorothioate analogues, GLQ‐223, etc.) were totally inactive in chronically infected macrophages. The different effects of various classes of HIV inhibitors in lymphocytes and macrophages suggests that AIDS therapy should consider all aspects of the pathogenesis of HIV infection and must be restricted to drugs, or combinations of drugs, active against both lymphocytes and M/M in all body compartments where the virus hides and replicates. J. Leukoc. Biol . 62: 138–143; 1997.