Failure of dideoxynucleosides to inhibit human immunodeficiency virus replication in cultured human macrophages.
Primary human monocyte-derived macrophages (MDM) were shown to have diminished deoxynucleoside kinase activities compared to T lymphoblasts, and a reduced ability to phosphorylate dideoxynucleosides with anti-human immunodeficiency virus (HIV) activity. These drugs, azidothymidine (AZT), dideoxycytidine (ddC), and dideoxyadenosine (ddA), which are potent anti-HIV agents in CD4 lymphocytes, did not inhibit HIV replication in MDM, even at concentrations of 100 microM. This drug concentration of AZT is approximately 100-fold higher than the levels attained in the serum of treated patients and the levels required to inhibit HIV replication in lymphocytes. These observations may explain the failure of AZT therapy to clear viremia, consistent with the presence of a drug-resistant reservoir of infected cells in vivo. New therapeutic approaches to inhibit the replication of HIV in MDM may be needed.
Richman
D D
DD
Department of Pathology, University of California, San Diego 92161.
Kornbluth
R S
RS
Carson
D A
DA
D000248:Adenosine Kinase / Q000378:metabolism; D002460:Cell Line; D003839:Deoxyadenosines / Q000031:analogs & derivatives* / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000378:metabolism; D016048:Dideoxyadenosine; D006678:HIV / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000382:microbiology*; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000187:drug effects / Q000382:microbiology; D013936:Thymidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013937:Thymidine Kinase / Q000378:metabolism; D014541:Uridine Kinase / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D016047:Zalcitabine; D015215:Zidovudine
D003839:Deoxyadenosines; D003841:Deoxycytidine; D015215:Zidovudine; D016048:Dideoxyadenosine; D016047:Zalcitabine; D000248:Adenosine Kinase; D013937:Thymidine Kinase; D014541:Uridine Kinase; D003842:Deoxycytidine Kinase; D013936:Thymidine