HIV REPLICATION IN CHRONICALLY INFECTED MACROPHAGES IS NOT INHIBITED BY THE TAT INHIBITORS RO-5-3335 AND RO-24-7429

Human immunodeficiency virus infects different cell types including CD4(+) lymphocytes and monocyte-derived macrophages (MDMs). We have examined the activity of the HIV-1 Tat inhibitors Re-5-3335 and Re-24-7429 in cultured human peripheral MDMs. Monocytes were isolated from HIV-seronegative donors by gradient centrifugation and plastic adherence. MDMs and unfractionated peripheral blood mononuclear cells (PBMCs) were infected with HIV Ba-L and then treated with drug either immediately (acute infection) or after 4 days (PBMCs) or 14 days (MDMs) (chronic infection). Inhibition of HIV replication by each drug was assessed by quantitation of HIV p24 antigen in culture supernatant using an enzyme immunoassay. In acutely infected MDMs, Re-5-3335 (10 mu M) and Re-24-7429 (10 mu M) resulted in 77% and 99% mean inhibition, respectively, of HIV replication with a clear dose response at lower concentrations; chronically infected MDMs were much less susceptible to these drugs, with both compounds inhibiting p24 antigen production by less than 50% at 10 mu M The drugs had no deleterious effect on cell viability at any concentration tested. In acutely infected PBMCs Re-5-3335 and Re-24-7429 resulted in 68% and 68.5% mean inhibition at 10 mu M; when the compounds were added 4 days after infection inhibition was less than 50% compared with controls. Thus, the Tat inhibitors were effective in inhibiting acute HIV infection in MDMs but not in chronically infected cells, findings that differ from those of published studies using continuous lymphoblastoid cell lines.