Three-drug synergistic inhibition of HIV-1 replication in vitro by zidovudine, recombinant soluble CD4, and recombinant interferon-alpha A.
Optimal management of human immunodeficiency virus type 1 (HIV-1) infections may require combinations of agents that attack different targets in the viral replicative cycle. Zidovudine (AZT), recombinant soluble CD4 (rsCD4), and recombinant interferon-alpha A (rIFN-alpha A) were evaluated in 2- and 3-drug regimens against HIV-1 replication in vitro. Peripheral blood mononuclear cells and a CD4+ T cell line (H9) were studied using multiple HIV-1 replicative end points. Drug interactions were evaluated by the median-effect principle and the isobologram technique. AZT, rsCD4, and rIFN-alpha A inhibited HIV-1 synergistically in 2- and 3-drug combinations. The 3-drug regimen provided more complete virus suppression than the 2-drug regimens. In H9 cells, single-drug regimens lost effectiveness at 10-14 days and 2-drug regimens lost effectiveness at 14-18 days. In contrast, the 3-drug regimen showed nearly complete suppression over 28 days in culture without toxicity. Clinical trials of these 3 drugs in combination should be considered.
Johnson
V A
VA
Infectious Disease Unit, Massachusetts General Hospital, Boston, MA 02114.
Barlow
M A
MA
Merrill
D P
DP
Chou
T C
TC
Hirsch
M S
MS
D015704:CD4 Antigens / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000382:microbiology; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000382:microbiology; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology*
D015704:CD4 Antigens; D007370:Interferon Type I; D011994:Recombinant Proteins; D015215:Zidovudine