Anti-human immunodeficiency virus type 1 activity of an anti-CD4 immunoconjugate containing pokeweed antiviral protein

The ability of an αCD4-pokeweed antiviral protein (PAP) immunoconjugate to inhibit replication of human immunodeficiency virus type 1 (HIV-1) was evaluated in vitro with 22 clinical HIV-1 strains obtained from four seropositive asymptomatic individuals, three patients with AIDS-related complex, and four patients with AIDS. Fifteen isolates were from zidovudine- untreated individuals, whereas seven isolates were obtained after 24 to 104 weeks of therapy with zidovudine, alone or alternating with zalcitabine. Mean zidovudine 50% inhibitory concentrations (IC₅₀s) were 126 nM (range, 1 to 607 nM) for isolates from zidovudine-untreated individuals and 2,498 nM (range, 14 to 6,497 nM) for strains from patients treated with antiretroviral agents. Mean αCD4-PAP IC₅₀s were 48 x 10^-3 nM (range, 0.02 x 10^-3 to 212 x 10^-3 nM) for isolates from zidovudine-untreated individuals, and 16 x 10^-3 nM (range, 2 x 10^-3 to 28 x 10^-3 nM) for isolates from treated patients. Overall, higher concentrations of αCD4-PAP were necessary to inhibit HIV-1 strains from untreated individuals at more advanced stages of disease. Seventeen isolates were susceptible to zidovudine (mean IC₅₀, 117 nM), and five were resistant to zidovudine (mean IC₅₀, 3,724 nM). Mean αCD4-PAP IC₅₀s were 43 x 10^-3 nM for zidovudine-susceptible isolates and 19 x 10^-3 nM for isolates resistant to zidovudine. All HIV-1 strains had IC₅₀s greater than 0.5 nM for unconjugated PAP, the αCD19-PAP immunoconjugate, and monoclonal antibody αCD4. At concentrations as high as 5,000 nM, αCD4-PAP did not inhibit colony formation by normal bone marrow progenitor cells (BFU-E, CFU-GM, and CFU-GEMM) or myeloid cell lines (KG-1 and HL-60) and did not decrease cell viabilities of T-cell (Jurkat) or B- cell (FL-112 and Raji) precursor lines. Overall, αCD4-PAP demonstrated more potent anti-HIV-1 activity than zidovudine and inhibited replication of zidovudine-susceptible and zidovudine-resistant viruses at concentrations that were not toxic to lymphohematopoietic cell populations.