Erice A, Balfour H H, Myers D E, Leske V L, Sannerud K J, Kuebelbeck V, Irvin J D, Uckun F M
Department of Laboratory Medicine, University of Minnesota Health Sciences Center, Minneapolis 55455, USA.
Antimicrob Agents Chemother. 1993 Apr;37(4):835-8. doi: 10.1128/AAC.37.4.835.
The ability of an alpha CD4-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 alpha CD4-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 alpha CD4-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 alpha CD4-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 alpha CD19-PAP immunoconjugate, and monoclonal antibody alpha CD4. At concentrations as high as 5,000 nM, alphaCD4-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, alphaCD4-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.
用从4名血清反应阳性无症状个体、3名艾滋病相关综合征患者和4名艾滋病患者身上获取的22株临床HIV-1毒株，在体外评估了α-CD4-商陆抗病毒蛋白（PAP）免疫缀合物抑制1型人类免疫缺陷病毒（HIV-1）复制的能力。15株分离株来自未接受齐多夫定治疗的个体，而7株分离株是在单独使用齐多夫定或与扎西他滨交替使用24至104周治疗后获得的。未接受齐多夫定治疗个体的分离株的平均齐多夫定50%抑制浓度（IC50）为126 nM（范围为1至607 nM），接受抗逆转录病毒药物治疗患者的毒株的平均齐多夫定50%抑制浓度（IC50）为2498 nM（范围为14至6497 nM）。未接受齐多夫定治疗个体的分离株的平均α-CD4-PAP IC50为48×10⁻³ nM（范围为0.02×10⁻³至212×10⁻³ nM），接受治疗患者的分离株的平均α-CD4-PAP IC50为16×10⁻³ nM（范围为2×10⁻³至28×10⁻³ nM）。总体而言，需要更高浓度的α-CD4-PAP来抑制疾病更晚期未治疗个体的HIV-1毒株。17株分离株对齐多夫定敏感（平均IC50为117 nM），5株对齐多夫定耐药（平均IC50为3724 nM）。齐多夫定敏感分离株的平均α-CD4-PAP IC50为43×10⁻³ nM，对齐多夫定耐药的分离株的平均α-CD4-PAP IC50为19×10⁻³ nM。所有HIV-1毒株对未缀合的PAP、α-CD19-PAP免疫缀合物和单克隆抗体α-CD4的IC50均大于0.5 nM。在高达5000 nM的浓度下，α-CD4-PAP不抑制正常骨髓祖细胞（BFU-E、CFU-GM和CFU-GEMM）或髓系细胞系（KG-1和HL-60）的集落形成，也不降低T细胞（Jurkat）或B细胞（FL-112和Raji）前体细胞系的细胞活力。总体而言，α-CD4-PAP表现出比齐多夫定更强的抗HIV-1活性，并在对淋巴造血细胞群体无毒的浓度下抑制齐多夫定敏感和齐多夫定耐药病毒的复制。
