Kennedy P E, Moss B, Berger E A
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Virology. 1993 Jan;192(1):375-9. doi: 10.1006/viro.1993.1047.
Despite the ability of soluble forms of CD4 (sCD4) and related CD4 derivatives to neutralize human immunodeficiency type 1 (HIV-1) infectivity in vitro, these agents have shown little evidence of efficacy in clinical trials with infected individuals. These disappointing findings may be related to recent observations that much higher concentrations of sCD4 are required for in vitro neutralization of primary HIV-1 isolates compared to laboratory-adapted strains. An alternative CD4-based therapeutic strategy exploits CD4 as a targeting agent to direct cytotoxic molecules to selectively kill HIV-infected cells. In this report we demonstrate that CD4-Pseudomonas exotoxin inhibits spreading infection by primary HIV-1 isolates known to be highly refractory to neutralization by soluble CD4; the observed potency is at least as great as for a prototypic sCD4-sensitive, laboratory-adapted HIV-1 strain. Thus, the in vitro efficacy of a CD4-based agent, which acts by targeted killing of infected cells, appears not to be compromised by features which render primary HIV-1 isolates refractory to neutralization by sCD4 derivatives. These results have important conceptual and practical implications for CD4-based therapeutic strategies.
尽管可溶性CD4（sCD4）及其相关的CD4衍生物在体外具有中和人类免疫缺陷病毒1型（HIV-1）感染性的能力，但在针对感染个体的临床试验中，这些药物几乎没有显示出疗效证据。这些令人失望的结果可能与最近的观察结果有关，即与实验室适应株相比，体外中和原发性HIV-1分离株需要更高浓度的sCD4。一种基于CD4的替代治疗策略利用CD4作为靶向剂，引导细胞毒性分子选择性杀死HIV感染细胞。在本报告中，我们证明CD4-铜绿假单胞菌外毒素可抑制已知对可溶性CD4中和具有高度抗性的原发性HIV-1分离株的扩散感染；观察到的效力至少与对原型sCD4敏感的、实验室适应的HIV-1株一样大。因此，一种通过靶向杀死感染细胞起作用的基于CD4的药物的体外疗效，似乎不会因使原发性HIV-1分离株对sCD4衍生物中和具有抗性的特征而受到影响。这些结果对基于CD4的治疗策略具有重要的概念和实际意义。
