Hoffman T L, Stephens E B, Narayan O, Doms R W
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11360-5. doi: 10.1073/pnas.95.19.11360.
The envelope (Env) proteins of primate lentiviruses interact sequentially with CD4 and a coreceptor to infect cells. Changes in coreceptor use strongly influence viral tropism and pathogenesis. We followed the evolution of coreceptor use in pig-tailed macaques that developed severe CD4 T-cell loss during the derivation of a pathogenic simian HIV (SHIV) that contained the tat, rev, vpu, and env genes of the HXBc2 strain of HIV-1 in a genetic background of SIVmac239. The Env from the parental virus as well as one derived from the first macaque to develop AIDS exclusively used CXCR4 as a coreceptor, indicating that CXCR4 can function as a coreceptor in macaques even though it is rarely used by simian immunodeficiency viruses. One Env (Pnb5), obtained from a macrophage-tropic virus isolated from the cerebral spinal fluid, did not use CCR5 or CXCR4. Instead, it used CCR2b and to a lesser extent CCR3, STRL33, and APJ to infect cells. Chimeras between Pnb5 and the parental X4 Env indicated that the V3 loop is the major determinant of CXCR4 use, with other regions of Env influencing the efficiency with which this coreceptor was used. In contrast, the Pnb5 V1/2 and V3 regions in combination were both necessary and sufficient to confer full use of CCR2b, CCR3, STRL33, and APJ to the parental X4 Env protein. These results are consistent with a single, conserved binding site in Env that interacts with multiple coreceptors in conjunction with the V1/2 and V3 loops, and suggest that the V1/2 region plays a more important role in governing the use of CCR2b, CCR3, STRL33, and APJ than for CXCR4.
灵长类慢病毒的包膜（Env）蛋白依次与CD4和一种共受体相互作用以感染细胞。共受体使用的变化强烈影响病毒嗜性和发病机制。我们追踪了食蟹猴中共受体使用情况的演变，这些食蟹猴在一种致病性猿猴免疫缺陷病毒（SHIV）的衍生过程中出现了严重的CD4 T细胞损失，该SHIV在猴免疫缺陷病毒（SIVmac239）的遗传背景中包含HIV-1 HXBc2株的tat、rev、vpu和env基因。亲本病毒以及从第一只患艾滋病的食蟹猴分离出的一种病毒所产生的Env仅使用CXCR4作为共受体，这表明CXCR4在食蟹猴中可作为共受体发挥作用，尽管猿猴免疫缺陷病毒很少使用它。从脑脊液中分离出的一种巨噬细胞嗜性病毒获得的一个Env（Pnb5）不使用CCR5或CXCR4。相反，它使用CCR2b，并在较小程度上使用CCR3、STRL33和APJ来感染细胞。Pnb5与亲本X4 Env之间的嵌合体表明，V3环是使用CXCR4的主要决定因素，Env的其他区域影响该共受体的使用效率。相比之下，Pnb5的V1/2和V3区域共同对于亲本X4 Env蛋白充分使用CCR2b、CCR3、STRL33和APJ而言既是必要的也是充分的。这些结果与Env中一个单一的保守结合位点一致，该位点与V1/2和V3环一起与多种共受体相互作用，并表明V1/2区域在控制CCR2b、CCR3、STRL33和APJ的使用方面比控制CXCR4的使用发挥更重要的作用。
