Michael N L, Nelson J A, KewalRamani V N, Chang G, O'Brien S J, Mascola J R, Volsky B, Louder M, White G C, Littman D R, Swanstrom R, O'Brien T R
Division of Retrovirology, Walter Reed Army Institute of Research, National Cancer Institute, Rockville, Maryland 20852, USA.
J Virol. 1998 Jul;72(7):6040-7. doi: 10.1128/JVI.72.7.6040-6047.1998.
Individuals who are homozygous for the 32-bp deletion in the gene coding for the chemokine receptor and major human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 (CCR5 -/-) lack functional cell surface CCR5 molecules and are relatively resistant to HIV-1 infection. HIV-1 infection in CCR5 -/- individuals, although rare, has been increasingly documented. We now report that the viral quasispecies from one such individual throughout disease is homogenous, T cell line tropic, and phenotypically syncytium inducing (SI); exclusively uses CXCR4; and replicates well in CCR5 -/- primary T cells. The recently discovered coreceptors BOB and Bonzo are not used. Although early and persistent SI variants have been described in longitudinal studies, this is the first demonstration of exclusive and persistent CXCR4 usage. With the caveat that the earliest viruses available from this subject were from approximately 4 years following primary infection, these data suggest that HIV-1 infection can be mediated and persistently maintained by viruses which exclusively utilize CXCR4. The lack of evolution toward the available minor coreceptors in this subject underscores the dominant biological roles of the major coreceptors CCR5 and CXCR4. This and two similar subjects (R. Biti, R. Ffrench, J. Young, B. Bennetts, G. Stewart, and T. Liang, Nat. Med. 3:252-253, 1997; I. Theodoreu, L. Meyer, M. Magierowska, C. Katlama, and C. Rouzioux, Lancet 349:1219-1220, 1997) showed relatively rapid CD4+ T-cell declines despite average or low initial viral RNA load. Since viruses which use CXCR4 exclusively cannot infect macrophages, these data have implications for the relative infection of the T-cell compartment versus the macrophage compartment in vivo and for the development of CCR5-based therapeutics.
趋化因子受体及主要人类免疫缺陷病毒1型（HIV-1）共受体CCR5编码基因中存在32碱基对缺失的纯合个体（CCR5 -/-）缺乏功能性细胞表面CCR5分子，对HIV-1感染具有相对抗性。CCR5 -/-个体中的HIV-1感染虽然罕见，但已有越来越多的文献记载。我们现在报告，来自一名此类个体整个病程中的病毒准种是均一的，嗜T细胞系，且表型上为合胞体诱导型（SI）；仅使用CXCR4；并能在CCR5 -/-原代T细胞中良好复制。最近发现的共受体BOB和Bonzo未被使用。尽管在纵向研究中已描述了早期和持续存在的SI变异株，但这是首次证明专一且持续使用CXCR4。需要说明的是，该个体可获得的最早病毒来自初次感染后约4年，这些数据表明HIV-1感染可由仅利用CXCR4的病毒介导并持续维持。该个体缺乏向可用次要共受体的进化，突出了主要共受体CCR5和CXCR4的主导生物学作用。该个体以及另外两名类似个体（R. Biti、R. Ffrench、J. Young、B. Bennetts、G. Stewart和T. Liang，《自然医学》3:252 - 253，1997；I. Theodoreu、L. Meyer、M. Magierowska、C. Katlama和C. Rouzioux，《柳叶刀》349:1219 - 1220，1997）尽管初始病毒RNA载量处于平均水平或较低，但CD4 + T细胞下降相对较快。由于仅使用CXCR4的病毒不能感染巨噬细胞，这些数据对体内T细胞区室与巨噬细胞区室的相对感染以及基于CCR5的治疗方法的开发具有启示意义。
