van Rij R P, Blaak H, Visser J A, Brouwer M, Rientsma R, Broersen S, de Roda Husman A M, Schuitemaker H
Department of Clinical Viro-Immunology, CLB Sanquin and Laboratory of Experimental and Clinical Immunology, University of Amsterdam, Amsterdam, The Netherlands.
J Clin Invest. 2000 Oct;106(8):1039-52. doi: 10.1172/JCI7953.
We demonstrated previously that CD45RA(+) CD4(+) T cells are infected primarily by syncytium-inducing (SI) HIV-1 variants, whereas CD45RO(+) CD4(+) T cells harbor both non-SI (NSI) and SI HIV-1 variants. Here, we studied evolution of tropism for CD45RA(+) and CD45RO(+) CD4(+) cells, coreceptor usage, and molecular phylogeny of coexisting NSI and SI HIV-1 clones that were isolated from four patients in the period spanning SI conversion. NSI variants were CCR5-restricted and could be isolated throughout infection from CD45RO(+) CD4(+) cells. SI variants seemed to evolve in CD45RO(+) CD4(+) cells, but, in time, SI HIV-1 infection of CD45RA(+) CD4(+) cells equaled infection of CD45RO(+) CD4(+) cells. In parallel with this shift, SI HIV-1 variants first used both coreceptors CCR5 and CXCR4, but eventually lost the ability to use CCR5. Phylogenetically, NSI and SI HIV-1 populations diverged over time. We observed a differential expression of HIV-1 coreceptors within CD45RA(+) and CD45RO(+) cells, which allowed us to isolate virus from purified CCR5(+) CXCR4(-) and CCR5(-) CXCR4(+) CD4(+) cells. The CCR5(+) subset was exclusively infected by CCR5-dependent HIV-1 clones, whereas SI clones were preferentially isolated from the CXCR4(+) subset. The differential expression of HIV-1 coreceptors provides distinct cellular niches for NSI and SI HIV-1, contributing to their coexistence and independent evolutionary pathways.
我们之前证明，CD45RA(+) CD4(+) T细胞主要被诱导合胞体形成（SI）的HIV-1变异株感染，而CD45RO(+) CD4(+) T细胞则同时含有非SI（NSI）和SI HIV-1变异株。在此，我们研究了在SI转换期间从4名患者中分离出的共存NSI和SI HIV-1克隆对CD45RA(+)和CD45RO(+) CD4(+)细胞的嗜性演变、共受体使用情况以及分子系统发育。NSI变异株受CCR5限制，在整个感染过程中均可从CD45RO(+) CD4(+)细胞中分离得到。SI变异株似乎在CD45RO(+) CD4(+)细胞中进化，但随着时间推移，CD45RA(+) CD4(+)细胞被SI HIV-1感染的情况与CD45RO(+) CD4(+)细胞相当。与此转变同时发生的是，SI HIV-1变异株最初同时使用CCR5和CXCR4两种共受体，但最终失去了使用CCR5的能力。从系统发育角度看，NSI和SI HIV-1群体随时间逐渐分化。我们观察到HIV-1共受体在CD45RA(+)和CD45RO(+)细胞内存在差异表达，这使我们能够从纯化的CCR5(+) CXCR4(-)和CCR5(-) CXCR4(+) CD4(+)细胞中分离出病毒。CCR5(+)亚群仅被依赖CCR5的HIV-1克隆感染，而SI克隆则优先从CXCR4(+)亚群中分离得到。HIV-1共受体的差异表达为NSI和SI HIV-1提供了不同的细胞微环境，有助于它们的共存及独立进化途径。
