Spudich Serena S, Huang Wei, Nilsson Annelie C, Petropoulos Christos J, Liegler Teri J, Whitcomb Jeannette M, Price Richard W
Department of Neurology, University of California-San Francisco, San Francisco, California, USA.
J Infect Dis. 2005 Mar 15;191(6):890-8. doi: 10.1086/428095. Epub 2005 Feb 9.
Chemokine receptors serve as coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, influence cell tropism, and may critically determine central nervous system infection pathogenesis. Using an in vitro functional entry assay, we examined utilization of 2 principal coreceptors in cerebrospinal fluid (CSF) and plasma in 46 subjects.
Paired CSF and plasma samples were selected from subjects with a range of CD4 T cell counts. Amplified populations of env sequences were characterized as using CCR5 (R5), CXCR4 (X4), or both receptors (R5+X4). Individual clones derived from 3 subjects were analyzed for viral tropism and phylogeny.
CSF and plasma pairs were mainly concordant for R5 (36/46) or R5+X4 (5/46) viruses. However, 5 pairs were discordant, 2 of which had the R5+X4 phenotype in CSF despite having the R5 phenotype in plasma. Although R5+X4 tropism was associated with advanced immunodeficiency, all 4 subjects with acquired immunodeficiency syndrome dementia complex had R5 tropism in CSF. Clones derived from R5+X4-tropic populations revealed mixtures of R5 and X4 viruses and viruses able to utilize either coreceptor, suggesting both virus exchange between compartments and autonomous CSF virus evolution.
Although R5 viruses predominate in the CSF, HIV-1 populations able to utilize CXCR4 are also present. Discordant tropism in CSF and plasma may have implications for R5 inhibitor therapy.
趋化因子受体作为1型人类免疫缺陷病毒（HIV-1）进入细胞的共受体，影响细胞嗜性，并可能在中枢神经系统感染发病机制中起关键作用。我们采用体外功能性进入试验，检测了46名受试者脑脊液（CSF）和血浆中两种主要共受体的利用情况。
从一系列CD4 T细胞计数的受试者中选取配对的脑脊液和血浆样本。扩增的env序列群体被鉴定为使用CCR5（R5）、CXCR4（X4）或两种受体（R5+X4）。对来自3名受试者的单个克隆进行病毒嗜性和系统发育分析。
脑脊液和血浆配对样本中，R5病毒（36/46）或R5+X4病毒（5/46）为主。然而，有5对样本不一致，其中2对脑脊液中为R5+X4表型，而血浆中为R5表型。尽管R5+X4嗜性与晚期免疫缺陷相关，但所有4例获得性免疫缺陷综合征痴呆综合征患者脑脊液中的病毒均为R5嗜性。来自R5+X4嗜性群体的克隆显示R5和X4病毒以及能够利用任一受体的病毒混合存在，提示不同区室之间存在病毒交换以及脑脊液病毒自主进化。
尽管脑脊液中R5病毒占主导，但也存在能够利用CXCR4的HIV-1群体。脑脊液和血浆中嗜性不一致可能对R5抑制剂治疗有影响。
