HIV感染及疾病进展、宿主遗传和免疫保护机制的细胞和分子基础

Cellular and Molecular Basis of Hostgenetic and lmmune Protection from HIV Infection and Disease Progression

宿主的免疫和遗传因素对接触ＨＩＶ后的结果和其后ＨＩＶ病的发展都起着重要的作用。ＨＩＶ主要是靠ｇｐ１２０与靶细胞的ＣＤ４分子结合而进入细胞内的，而病毒与靶细胞膜的融合是通过ｇｐ１２０与共受体ＣＣＲ５（趋化因子受体）结合来完成的。现已证明，３２ｂｐ缺失的突变ＣＣＲ５基因（ＣＣＲ５－△３２）不但影响宿主对ＨＩＶ感染的敏感性而且还影响ＨＩＶ感染个体的疾病进展。突变ＣＣＲ５纯合子显示出对ＨＩＶ感染的完全性保护；而（ＣＣＲ５－△３２）半合子对ＨＩＶ感染的个体的疾病进展则具有部分性保护作用。现已观察到，某些ＨＬＡ半合型与ＨＩＶ感染的抗性及ＨＩＶ病发展快慢有明显的相关性。对ＨＩＶ感染的抗性研究表明，ＨＬＡ－Ａ２和ＨＬＡ－ＤＲ１３半合型与ＨＩＶ感染性有关，ＨＬＡ－Ｂ２７、Ｂ５７和Ｂ５１与ＨＩＶ疾病的缓慢进展有关，而ＨＬＡ－Ａ２３、Ｂ３７和Ｂ４９与ＨＩＶ疾病的快速进展有关。ＨＬＡ半合型对ＨＩＶ病的进展所产生的影响可达６倍之大。ＨＩＶ特异性的细胞毒Ｔ细胞（ＣＴＬ）对控制ＨＩＶ的复制和播散起着重要作用。在长期无进展患者检出ＨＩＶ特异性ＣＴＬ前体明显高于快速进展者。在ＨＩＶ感染患者所进行的Ｔ细胞受体Ｖβ谱偏移研究表明，在初始感染时能?

It is quite clear that host immune and genetic factors play an improtant role in determining the outcome of exposure to HIV and the subsequent progression of HIV disease. The entry of HIV into a cell is initiated by gp120 binding to CD4 molecule on the target cell. Fusion of the viral and target cell membranes is subsequently facilitated by the binding of CCR5, a target cell co-receptor of the chemokine family. A mutant allele of the CCR5 gene which contains an internal 32 base pair deletion (CCR5-△32) resulting in a truncated protein, has an important influence on susceptibility to HIV infection and on rates of diseaase progression in HIV-infected individuals. Homozygosity for the CCR5 mutation results in almost total protection from HIV-1 infection. Heterozygosity for CCR5-△32 may confer partial protection against disease progression in HIV-inferent individuals. Close associations have been observed between certain HLA haplotypes and HIV infection as well as different rates of HIV disease progression. The results form studies on resistance to HIV infection reveal that HLA-A2 and HLA-DR13 haplotypes are linked to resistance to HIV infection. HLA-B27,B57, and B51 were most strongly associated with slow progression of HIV disease, while HLA-A23,B37, and B49 were associated wth rapid progression. HLA haplotypes may have affect the rates of disease progression in a 6-fold difference between rapid versus slow progressors. HIV-specific CTLs play an important role in the control of HIV replication and spread. High precursor frequencies of HIV-specific CTL have been consistently detected in long-term non-progressors (LTNP) compared to fast progressors (FP).Studies on the skewing of the T cell receptor Vβ repertoire in HIV-infected patients has revealed that the a better control of viral replication and an improved prognosis is linked to the ability to recruit an HIV-specific CTL response composed of a heterogeneous group of Vβ families during primary infection compared to mobilization and expansion of CTL from only one or two Vβ families. CTL clonal exhaustion has been found to occur to some degree in HIV-infected patients whose certain originally expanded CTL clonotypes disappeared in the absence of viral escape mutations that might otherwise explain the phenomenon. The evidence above argues against an immunopathogenic role for CTL in HIV disease.