Paxton W A, Kang S, Koup R A
Aaron Diamond AIDS Research Center, and The Rockefeller University, New York, New York 10016, USA.
AIDS Res Hum Retroviruses. 1998 Apr;14 Suppl 1:S89-92.
The purified CD4+ lymphocytes of a group of highly exposed but HIV-1-uninfected individuals were determined to be less susceptible to infection with multiple non-syncytium-inducing (NSI) primary isolates of HIV-1 than were CD4+ lymphocytes from nonexposed control individuals. This relative resistance to HIV-1 infection did not extend to T cell line-adapted or syncytium-inducing (SI) primary viral isolates, was restricted by the envelope glycoprotein, and was associated with an increased production of the C-C chemokines RANTES, MIP-1alpha, and MIP-1beta. The block to replication in CD4+ lymphocytes from two exposed-uninfected subjects was at the point of entry, as was the block imposed by the recombinant C-C chemokines RANTES, MIP-1alpha, and MIP-1beta. Resistance to infection and the high production of beta chemokines were characteristic of every CD4+ lymphocyte clone from the exposed-uninfected subjects. We have now identified the mechanism underlying this in vitro and in vivo resistance to infection: These individuals have inherited a homozygous 32-bp nucleotide deletion (delta32) within the gene encoding the coreceptor for primary NSI isolates of HIV-1 (CCR5). This deletion encodes a severely truncated and unstable protein that is not expressed on the cell surface. This allele is common in the Caucasian population, with a frequency of 0.0808, but is not found in people of African or Asian ancestry. To determine its role in HIV-1 transmission and disease progression, we analyzed the CCR5 genotype of 1252 homosexual men enrolled in the Chicago component of the Multicenter AIDS Cohort Study (MACS). No infected participant was found to be homozygous for the delta32 allele whereas 3.6% of at-risk but uninfected Caucasian participants were homozygous, showing the highly protective role of this genotype against sexual acquisition of HIV-1. No evidence was found to suggest that heterozygotes were protected against HIV-1 infection, but a limited protective role against disease progression was noted. The delta32 allele of CCR5 is therefore an important host factor in HIV-1 transmission and pathogenesis.
研究发现，一组高暴露但未感染HIV-1的个体的纯化CD4+淋巴细胞，相较于未暴露的对照个体的CD4+淋巴细胞，对多种HIV-1非合胞体诱导（NSI）原始毒株感染的易感性更低。这种对HIV-1感染的相对抗性并不适用于T细胞系适应型或合胞体诱导（SI）原始病毒毒株，其受到包膜糖蛋白的限制，并且与C-C趋化因子RANTES、MIP-1α和MIP-1β的产生增加有关。来自两名暴露但未感染个体的CD4+淋巴细胞中的复制阻断发生在病毒进入阶段，重组C-C趋化因子RANTES、MIP-1α和MIP-1β所造成的阻断也是如此。对感染的抗性以及β趋化因子的高产量是暴露但未感染个体的每个CD4+淋巴细胞克隆的特征。我们现已确定了这种体外和体内抗感染抗性的潜在机制：这些个体在编码HIV-1原始NSI毒株共受体（CCR5）的基因内遗传了一个纯合的32碱基对核苷酸缺失（Δ32）。这种缺失编码了一种严重截短且不稳定的蛋白质，该蛋白质不在细胞表面表达。此等位基因在白种人群中较为常见，频率为0.0808，但在非洲或亚洲血统的人群中未发现。为确定其在HIV-1传播和疾病进展中的作用，我们分析了参与多中心艾滋病队列研究（MACS）芝加哥部分的1252名同性恋男性的CCR5基因型。未发现感染参与者为Δ32等位基因的纯合子，而有风险但未感染的白种参与者中有3.6%为纯合子，这表明该基因型对通过性接触感染HIV-1具有高度保护作用。未发现有证据表明杂合子对HIV-1感染有保护作用，但注意到其对疾病进展有有限的保护作用。因此，CCR5的Δ32等位基因是HIV-1传播和发病机制中的一个重要宿主因素。
