SIGNIFICANCE OF SIV CELL SPECIFICITY FOR AIDS DISEASE PROCESSES

大量的研究强烈表明， 包膜基因（env）决定HIV-1的细胞特异性， 表明人类免疫缺陷病毒的细胞特异性 1（HIV-1）是理解艾滋病复杂性的关键之一。 艾滋病的发病过程。 HIV-1具有高复制能力， 对于巨噬细胞，可能在传输中起重要作用， HIV-1的持续存在，T淋巴细胞可能是导致 免疫缺陷的临床表现。 的分子机制 细胞类型特异性HIV-1通过其影响疾病进程， 然而，疾病表现仍有待阐明。 我们探讨了病毒细胞特异性对 利用猿猴免疫缺陷病毒研究艾滋病的疾病过程 (SIV)/rhesus macaque模型系统。 SIVmac 155/TT变体具有高的 恒河猴T淋巴细胞的复制和细胞病变能力 淋巴结的恒河猴，死亡后感染 分离克隆的SIVmac 239。 SIVmac 155/MT变体具有高的 淋巴结巨噬细胞的复制能力 个人也被隔离。 序列分析显示 gp 120的V1至V2和V3区域中的特定氨基酸变化。 含有TT衍生的gp 120序列的Ev/T3 env重组体， 含有MT衍生的gp 120序列的Ev/M3 env重组体 对T淋巴细胞表现出很强的复制能力， 巨噬细胞。 序列分析显示TT型env 在淋巴结中特异性地存在MT型，但MT型env 变异体存在于动物的淋巴结和脑中。 这些数据表明，SIV的gp 120不仅对 决定细胞特异性，但也可能有助于SIV 体内组织定位。 SIV gp 120基因序列对病毒致病性的意义 通过实验接种四只恒河猴， 携带Ev/T3或SIVmac 239的猕猴。 所有的猕猴都建立了 通过血浆SIV抗原血症和抗SIV确定的病毒感染 抗体反应。 令人惊讶的是，所有四只感染Ev/T3的猕猴 显示非常快速、严重和选择性的CD 4 + T细胞耗竭 在接种后2周外周血中。 相比之下， SIVmac 239感染的猕猴显示CD 4 + T细胞耗竭， 感染的过程。 淋巴结中的CD_4/CD_8比值也是 在感染Ev/T3但不感染SIVmac 239的猕猴中严重倒置。 这些研究表明，高复制和细胞病变， Ev/T3在体外CD 4 + T细胞中的能力显著反映了 这种克隆病毒诱导CD 4 + T细胞耗竭的潜力， vivo.

A substantial number of studies strongly indicate that the viral envelope gene (env) determines the cell specificity of HIV-1 and suggest that the cell specificity of human immunodeficiency virus type 1 (HIV-1) is one of the keys to understanding the complex nature of disease processes in AIDS. HIV-1, with its high replicative ability for macrophages, may have an important role in the transmission and persistence of HIV-1, and T-lymphocytes may be responsible for the clinical manifestation of immunodeficiency. The molecular mechanisms by which cell type-specific HIV-1 influences the disease course and disease manifestation, however, remain to be elucidated. We explored the significance of viral cell specificity for the disease processes of AIDS using the simian immunodeficiency virus (SIV)/rhesus macaque model system. An SIVmac155/TT variant with high replicative and cytopathic ability for rhesus T-lymphocytes from the lymph nodes of a rhesus macaque that died following infection with cloned SIVmac239 was isolated. An SIVmac155/MT variant with high replicative ability for macrophages from the lymph nodes of the same individual was also isolated. Sequence analysis revealed variant specific amino acid changes in the V1 to V2 and V3 regions of gp120. Ev/T3 env recombinant containing the TT-derived gp120 sequences and Ev/M3 env recombinant containing the MT-derived gp120 sequences displayed strong replicative ability for T-lymphocytes and macrophages, respectively. Sequence analysis revealed TT-type env variant was specifically present in the lymph nodes, but MT type env variants were present in the lymph nodes and brain of the animal. These data suggest that the gp120 of SIV is not only important for determining the cell specificity, but may also contribute to SIV tissue localization in vivo. The significance of gp120 sequences of SIV for viral pathogenicity in vivo was examined by experimental inoculation of four rhesus macaques with either Ev/T3 or SIVmac239. All macaques established virus infection as determined by plasma SIV antigenemia and anti-SIV antibody responses. Surprisingly, all four macaques infected by Ev/T3 displayed very rapid, severe and selective depletion of CD4+ T cells in peripheral blood at 2 weeks post-inoculation. In contrast, no macaques infected by SIVmac239 displayed CD4+ T cell depletion through the course of infection. The CD4/CD8 ratio in lymph nodes was also severely inverted in macaques infected with Ev/T3, but not SIVmac239. These studies demonstrated that the high replicative and cytopathic abilities of Ev/T3 in CD4+ T cells in vitro remarkably reflect the potential of this cloned virus to induce CD4+ T cell depletion in vivo.