MOLECULAR ANALYSIS OF THIRD VARIABLE ENVELOPE REGIONS OF SIV

尽管HIV-1的V3序列是HIV-1的主要遗传基因， 病毒细胞特异性的决定因素，很少有人知道 SIV V3序列的作用。 为了了解SIV V3序列的作用， 我们专注于分子克隆的SIV，命名为EvT 3， 显示独特的V3序列，体外细胞特异性和致病性 体内潜力 与SIVmac 239相比，EvT 3 V3具有六个氨基酸残基， SIV V3的32个氨基酸区段内的取代。 在文化中， EvT 3不会在高度表达的人类T细胞系中复制 对SIVmac 239感染敏感。 当实验感染到 恒河猴，EvT 3，而不是SIVmac 239，诱导严重和快速的， CD 4 + T细胞耗竭。 我们研究了EvT 3的意义 V3序列在通过构建确定生物学特性中的应用 EvT 3和SIVmac 239之间的V3重组病毒。 我们的数据 记录了EvT 3 V3序列导致无法 体外在人类T细胞系中复制，它们也是必不可少的 用于体内诱导CD 4 + T细胞耗竭。 有趣的是，EvT 3 V3比SIVmac 239 V3更带正电荷和亲水性，SIVmac 239 V3 具有类似于嗜T细胞HIV-1的V3的性质。 近日更 已经表明，含有带正电荷的V3的嗜T细胞的HIV-1 序列利用CXCR 4作为病毒进入的共受体。 一致 结合V3序列的性质，我们发现EvT 3序列可以有效地 利用CXCR 4进行病毒进入。 相比之下，SIVmac 239利用CCR 5 而不是类似于Mm嗜性HIV-1的CXCR 4。 我们的数据使用V3 重组病毒表明，不同的共受体用途， EvT 3和SIVmac 239之间的差异也由它们的V3序列决定。 这些数据表明SIV V3序列在SIV感染中起重要作用。 确定病毒细胞特异性、致病潜力和 共受体用途。 我们目前正在努力确定 V3中的遗传决定因素决定了 SIV，并进一步研究其生物化学基础， V3和辅助受体之间的相互作用， 确定体外细胞特异性和可能的致病性 体内潜力

Although V3 sequences of HIV-1 are the principal genetic determinants of the viral cell specificity, little is known about the role of SIV V3 sequences. To understand the role of SIV V3 sequences, we have focused on a molecularly cloned SIV, designated as EvT3, which displays unique V3 sequences, cell specificity in vitro and pathogenic potential in vivo. Compared to SIVmac239, EvT3 V3 has six amino acid substitutions within the 32 amino acid stretch of SIV V3. In culture, EvT3 does not replicate in human T cell lines that are highly sensitive to SIVmac239 infection. When experimentally infected into rhesus macaques, EvT3, but not SIVmac239, induces severe and rapid CD4+ T cell depletion. We have investigated the significance of EvT3 V3 sequences in determining the biological properties by construction of V3 recombinant viruses between EvT3 and SIVmac239. Our data have documented that EvT3 V3 sequences are responsible for the inability to replicate in human T cell lines in vitro, and they are also essential for induction of CD4+ T cell depletion in vivo. Interestingly, EvT3 V3 is more positively charged and hydrophilic than SIVmac239 V3, which has a property similar to V3 of T cell-tropic HIV-1. Recently, it has been shown that T cell-tropic HIV-1 containing positively charged V3 sequences utilized CXCR4 as a co-receptor for virus entry. Consistent with the properties of V3 sequences, we found that EvT3 efficiently utilized CXCR4 for virus entry. In contrast, SIVmac239 utilized CCR5 but not CXCR4 similar to Mm-tropic HIV-1. Our data using V3 recombinant viruses indicated that the distinct co-receptor usages between EvT3 and SIVmac239 are also determined by their V3 sequences. These data indicate that SIV V3 sequences play important roles in determining the viral cell specificity, pathogenic potential and co-receptor usages. We are currently making efforts to identify the genetic determinant(s) in V3 determining the biological properties of SIV, and further investigating the biochemical basis underlying the interaction between V3 and co-receptor which is important in determining the cell specificity in vitro and possibly pathogenic potential in vivo.