INDUCTION OF AIDS BY SIV LACKING NF KB & SP1 BINDING ELEMENTS

我们正在制定一项战略， 一种依赖于基因缺失的艾滋病疫苗。 朝向 为了实现这一目标，我们构建了突变的病毒株， 转录控制元件，并分析了它们的性质， 恒河猴 恒河猴（Macaca mulatta）感染了 5种猴免疫缺陷病毒（SIV）， NF-κ B中含有缺失（）或取代（subst）的SIVmac 239 和Sp1结合位点。 我们之前已经证明， 这些区域仍然允许在主服务器中进行有效的SIVmac复制， 淋巴样细胞培养物（Ilyinskii和Desrosiers，J. Virol. 70：3118-3126，1996）。 两只动物静脉接种 SIVmac239 NFkB，Sp1234， NFkB Sp1234、substSp 12和substSp 1234。 除了一个感染者 动物显示血浆抗原血症的早期峰值，维持高水平 病毒负荷，有显着变化的淋巴组织和6个有 在感染后60周内死于艾滋病。 之一 感染SIV毒株NFkB Sp1234的动物显示出较低的水平， 血浆抗原血症和较低的病毒负荷;另一种动物 17周后死于艾滋病 接种。 没有一致的新突变或回复， 在来自感染以下病毒的动物的前病毒序列中检测到 缺失突变体和substSp 12突变体在20周后 感染 点突变序列在两个基因组中都部分缺失， 感染substSp 1234菌株的动物。 这些结果表明 NF-kB和Sp1结合位点对于细胞的生长不是必需的。 SIVmac 239诱导AIDS。 他们还提供了间接证据 在U3区的新的增强子元件的重要性， 位于NF-κ B结合上游的SIVmac LTR 在nef编码序列的C-末端区域内的位点。

We are working on a strategy for development of a live attenuated vaccine for AIDS that depends on deletion of genetic elements. Toward this goal, we have constructed virus strains with mutations in transcriptional control elements and analyzed their properties in rhesus monkeys. Rhesus monkeys (Macaca mulatta) were infected with five strains of simian immunodeficiency virus (SIV) derived from SIVmac239 containing deletions ( ) or substitutions (subst) in NF-kB and Sp1 binding sites. We have shown previously that mutations in these regions still allow efficient SIVmac replication in primary lymphoid cell cultures (Ilyinskii and Desrosiers, J. Virol. 70:3118-3126, 1996). Two animals were inoculated intravenously with each mutant strain of SIVmac239 NFkB, Sp1234, NFkB Sp1234, substSp12 and substSp1234. All but one of the infected animals showed an early spike in plasma antigenemia, maintained high virus burdens, had significant changes in lymphoid tissues and 6 have died with AIDS within the first sixty weeks of infection. One of the animals infected with the SIV strain NFkB Sp1234 showed lower levels of plasma antigenemia and lower virus burdens; the other animal infected with this same mutant strain died with AIDS 17 weeks after inoculation. No consistent novel mutations or reversions were detected in proviral sequences derived from the animals infected with the deletion mutants and the substSp12 mutant by 20 weeks post infection. Point mutated sequences were partially deleted in both animals infected with the substSp1234 strain. These results indicate that the NF-kB and Sp1 binding sites are not essential for the induction of AIDS by SIVmac239. They also provide indirect evidence for the importance of a novel enhancer element in the U3 region of the SIVmac LTR that is located immediately upstream of the NF-kB binding site within the C-terminal region of the nef coding sequence.