Jere Abhay, Tripathy Srikanth, Agnihotri Kalpana, Jadhav Sushama, Paranjape Ramesh
National AIDS Research Institute, 73 'G' Block, MIDC, Bhosari, Pune 411026, India.
Microbes Infect. 2004 Mar;6(3):279-89. doi: 10.1016/j.micinf.2003.11.012.
HIV-1 subtype C is predominant in India and globally. In the present study, we analyze HIV-1 subtype C regulatory protein Nef sequences from five recent Indian seroconverters and five long-term survivors (LTSs) for variability at crucial functional domains. Sequence analysis suggested the possibility of using regulatory gene sequences for viral subtyping and evolutionary studies apart from structural genes. In the phylogenetic tree, Indian nef sequences segregated away from other reported subtype C sequences, forming an Indian subclade within subtype C. Our studies also suggested no evidence for the association of truncated Nef with slow progression of disease, as all LTSs had intact Nef. We could identify some variations in juxtapositions to crucial functional domains, especially in seroconverter sequences, when comparing them with others. In phylogenetic analysis, specifically for the base-pair regions 411-428 and 478-525, our seroconverter sequences segregated away from those reported earlier in the literature, indicating specific evolutionary changes in these conserved regions of nef in currently circulating viruses. But the dN/dS ratio for our samples was less than one on comparing them with reported subtype C and representative sequences of different clades, strongly emphasizing the necessity of sequence conservation at different disease stages and even across clades. HLA-I binding epitope predictions for common Indian HLAs indicated that specific mutations in seroconverter Nef may alter the intensity of epitope binding, which may alter the outcome of the immune response. Hence these data would be useful in designing Nef epitopes to be included in multi-epitope HIV-1 vaccine for the Indian population and would also be of immense help in HIV-1 evolutionary studies.
HIV-1 C亚型在印度及全球范围内都占主导地位。在本研究中，我们分析了来自5名近期血清转化者和5名长期存活者（LTSs）的HIV-1 C亚型调节蛋白Nef序列，以了解关键功能域的变异性。序列分析表明，除了结构基因外，调节基因序列可用于病毒分型和进化研究。在系统发育树中，印度的nef序列与其他已报道的C亚型序列分离，在C亚型内形成一个印度亚分支。我们的研究还表明，没有证据表明截短的Nef与疾病的缓慢进展有关，因为所有LTSs的Nef都是完整的。与其他序列相比，我们能够识别出关键功能域附近的一些变异，特别是在血清转化者序列中。在系统发育分析中，特别是对于碱基对区域411 - 428和478 - 525，我们的血清转化者序列与文献中先前报道的序列分离，表明在当前流行病毒的nef这些保守区域发生了特定的进化变化。但与已报道的C亚型和不同分支的代表性序列相比，我们样本的dN/dS比率小于1，这强烈强调了在不同疾病阶段甚至不同分支中序列保守的必要性。对常见印度HLA的HLA-I结合表位预测表明，血清转化者Nef中的特定突变可能会改变表位结合的强度，这可能会改变免疫反应的结果。因此，这些数据将有助于设计包含在针对印度人群的多表位HIV-1疫苗中的Nef表位，也将对HIV-1进化研究有极大帮助。
