HIV type 1 Vaccines for worldwide use: Predicting in-clade and cross-clade breadth of immune responses
HIV type 1 Vaccines for worldwide use: Predicting in-clade and cross-clade breadth of immune responses
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DOI：
10.1089/aid.2007.0098
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发表时间：
2007-10-01
影响因子：
1.5
通讯作者：
Condra, Jon H.
中科院分区：
文献类型：
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作者：
Finnefrock, Adam C.;Liu, Xiaomei;Condra, Jon H.
HIV疫苗开发的最大挑战之一是适应HIV-1病毒的全球序列多样性。为了了解病毒序列多样性如何影响旨在引发抗病毒T细胞免疫的HIV-1疫苗的潜在广度，我们开发了新的方法来评估氨基酸水平上的序列保守性，其中发挥了疫苗的作用。将来自LANL 2004氨基酸比对的每个序列作为潜在的疫苗或作为攻击病毒，通过两种方法评估序列的所有成对组合：第一，比对序列的传统比较，第二，通过选择以强调MHC-I表位的典型长度的新的步行9聚体算法。比较疫苗和攻击序列之间错配的9-mer对的规则是从Nef特异性CD 8表位和来自自然HIV-1感染患者的病毒序列的实验中经验性地推导出来的。对结果进行加权，使得每个进化枝的贡献与其全球流行率成比例。对于编码Pol和Gag的疫苗，最好地维持了反应的交叉进化枝宽度，而通常提出的基于Envand Tat的疫苗将对进化枝更敏感。我们评估了包括共有序列和祖先序列在内的多分支疫苗所能预期的额外宽度。对于更多样化的蛋白质，添加第二种菌株可以显著增加宽度，尽管对于三种或更多种菌株，蛋白质的内在多样性导致改善减少。
One of the greatest challenges in HIV vaccine development is accommodating the worldwide sequence diversity of the HIV-1 virus. To understand how viral sequence diversity may affect the potential breadth of HIV-1 vaccines designed to elicit antiviral T cell immunity, we have developed novel approaches to assess sequence conservation at the amino acid level, where vaccine effects are exerted. Taking each sequence from the LANL 2004 amino acid alignments as a potential vaccine or as a challenge virus, all pairwise combinations of sequences were evaluated by two methods: first, a traditional comparison of aligned sequences, and second, by a new walking 9-mer algorithm chosen to emphasize the typical length of an MHC-I epitope. The rules for comparing mismatched 9-mer pairs between vaccine and challenge sequences were empirically deduced from an experiment on Nef-specific CD8 epitopes and the viral sequences from naturally HIV-1-infected patients. Results were weighted such that each clade contributed in proportion to its global prevalence. Cross-clade breadth of response is best maintained for vaccines encoding Pol and Gag, while commonly proposed Envand Tat-based vaccines would be more clade sensitive. We evaluated the additional breadth that could be expected from multiclade vaccines including consensus and ancestral sequences. For more diverse proteins, adding a second strain can add a significant increase in breadth, although for three or more strains the intrinsic diversity of the protein leads to diminishing improvement.