Matthews Philippa C, Prendergast Andrew, Leslie Alasdair, Crawford Hayley, Payne Rebecca, Rousseau Christine, Rolland Morgane, Honeyborne Isobella, Carlson Jonathan, Kadie Carl, Brander Christian, Bishop Karen, Mlotshwa Nonkululeko, Mullins James I, Coovadia Hoosen, Ndung'u Thumbi, Walker Bruce D, Heckerman David, Goulder Philip J R
Department of Paediatrics, Peter Medawar Building for Pathogen Research, United Kingdom.
J Virol. 2008 Sep;82(17):8548-59. doi: 10.1128/JVI.00580-08. Epub 2008 Jul 2.
Much uncertainty still exists over what T-cell responses need to be induced by an effective human immunodeficiency virus (HIV) vaccine. Previous studies have hypothesized that the effective CD8(+) T-cell responses are those driving the selection of escape mutations that reduce viral fitness and therefore revert post-transmission. In this study, we adopted a novel approach to define better the role of reverting escape mutations in immune control of HIV infection. This analysis of sequences from 710 study subjects with chronic C-clade HIV type 1 infection demonstrates the importance of mutations that impose a fitness cost in the control of viremia. Consistent with previous studies, the viral set points associated with each HLA-B allele are strongly correlated with the number of Gag-specific polymorphisms associated with the relevant HLA-B allele (r = -0.56, P = 0.0034). The viral set points associated with each HLA-C allele were also strongly correlated with the number of Pol-specific polymorphisms associated with the relevant HLA-C allele (r = -0.67, P = 0.0047). However, critically, both these correlations were dependent solely on the polymorphisms identified as reverting. Therefore, despite the inevitable evolution of viral escape, viremia can be controlled through the selection of mutations that are detrimental to viral fitness. The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses.
对于有效的人类免疫缺陷病毒（HIV）疫苗需要诱导何种T细胞反应，目前仍存在诸多不确定性。先前的研究推测，有效的CD8(+) T细胞反应是那些驱动选择逃逸突变的反应，这些突变会降低病毒适应性，从而在传播后发生逆转。在本研究中，我们采用了一种新方法来更好地定义逆转逃逸突变在HIV感染免疫控制中的作用。对710名慢性C型1型HIV感染研究对象的序列分析表明，在控制病毒血症方面，产生适应性代价的突变具有重要意义。与先前的研究一致，与每个HLA - B等位基因相关的病毒载量设定点与相关HLA - B等位基因相关的Gag特异性多态性数量密切相关（r = -0.56，P = 0.0034）。与每个HLA - C等位基因相关的病毒载量设定点也与相关HLA - C等位基因相关的Pol特异性多态性数量密切相关（r = -0.67，P = 0.0047）。然而，至关重要的是，这两种相关性仅取决于被鉴定为逆转的多态性。因此，尽管病毒逃逸不可避免地会发生进化，但通过选择对病毒适应性有害的突变，可以控制病毒血症。这些结果的意义在于突出了一种能够诱导这些广泛反应的HIV疫苗的基本原理。
