Piantadosi Anne, Humes Daryl, Chohan Bhavna, McClelland R Scott, Overbaugh Julie
Fred Hutchinson Cancer Center, Seattle, WA 98109-1024, USA.
J Virol. 2009 Aug;83(16):7805-14. doi: 10.1128/JVI.00280-09. Epub 2009 Jun 3.
Hypermutation, the introduction of excessive G-to-A substitutions by host proteins in the APOBEC family, can impair replication of the human immunodeficiency virus (HIV). Because hypermutation represents a potential antiviral strategy, it is important to determine whether greater hypermutation is associated with slower disease progression in natural infection. We examined the level of HIV-1 hypermutation among 28 antiretroviral-naive Kenyan women at two times during infection. By examining single-copy gag sequences from proviral DNA, hypermutation was detected in 16 of 28 individuals. Among individuals with any hypermutation, a median of 15% of gag sequences were hypermutated (range, 5 to 43%). However, there was no association between the level of gag hypermutation and the viral load or CD4 count. Thus, we observed no overall relationship between hypermutation and markers of disease progression among individuals with low to moderate levels of hypermutation. In addition, one individual sustained a typical viral load despite having a high level of hypermutation. This individual had 43% of gag sequences hypermutated and harbored a partially defective Vif, which was found to permit hypermutation in a peripheral blood mononuclear cell culture. Overall, our results suggest that a potential antiviral therapy based on hypermutation may need to achieve a substantially higher level of hypermutation than is naturally seen in most individuals to impair virus replication and subsequent disease progression.
超突变是载脂蛋白B mRNA编辑酶催化多肽样蛋白家族（APOBEC家族）中的宿主蛋白引入过多的G到A替换，可损害人类免疫缺陷病毒（HIV）的复制。由于超突变代表一种潜在的抗病毒策略，因此确定在自然感染中更高程度的超突变是否与疾病进展较慢相关很重要。我们在感染期间的两个时间点检查了28名未接受过抗逆转录病毒治疗的肯尼亚女性体内HIV-1的超突变水平。通过检测前病毒DNA中的单拷贝gag序列，在28名个体中的16名中检测到超突变。在有任何超突变的个体中，gag序列超突变的中位数为15%（范围为5%至43%）。然而，gag超突变水平与病毒载量或CD4细胞计数之间没有关联。因此，在超突变水平低至中等的个体中，我们未观察到超突变与疾病进展标志物之间存在总体关系。此外，一名个体尽管超突变水平很高，但病毒载量维持在典型水平。该个体有43%的gag序列超突变，并且携带部分缺陷的Vif，发现在外周血单核细胞培养中其允许超突变。总体而言，我们的结果表明，基于超突变的潜在抗病毒疗法可能需要达到比大多数个体自然出现的超突变水平高得多的水平，才能损害病毒复制及随后的疾病进展。
