High intrapatient HIV-1 evolutionary rate is associated with CCR5-to-CXCR4 coreceptor switch

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• 作者：Mattias Mild ; Rebecca R. Gray ; Anders Kvist ; Philippe Lemey ; Maureen M. Goodenow ; Eva Maria Feny? ; Jan Albert ; Marco Salemi ; Joakim Esbj?rnsson ; Patrik Medstr
• 关键词：Intrapatient HIV-1 evolutionary rate ; Coreceptor switch ; CCR5 and CXCR4 use ; R5 and X4 virus populations ; Synonymous and non-synonymous substitutions ; Hierarchical phylogenetic model
• 刊名：Infection, Genetics and Evolution
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：19
• 期：Complete
• 页码：369-377
• 全文大小：433 K

文摘

In approximately 70 % of individuals infected with HIV-1 subtype B, the virus switches coreceptor use from exclusively CCR5 use (R5 virus) to either inclusion of or exclusively CXCR4 use (X4 virus) during infection. This switch is associated with an accelerated loss of CD4⁺ T-cells and a faster progression to AIDS. Despite intensive research, the mechanisms responsible for coreceptor switch remains elusive. In the present study, we investigated associations between viral evolutionary rate and selection pressure versus viral coreceptor use and rate of disease progression in eight patients with longitudinally sampled HIV-1 env V1-V3 sequences. By employing a Bayesian hierarchical phylogenetic model, we found that the HIV-1 evolutionary rate was more strongly associated with coreceptor switch than with rate of disease progression in terms of CD4⁺T-cell decline. Phylogenetic analyses showed that X4 variants evolved from R5 populations. In addition, coreceptor switch was associated with higher evolutionary rates on both the synonymous and non-synonymous substitution level, but not with dN/dS ratio rates. Our findings suggest that X4 viruses evolved from pre-existing R5 viral populations and that the evolution of coreceptor switch is governed by high replication rates rather than by selective pressure. Furthermore, the association of viral evolutionary rate was more strongly associated with coreceptor switch than disease progression. This adds to the understanding of the complex virus-host interplay that influences the evolutionary dynamics of HIV-1 coreceptor use.