Borrego Pedro, Marcelino José Maria, Rocha Cheila, Doroana Manuela, Antunes Francisco, Maltez Fernando, Gomes Perpétua, Novo Carlos, Barroso Helena, Taveira Nuno
URIA-CPM, Faculdade de Farmácia de Lisboa, Avenida das Forças Armadas, 1649-019 Lisbon, Portugal.
Retrovirology. 2008 Sep 8;5:78. doi: 10.1186/1742-4690-5-78.
This study was designed to investigate, for the first time, the short-term molecular evolution of the HIV-2 C2, V3 and C3 envelope regions and its association with the immune response. Clonal sequences of the env C2V3C3 region were obtained from a cohort of eighteen HIV-2 chronically infected patients followed prospectively during 2-4 years. Genetic diversity, divergence, positive selection and glycosylation in the C2V3C3 region were analysed as a function of the number of CD4+ T cells and the anti-C2V3C3 IgG and IgA antibody reactivity
The mean intra-host nucleotide diversity was 2.1% (SD, 1.1%), increasing along the course of infection in most patients. Diversity at the amino acid level was significantly lower for the V3 region and higher for the C2 region. The average divergence rate was 0.014 substitutions/site/year, which is similar to that reported in chronic HIV-1 infection. The number and position of positively selected sites was highly variable, except for codons 267 and 270 in C2 that were under strong and persistent positive selection in most patients. N-glycosylation sites located in C2 and V3 were conserved in all patients along the course of infection. Intra-host variation of C2V3C3-specific IgG response over time was inversely associated with the variation in nucleotide and amino acid diversity of the C2V3C3 region. Variation of the C2V3C3-specific IgA response was inversely associated with variation in the number of N-glycosylation sites.
The evolutionary dynamics of HIV-2 envelope during chronic aviremic infection is similar to HIV-1 implying that the virus should be actively replicating in cellular compartments. Convergent evolution of N-glycosylation in C2 and V3, and the limited diversification of V3, indicates that there are important functional constraints to the potential diversity of the HIV-2 envelope. C2V3C3-specific IgG antibodies are effective at reducing viral population size limiting the number of virus escape mutants. The C3 region seems to be a target for IgA antibodies and increasing N-linked glycosylation may prevent HIV-2 envelope recognition by these antibodies. Our results provide new insights into the biology of HIV-2 and its relation with the human host and may have important implications for vaccine design.
本研究首次旨在调查HIV-2 C2、V3和C3包膜区域的短期分子进化及其与免疫反应的关联。从18名慢性感染HIV-2的患者队列中获取env C2V3C3区域的克隆序列，这些患者在2至4年期间接受前瞻性随访。分析C2V3C3区域的遗传多样性、分歧、正选择和糖基化与CD4 + T细胞数量以及抗C2V3C3 IgG和IgA抗体反应性的关系。
宿主内核苷酸平均多样性为2.1%（标准差，1.1%），在大多数患者中随感染进程增加。V3区域氨基酸水平的多样性显著较低，C2区域则较高。平均分歧率为0.014个替换/位点/年，与慢性HIV-1感染中报道的相似。除了C2中的267和270密码子在大多数患者中受到强烈且持续的正选择外，正选择位点的数量和位置高度可变。位于C2和V3的N-糖基化位点在所有患者的感染过程中均保守。C2V3C3特异性IgG反应随时间的宿主内变异与C2V3C3区域核苷酸和氨基酸多样性的变异呈负相关。C2V3C3特异性IgA反应的变异与N-糖基化位点数量的变异呈负相关。
慢性病毒血症感染期间HIV-2包膜的进化动态与HIV-1相似，这意味着病毒应在细胞区室中积极复制。C2和V3中N-糖基化的趋同进化以及V3的有限多样化表明，HIV-2包膜的潜在多样性存在重要的功能限制。C-2V3C3特异性IgG抗体可有效减少病毒种群大小，限制病毒逃逸突变体的数量。C3区域似乎是IgA抗体的靶点，增加N-连接糖基化可能会阻止这些抗体识别HIV-2包膜。我们的结果为HIV-2生物学及其与人类宿主的关系提供了新见解，可能对疫苗设计具有重要意义。
