HIV-1 co-receptor tropism is central for understanding the transmission and pathogenesis of HIV-1 infection. We performed a genome-wide comparison between the adaptive evolution of R5 and X4 variants from HIV-1 subtyp...HIV-1 co-receptor tropism is central for understanding the transmission and pathogenesis of HIV-1 infection. We performed a genome-wide comparison between the adaptive evolution of R5 and X4 variants from HIV-1 subtypes B and C. The results showed that R5 and X4 variants experienced differential evolutionary patterns and different HIV-1 genes encountered various positive selection pressures, suggesting that complex selection pressures are driving HIV-1 evolution. Compared with other hypervariable regions of Gp120, significantly more positively selected sites were detected in the V3 region of subtype B X4 variants, V2 region of subtype B R5 variants, and V1 and V4 regions of subtype C X4 variants, indicating an association of positive selection with co-receptor recognition/binding. Intriguingly, a significantly higher proportion (33.3% and 55.6%, P【0.05) of positively selected sites were identified in the C3 region than other conserved regions of Gp120 in all the analyzed HIV-1 variants, indicating that the C3 region might be more important to HIV-1 adaptation than previously thought. Approximately half of the positively selected sites identified in the env gene were identical between R5 and X4 variants. There were three common positively selected sites (96, 113 and 281) identified in Gp41 of all X4 and R5 variants from subtypes B and C. These sites might not only suggest a functional importance in viral survival and adaptation, but also imply a potential cross-immunogenicity between HIV-1 R5 and X4 variants, which has important implications for AIDS vaccine development.展开更多
Background： Human immunodeficiency virus isolates most often use chemokine receptor CCR5 or CXCR4 as a coreceptor to enter target cells. During early stages of HIV-1 infection, CCR5-tropic viruses are the predominant...Background： Human immunodeficiency virus isolates most often use chemokine receptor CCR5 or CXCR4 as a coreceptor to enter target cells. During early stages of HIV-1 infection, CCR5-tropic viruses are the predominant species. The CXCR4-tropic viruses may emerge late in infection. Recognition of factors influencing this phenotypic switch may give some hints on the antiviral strategies like anti-H1V/AIDS drugs, gene therapy and vaccines. Methods： To investigate the mechanism that triggers R5 to X4 phenotypic switch, we performed a systematic sensitivity analysis based on a five-dimensional model with time-varying parameters. We studied the sensitivity of each factor to the CCR5-to-CXCR4 tropism switch and acquired some interesting outcomes beyond expectation. Results： The death rate of free virus （dv）, rate that uninfected CD4＋ T cells arise from precursors （s） and proliferate as stimulated by antigens （r）, and in vivo viral burst size （N） are four robust factors which are constantly observed to have a strong correlation with the evolution of viral phenotype for most patients longitudinally. Conclusions： Crucial factors, which are essential to phenotypie switch and disease progression, are almost the same for different patients at different time points, including the production of both virus and CD4＋ T cells and the decay of virion. It is also worth mentioning that although the sequence of factors sorted by the influence varies between patients, the trends of influences engendered by most factors as disease progresses are similar inter-patients.展开更多
基金supported by the National Natural Science Foundation of China (Grant No. 30600352)the "Top-notch Personnel" Project of Ji-angsu University, the National Basic Research Program of China (Grant No. 2006CB504200)the Open Research Fund Program of the State Key Laboratory of Virology of China (Grant No. 2009008)
文摘HIV-1 co-receptor tropism is central for understanding the transmission and pathogenesis of HIV-1 infection. We performed a genome-wide comparison between the adaptive evolution of R5 and X4 variants from HIV-1 subtypes B and C. The results showed that R5 and X4 variants experienced differential evolutionary patterns and different HIV-1 genes encountered various positive selection pressures, suggesting that complex selection pressures are driving HIV-1 evolution. Compared with other hypervariable regions of Gp120, significantly more positively selected sites were detected in the V3 region of subtype B X4 variants, V2 region of subtype B R5 variants, and V1 and V4 regions of subtype C X4 variants, indicating an association of positive selection with co-receptor recognition/binding. Intriguingly, a significantly higher proportion (33.3% and 55.6%, P【0.05) of positively selected sites were identified in the C3 region than other conserved regions of Gp120 in all the analyzed HIV-1 variants, indicating that the C3 region might be more important to HIV-1 adaptation than previously thought. Approximately half of the positively selected sites identified in the env gene were identical between R5 and X4 variants. There were three common positively selected sites (96, 113 and 281) identified in Gp41 of all X4 and R5 variants from subtypes B and C. These sites might not only suggest a functional importance in viral survival and adaptation, but also imply a potential cross-immunogenicity between HIV-1 R5 and X4 variants, which has important implications for AIDS vaccine development.
文摘Background： Human immunodeficiency virus isolates most often use chemokine receptor CCR5 or CXCR4 as a coreceptor to enter target cells. During early stages of HIV-1 infection, CCR5-tropic viruses are the predominant species. The CXCR4-tropic viruses may emerge late in infection. Recognition of factors influencing this phenotypic switch may give some hints on the antiviral strategies like anti-H1V/AIDS drugs, gene therapy and vaccines. Methods： To investigate the mechanism that triggers R5 to X4 phenotypic switch, we performed a systematic sensitivity analysis based on a five-dimensional model with time-varying parameters. We studied the sensitivity of each factor to the CCR5-to-CXCR4 tropism switch and acquired some interesting outcomes beyond expectation. Results： The death rate of free virus （dv）, rate that uninfected CD4＋ T cells arise from precursors （s） and proliferate as stimulated by antigens （r）, and in vivo viral burst size （N） are four robust factors which are constantly observed to have a strong correlation with the evolution of viral phenotype for most patients longitudinally. Conclusions： Crucial factors, which are essential to phenotypie switch and disease progression, are almost the same for different patients at different time points, including the production of both virus and CD4＋ T cells and the decay of virion. It is also worth mentioning that although the sequence of factors sorted by the influence varies between patients, the trends of influences engendered by most factors as disease progresses are similar inter-patients.
