A systematic analysis of intrinsic regulators for HIV-1 R5 to X4 phenotypic switch

摘要

Background: Human immunodeficiency virus isolates most often use chemokine receptor CCR5 or CXCR4 as a co-receptor 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-HIV/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 phenotypic 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.