Weinberger Ariel D, Perelson Alan S, Ribeiro Ruy M, Weinberger Leor S
Biophysics Graduate Group, University of California, Berkeley, CA, USA.
PLoS Comput Biol. 2009 Aug;5(8):e1000467. doi: 10.1371/journal.pcbi.1000467. Epub 2009 Aug 14.
In 50% of progressing HIV-1 patients, CXCR4-tropic (X4) virus emerges late in infection, often overtaking CCR5-tropic (R5) virus as the dominant viral strain. This "phenotypic switch" is strongly associated with rapidly declining CD4(+) T cell counts and AIDS onset, yet its causes remain unknown. Here, we analyze a mathematical model for the mechanism of X4 emergence in late-stage HIV infection and use this analysis to evaluate the utility of a promising new class of antiretroviral drugs -- CCR5 inhibitors -- in dual R5, X4 infection. The model shows that the R5-to-X4 switch occurs as CD4(+) T cell activation levels increase above a threshold and as CD4(+) T cell counts decrease below a threshold during late-stage HIV infection. Importantly, the model also shows that highly active antiretroviral therapy (HAART) can inhibit X4 emergence but that monotherapy with CCR5 blockers can accelerate X4 onset and immunodeficiency if X4 infection of memory CD4(+) T cells occurs at a high rate. Fortunately, when CXCR4 blockers or HAART are used in conjunction with CCR5 blockers, this risk of accelerated immunodeficiency is eliminated. The results suggest that CCR5 blockers will be more effective when used in combination with CXCR4 blockers and caution against CCR5 blockers in the absence of an effective HAART regimen or during HAART failure.
在50%病情进展的HIV-1患者中，嗜CXCR4（X4）型病毒在感染后期出现，常常取代嗜CCR5（R5）型病毒成为主要毒株。这种“表型转换”与CD4(+) T细胞计数迅速下降及艾滋病发作密切相关，但其成因尚不清楚。在此，我们分析了一个关于HIV感染后期X4型病毒出现机制的数学模型，并利用该分析评估一类有前景的新型抗逆转录病毒药物——CCR5抑制剂——在R5、X4双重感染中的效用。该模型显示，在HIV感染后期，当CD4(+) T细胞激活水平升至阈值以上且CD4(+) T细胞计数降至阈值以下时，就会发生R5向X4的转换。重要的是，该模型还显示，高效抗逆转录病毒疗法（HAART）可抑制X4型病毒出现，但如果记忆性CD4(+) T细胞被X4型病毒感染的发生率很高，那么用CCR5阻断剂进行单一疗法会加速X4型病毒出现和免疫缺陷。幸运的是，当CXCR4阻断剂或HAART与CCR5阻断剂联合使用时，这种加速免疫缺陷的风险就会消除。结果表明，CCR5阻断剂与CXCR4阻断剂联合使用时会更有效，并警示在缺乏有效的HAART方案或HAART治疗失败期间使用CCR5阻断剂时需谨慎。
