Ribeiro Ruy M, Hazenberg Mette D, Perelson Alan S, Davenport Miles P
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
J Virol. 2006 Jan;80(2):802-9. doi: 10.1128/JVI.80.2.802-809.2006.
Early human immunodeficiency virus infection is characterized by the predominance of CCR5-tropic (R5) virus. However, in many individuals CXCR4-tropic (X4) virus appears in late infection. The reasons for this phenotypic switch are unclear. The patterns of chemokine receptor expression suggest that X4 and R5 viruses have a preferential tropism for naïve and memory T cells, respectively. Since memory cells divide approximately 10 times as often as naïve cells in uninfected individuals, a tropism for memory cells in early infection may provide an advantage. However, with disease progression both naïve and memory cell division frequencies increase, and at low CD4 counts, the naïve cell division frequency approaches that of memory cells. This may provide a basis for the phenotypic switch from R5 to X4 virus observed in late infection. We show that a model of infection using observed values for cell turnover supports this mechanism. The phenotypic switch from R5 to X4 virus occurs at low CD4 counts and is accompanied by a rapid rise in viral load and drop in CD4 count. Thus, low CD4 counts are both a cause and an effect of X4 virus dominance. We also investigate the effects of different antiviral strategies. Surprisingly, these results suggest that both conventional antiretroviral regimens and CCR5 receptor-blocking drugs will promote R5 virus over X4 virus.
早期人类免疫缺陷病毒感染的特征是CCR5嗜性（R5）病毒占主导。然而，在许多个体中，CXCR4嗜性（X4）病毒在感染后期出现。这种表型转换的原因尚不清楚。趋化因子受体表达模式表明，X4和R5病毒分别对初始T细胞和记忆T细胞具有优先嗜性。由于在未感染个体中，记忆细胞的分裂频率大约是初始细胞的10倍，早期感染时对记忆细胞的嗜性可能具有优势。然而，随着疾病进展，初始细胞和记忆细胞的分裂频率均增加，在CD4细胞计数较低时，初始细胞的分裂频率接近记忆细胞。这可能为在感染后期观察到的从R5病毒到X4病毒的表型转换提供了基础。我们表明，使用观察到的细胞更新值的感染模型支持这一机制。从R5病毒到X4病毒的表型转换发生在CD4细胞计数较低时，并伴随着病毒载量的快速上升和CD4细胞计数的下降。因此，低CD4细胞计数既是X4病毒占主导的原因，也是其结果。我们还研究了不同抗病毒策略的效果。令人惊讶的是，这些结果表明，传统抗逆转录病毒疗法和CCR5受体阻断药物都会使R5病毒相对于X4病毒占优势。
