Bunnik Evelien M, Quakkelaar Esther D, van Nuenen Ad C, Boeser-Nunnink Brigitte, Schuitemaker Hanneke
Department of Clinical Viro-Immunology, Sanquin Research and Landsteiner Laboratory at the Academic Medical Center, University of Amsterdam and Center for Infection and Immunity Amsterdam (CINIMA), Amsterdam, The Netherlands.
J Virol. 2007 Jan;81(2):525-31. doi: 10.1128/JVI.01983-06. Epub 2006 Nov 1.
CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) variants evolve from CCR5-using (R5) variants relatively late in the natural course of infection in 50% of HIV-1 subtype B-infected individuals and subsequently coexist with R5 HIV-1 variants. This relatively late appearance of X4 HIV-1 variants is poorly understood. Here we tested the neutralization sensitivity for soluble CD4 (sCD4) and the broadly neutralizing antibodies IgG1b12, 2F5, 4E10, and 2G12 of multiple coexisting clonal R5 and (R5)X4 (combined term for monotropic X4 and dualtropic R5X4 viruses) HIV-1 variants that were obtained at two time points after the first appearance of X4 variants in five participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS. Recently emerged (R5)X4 viruses were significantly more sensitive to neutralization by the CD4-binding-site-directed agents sCD4 and IgG1b12 than their coexisting R5 viruses. This difference was less pronounced at the later time point. Early (R5)X4 variants from two out of four patients were also highly sensitive to neutralization by autologous serum (50% inhibition at serum dilutions of >200). Late (R5)X4 viruses from these two patients were neutralized at lower serum dilutions, which suggested escape of X4 variants from humoral immunity. Autologous neutralization of coexisting R5 and (R5)X4 variants was not observed in the other patients. In conclusion, the increased neutralization sensitivity of HIV-1 variants during the transition from CCR5 usage to CXCR4 usage may imply an inhibitory role for humoral immunity in HIV-1 phenotype evolution in some patients, thus potentially contributing to the late emergence of X4 variants.
在50%的B型人类免疫缺陷病毒1型（HIV-1）感染个体的自然感染过程中，使用CXC趋化因子受体4（CXCR4）的1型人类免疫缺陷病毒（X4 HIV-1）变体相对较晚地从使用C-C趋化因子受体5（CCR5）的变体（R5 HIV-1）进化而来，随后与R5 HIV-1变体共存。X4 HIV-1变体出现相对较晚的原因目前尚不清楚。在此，我们测试了在阿姆斯特丹HIV-1感染与艾滋病队列研究的5名参与者中，首次出现X4变体后的两个时间点获得的多个共存的克隆R5和（R5）X4（单向性X4和双嗜性R5X4病毒的合称）HIV-1变体对可溶性CD4（sCD4）以及广泛中和抗体IgG1b12、2F5、4E10和2G12的中和敏感性。最近出现的（R5）X4病毒比与其共存的R5病毒对CD4结合位点导向剂sCD4和IgG1b12的中和作用更为敏感。在较晚的时间点，这种差异不太明显。4名患者中有2名患者的早期（R5）X4变体对自身血清的中和作用也高度敏感（血清稀释度>200时抑制率达50%）。这两名患者的晚期（R5）X4病毒在较低的血清稀释度下被中和，这表明X4变体逃脱了体液免疫。在其他患者中未观察到共存的R5和（R5）X4变体的自身中和作用。总之，HIV-1变体在从使用CCR5转变为使用CXCR4的过程中，中和敏感性增加可能意味着在某些患者中体液免疫对HIV-1表型进化具有抑制作用，从而可能导致X4变体出现较晚。
