Heterosexual Transmission of Human Immunodeficiency Virus Type 1 Subtype C: Macrophage Tropism, Alternative Coreceptor Use, and the Molecular Anatomy of CCR5 Utilization
Heterosexual Transmission of Human Immunodeficiency Virus Type 1 Subtype C: Macrophage Tropism, Alternative Coreceptor Use, and the Molecular Anatomy of CCR5 Utilization
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DOI：
10.1128/jvi.00296-09
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发表时间：
2009-08-15
影响因子：
5.4
通讯作者：
Collman, Ronald G.
中科院分区：
文献类型：
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作者：
Isaacman-Beck, Jesse;Hermann, Emilia A.;Collman, Ronald G.
人类免疫缺陷病毒1型传播选择具有与供体准种不同的遗传特征的病毒变体，但有利于其传播或在新宿主中建立的生物学因素尚不清楚。我们比较了在赞比亚异性恋传播对急性感染时获得的供体和受体亚型C Envs的主要靶细胞倾向和进入共受体利用。供体和受体Envs均表现出适度的巨噬细胞趋向性，两组之间巨噬细胞或CD4 t细胞感染效率没有总体差异。几对个体在原代细胞感染中表现出供体/受体差异，但这些差异在两对之间并不一致。Envs出人意料地广泛使用GPR15、CXCR6和APJ，但很少或没有使用CCR2b、CCR3、CCR8、GPR1和CXCR4。捐助者总体上比受助者更好地使用GPR15。然而，尽管一些个体对GPR15和/或其他共受体表现出供体/受体差异，但差异的方向是不一致的，并且一些对具有独特的替代共受体模式，这些模式在传递屏障上是保守的。CCR5/CCR2b嵌合体表明，作为一个群体，受体比供体对CCR5细胞外环被CCR2b的相应区域取代更为敏感，但这一方向的显著差异在配对中并不一致。这些数据表明，性传播不会选择增强的巨噬细胞嗜性，也不会优先使用任何替代的辅助受体。受体env在使用CCR5的灵活性方面比供体更受限制，但这种模式并非适用于所有配对，这表明它不是绝对要求。
Human immunodeficiency virus type 1 transmission selects for virus variants with genetic characteristics distinct from those of donor quasispecies, but the biological factors favoring their transmission or establishment in new hosts are poorly understood. We compared primary target cell tropisms and entry coreceptor utilizations of donor and recipient subtype C Envs obtained near the time of acute infection from Zambian heterosexual transmission pairs. Both donor and recipient Envs demonstrated only modest macrophage tropism, and there was no overall difference between groups in macrophage or CD4 T-cell infection efficiency. Several individual pairs showed donor/recipient differences in primary cell infection, but these were not consistent between pairs. Envs had surprisingly broad uses of GPR15, CXCR6, and APJ, but little or no use of CCR2b, CCR3, CCR8, GPR1, and CXCR4. Donors overall used GPR15 better than did recipients. However, while several individual pairs showed donor/recipient differences for GPR15 and/or other coreceptors, the direction of the differences was inconsistent, and several pairs had unique alternative coreceptor patterns that were conserved across the transmission barrier. CCR5/CCR2b chimeras revealed that recipients as a group were more sensitive than were donors to replacement of the CCR5 extracellular loops with corresponding regions of CCR2b, but significant differences in this direction were not consistent within pairs. These data show that sexual transmission does not select for enhanced macrophage tropism, nor for preferential use of any alternative coreceptor. Recipient Envs are somewhat more constrained than are donors in flexibility of CCR5 use, but this pattern is not universal for all pairs, indicating that it is not an absolute requirement.