Yi Y, Isaacs S N, Williams D A, Frank I, Schols D, De Clercq E, Kolson D L, Collman R G
Divisions of Pulmonary and Critical Care, Philadelphia, Pennsylvania, and Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
J Virol. 1999 Sep;73(9):7117-25. doi: 10.1128/JVI.73.9.7117-7125.1999.
Dual-tropic human immunodeficiency virus type 1 (HIV-1) strains infect both primary macrophages and transformed T-cell lines. Prototype T-cell line-tropic (T-tropic) strains use CXCR4 as their principal entry coreceptor (X4 strains), while macrophagetropic (M-tropic) strains use CCR5 (R5 strains). Prototype dual tropic strains use both coreceptors (R5X4 strains). Recently, CXCR4 expressed on macrophages was found to support infection by certain HIV-1 isolates, including the dual-tropic R5X4 strain 89.6, but not by T-tropic X4 prototypes like 3B. To better understand the cellular basis for dual tropism, we analyzed the macrophage coreceptors used for Env-mediated cell-cell fusion as well as infection by several dual-tropic HIV-1 isolates. Like 89.6, the R5X4 strain DH12 fused with and infected both wild-type and CCR5-negative macrophages. The CXCR4-specific inhibitor AMD3100 blocked DH12 fusion and infection in macrophages that lacked CCR5 but not in wild-type macrophages. This finding indicates two independent entry pathways in macrophages for DH12, CCR5 and CXCR4. Three primary isolates that use CXCR4 but not CCR5 (tybe, UG021, and UG024) replicated efficiently in macrophages regardless of whether CCR5 was present, and AMD3100 blocking of CXCR4 prevented infection in both CCR5 negative and wild-type macrophages. Fusion mediated by UG021 and UG024 Envs in both wild-type and CCR5-deficient macrophages was also blocked by AMD3100. Therefore, these isolates use CXCR4 exclusively for entry into macrophages. These results confirm that macrophage CXCR4 can be used for fusion and infection by primary HIV-1 isolates and indicate that CXCR4 may be the sole macrophage coreceptor for some strains. Thus, dual tropism can result from two distinct mechanisms: utilization of both CCR5 and CXCR4 on macrophages and T-cell lines, respectively (dual-tropic R5X4), or the ability to efficiently utilize CXCR4 on both macrophages and T-cell lines (dual-tropic X4).
双嗜性人类免疫缺陷病毒1型（HIV-1）毒株可感染原代巨噬细胞和转化的T细胞系。原型T细胞系嗜性（T嗜性）毒株以CXCR4作为其主要进入共受体（X4毒株），而巨噬细胞嗜性（M嗜性）毒株则利用CCR5（R5毒株）。原型双嗜性毒株同时利用这两种共受体（R5X4毒株）。最近发现，巨噬细胞上表达的CXCR4可支持某些HIV-1分离株的感染，包括双嗜性R5X4毒株89.6，但不支持T嗜性X4原型毒株如3B的感染。为了更好地理解双嗜性的细胞基础，我们分析了用于Env介导的细胞-细胞融合以及几种双嗜性HIV-1分离株感染的巨噬细胞共受体。与89.6一样，R5X4毒株DH12可与野生型和CCR5阴性巨噬细胞融合并感染它们。CXCR4特异性抑制剂AMD3100可阻断DH12在缺乏CCR5的巨噬细胞中的融合和感染，但不能阻断在野生型巨噬细胞中的融合和感染。这一发现表明，DH12在巨噬细胞中有两条独立的进入途径，即CCR5和CXCR4。三种使用CXCR4但不使用CCR5的原代分离株（tybe、UG021和UG024），无论是否存在CCR5，均可在巨噬细胞中高效复制，而AMD3100对CXCR4的阻断可防止其在CCR5阴性和野生型巨噬细胞中的感染。UG021和UG024 Env在野生型和CCR5缺陷型巨噬细胞中介导的融合也被AMD3100阻断。因此，这些分离株仅利用CXCR4进入巨噬细胞。这些结果证实，巨噬细胞CXCR4可被原发性HIV-1分离株用于融合和感染，并表明CXCR4可能是某些毒株唯一的巨噬细胞共受体。因此，双嗜性可能由两种不同机制导致：分别在巨噬细胞和T细胞系上利用CCR5和CXCR（双嗜性R5X4），或在巨噬细胞和T细胞系上均有效利用CXCR4的能力（双嗜性X4）。
