Expression of CCR5 increases during monocyte differentiation and directly mediates macrophage susceptibility to infection by human immunodeficiency virus type 1
Expression of CCR5 increases during monocyte differentiation and directly mediates macrophage susceptibility to infection by human immunodeficiency virus type 1
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DOI：
10.1128/jvi.72.6.4962-4969.1998
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发表时间：
1998-06-01
影响因子：
5.4
通讯作者：
Goodenow, MM
中科院分区：
文献类型：
--
作者：
Tuttle, DL;Harrison, JK;Goodenow, MM
CD 4（+）细胞的分化阶段和谱系深刻地影响其对人类免疫缺陷病毒1型（HIV-1）感染的易感性，而患者中的CD 4（+）T淋巴细胞容易对HIV-1感染易感，外周血单核细胞在急性或早期感染时相对抵抗，尽管单核细胞也表达CD-1，并且具有巨噬细胞Ch 1-嗜性表型的病毒株占优势。CCR 5是嗜性病毒的主要辅助受体，它明显有助于CD 4（+）T细胞被感染的能力。为了确定低水平的CCR 5表达是否导致了单核细胞感染的阻断，我们在分化过程中检测了原代单核细胞谱系细胞。血液单核细胞培养5天导致来自80%单核细胞衍生的巨噬细胞（MDM）的CCR 5阳性细胞的平均数量增加。每个单核细胞的CCR 5表达水平通常低于MDM，可能低于有效感染所需的最低阈值水平。生产性感染可能局限于表达相对高水平的CCR 5的单核细胞的小子集。在MDM分化过程中，稳态CCR 5 mRNA水平也增加了4 - 5倍。高嗜性HIV-1（JRFL）感染MDM导致p24水平比单核细胞高10倍，MDM携带的HIV-1 DNA拷贝数比单核细胞高30倍。在存在CCR 5特异性单克隆抗体（MAb）2D 7的情况下，MDM中的病毒产生和HIV DNA的细胞水平降低了>80%，表明病毒进入被阻止。CCR 5水平与单核细胞向巨噬细胞的分化有直接关系。CCR 5的水平与单核细胞抵抗和巨噬细胞对感染的易感性有关，因为M嗜性株HIV-1（JRFL）的感染可以被MAb 2D 7阻断。这些结果提供了直接的证据表明，CCR 5作为一个辅助受体的HIV-1感染的原代巨噬细胞。
The stage of differentiation and the lineage of CD4(+) cells profoundly affect their susceptibility to infection by human immunodeficiency virus type 1 (HIV-1), While CD4(+) T lymphocytes in patients are readily susceptible to HIV-1 infection, peripheral blood monocytes are relatively resistant during acute or early infection, even though monocytes also express CD-l and viral strains with macrophage Chl)-tropic phenotypes predominate. CCR5, the main coreceptor for hi-tropic viruses, clearly contributes to the ability of CD4(+) T cells to be infected. To determine whether low levels of CCR5 expression account for the block in infection of monocytes, we examined primary monocyte lineage cells during differentiation. Culturing of blood monocytes for 5 days led to an increase in the mean number of CCR5-positive cells from 80% of monocyte-derived macrophages (MDM). Levels of CCR5 expression per monocyte were generally low er than those on MDM, perhaps below a minimum threshold level necessary for efficient infection. Productive infection may be restricted to the small subset of monocytes that express relatively high levels of CCR5. Steady-state CCR5 mRNA levels also increased four-to fivefold during MDM differentiation. Infection of MDM by hi-tropic HIV-1(JRFL) resulted in > 10-fold-higher levels of p24, and MDM harbored >30-fold more HIV-1 DNA copies than monocytes. In the presence of the CCR5-specific monoclonal antibody (MAb) 2D7, virus production and cellular levels of HIV DNA were decreased by >80% in MDM, indicating a block in viral entry. There was a direct association between levels of CCR5 and differentiation of monocytes to macrophages. Levels of CCR5 were related to monocyte resistance and macrophage susceptibility to infection because infection by the M-tropic strain HIV-1(JRFL) could be blocked by MAb 2D7. These results provide direct evidence that CCR5 functions as a coreceptor for HIV-1 infection of primary macrophages.