Tuttle D L, Harrison J K, Anders C, Sleasman J W, Goodenow M M
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
J Virol. 1998 Jun;72(6):4962-9. doi: 10.1128/JVI.72.6.4962-4969.1998.
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 CD4 and viral strains with macrophage (M)-tropic phenotypes predominate. CCR5, the main coreceptor for M-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 <20% of monocytes to >80% of monocyte-derived macrophages (MDM). Levels of CCR5 expression per monocyte were generally lower 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 M-tropic HIV-1JRFL 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-1 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-1JRFL could be blocked by MAb 2D7. These results provide direct evidence that CCR5 functions as a coreceptor for HIV-1 infection of primary macrophages.
CD4+细胞的分化阶段和谱系对其感染1型人类免疫缺陷病毒（HIV-1）的易感性有深远影响。虽然患者体内的CD4(+) T淋巴细胞很容易受到HIV-1感染，但外周血单核细胞在急性或早期感染期间相对具有抗性，尽管单核细胞也表达CD4且具有巨噬细胞（M）嗜性表型的病毒株占主导。CCR5是M嗜性病毒的主要共受体，显然有助于CD4+ T细胞被感染。为了确定低水平的CCR5表达是否是单核细胞感染受阻的原因，我们在分化过程中检测了原代单核细胞谱系细胞。将血液单核细胞培养5天导致CCR5阳性细胞的平均数量从单核细胞的<20%增加到单核细胞衍生巨噬细胞（MDM）的>80%。每个单核细胞的CCR5表达水平通常低于MDM上的水平，可能低于有效感染所需的最低阈值水平。有生产性的感染可能仅限于表达相对高水平CCR5的一小部分单核细胞。在MDM分化过程中，稳态CCR5 mRNA水平也增加了四到五倍。M嗜性HIV-1JRFL感染MDM导致p24水平升高>10倍，并且MDM中携带的HIV-1 DNA拷贝数比单核细胞多>30倍。在存在CCR5特异性单克隆抗体（MAb）2D7的情况下，MDM中的病毒产生和HIV-1 DNA的细胞水平降低了>80%，表明病毒进入受阻。CCR5水平与单核细胞向巨噬细胞的分化之间存在直接关联。CCR5水平与单核细胞抗性和巨噬细胞感染易感性相关，因为M嗜性毒株HIV-1JRFL的感染可被MAb 2D7阻断。这些结果提供了直接证据，证明CCR5作为HIV-1感染原代巨噬细胞的共受体发挥作用。
