Multiple human immunodeficiency virus type 1 Nef functions contribute to efficient replication in primary human macrophages
Multiple human immunodeficiency virus type 1 Nef functions contribute to efficient replication in primary human macrophages
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DOI：
10.1099/vir.0.79946-0
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发表时间：
2004-06-01
影响因子：
3.8
通讯作者：
Cheng-Mayer, C
中科院分区：
文献类型：
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作者：
Brown, A;Moghaddam, S;Cheng-Mayer, C
人类免疫缺陷病毒1型（HIV-1）Nef蛋白已被证明可加速原代人T淋巴细胞和巨噬细胞中的病毒生长动力学;然而，导致巨噬细胞中这种表型的Nef的具体功能尚不清楚。为了解决这一问题，产生了分子克隆的嗜巨噬细胞分离株HIV-1（SF 162）的突变体，其表达单点突变，该单点突变消除了Nef与细胞激酶相互作用或介导CD 4下调的能力。用这些突变病毒感染原代单核细胞衍生的巨噬细胞（MDM）表明，PXXP基序中的残基有助于有效复制。有趣的是，表达Nef等位基因的病毒在CD 4下调活性中有缺陷，在单轮试验中保留了野生型感染性水平，但在MDM中表现出延迟的复制动力学，并且与野生型病毒相比生长至较低的滴度。这些数据表明，有效的HIV-1复制依赖于Nef与细胞激酶相互作用并从感染的巨噬细胞表面去除CD 4的能力。
The human immunodeficiency virus type 1 (HIV-1) Nef protein has been shown to accelerate viral growth kinetics in primary human T-lymphocytes and macrophages; however, the specific function(s) of Nef responsible for this phenotype in macrophages is unknown. To address this issue, mutants of a molecularly cloned macrophage-tropic isolate, HIV-1(SF162), were generated expressing single point mutations that abrogate the ability of Nef to interact with cellular kinases or mediate CD4 down-regulation. Infection of primary monocyte-derived macrophages (MDM) with these mutant viruses revealed that residues in the PXXP motif contribute to efficient replication. Interestingly, viruses expressing alleles of Nef defective in CD4 down-modulation activity retain wild-type levels of infectivity in single-round assays but exhibited delayed replication kinetics and grew to lower titres compared to the wild-type virus in MDM. These data suggest that efficient HIV-1 replication is dependent on the ability of Nef to interact with cellular kinases and remove CD4 from the surface of infected macrophages.