Human Immunodeficiency Virus Type 1 Modified To Package Simian Immunodeficiency Virus Vpx Efficiently Infects Macrophages and Dendritic Cells
Human Immunodeficiency Virus Type 1 Modified To Package Simian Immunodeficiency Virus Vpx Efficiently Infects Macrophages and Dendritic Cells
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DOI：
10.1128/jvi.00346-11
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发表时间：
2011-07-01
影响因子：
5.4
通讯作者：
Landau, Nathaniel R.
中科院分区：
文献类型：
--
作者：
Sunseri, Nicole;O'Brien, Meagan;Landau, Nathaniel R.
慢病毒辅助蛋白Vpx被认为通过对抗未知宿主限制因子促进巨噬细胞和树突状细胞的感染。虽然人类免疫缺陷病毒1型（HIV-1）不编码Vpx，但这种辅助蛋白可以在病毒样颗粒中提供给单核细胞源性巨噬细胞（MDM）和单核细胞源性树突状细胞（MDDC），显著增强它们对HIV-1的易感性。Vpx和相关的辅助蛋白Vpr通过与Gag的p6羧基末端结构域的病毒特异性相互作用被包装成病毒粒子。我们将猴免疫缺陷病毒SIVmac(239) p6的最小Vpx包装基序定位到一个10个氨基酸的基序上，并将该序列引入感染性HIV-1原病毒。嵌合病毒包装了以反式提供的Vpx，并且在MDDC和MDM上的传染性比野生型病毒强得多。我们通过引入Vpx编码序列来代替nef进一步修饰病毒。由此产生的病毒产生Vpx，并在MDDC和MDM中高效复制。该病毒还在MDDC中诱导了强有力的I型干扰素反应。在共培养系统中，含有vpx的HIV-1更有效地从MDDC传播到T细胞。这些发现表明，在体内，Vpx可能促进病毒从树突状细胞传播到T细胞。此外，嵌合病毒可用于设计树突状细胞疫苗，诱导增强的先天免疫反应。这种方法也可用于设计转导这些相对耐药细胞的慢病毒载体。
The lentiviral accessory protein Vpx is thought to facilitate the infection of macrophages and dendritic cells by counteracting an unidentified host restriction factor. Although human immunodeficiency virus type 1 (HIV-1) does not encode Vpx, the accessory protein can be provided to monocyte-derived macrophages (MDM) and monocyte-derived dendritic cells (MDDC) in virus-like particles, dramatically enhancing their susceptibility to HIV-1. Vpx and the related accessory protein Vpr are packaged into virions through a virus-specific interaction with the p6 carboxy-terminal domain of Gag. We localized the minimal Vpx packaging motif of simian immunodeficiency virus SIVmac(239) p6 to a 10-amino-acid motif and introduced this sequence into an infectious HIV-1 provirus. The chimeric virus packaged Vpx that was provided in trans and was substantially more infectious on MDDC and MDM than the wild-type virus. We further modified the virus by introducing the Vpx coding sequence in place of nef. The resulting virus produced Vpx and replicated efficiently in MDDC and MDM. The virus also induced a potent type I interferon response in MDDC. In a coculture system, the Vpx-containing HIV-1 was more efficiently transmitted from MDDC to T cells. These findings suggest that in vivo, Vpx may facilitate transmission of the virus from dendritic cells to T cells. In addition, the chimeric virus could be used to design dendritic cell vaccines that induce an enhanced innate immune response. This approach could also be useful in the design of lentiviral vectors that transduce these relatively resistant cells.