Marsden Valerie, Donaghy Heather, Bertram Kirstie M, Harman Andrew N, Nasr Najla, Keoshkerian Elizabeth, Merten Steven, Lloyd Andrew R, Cunningham Anthony L
Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia 2145; Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia 2006;
Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia 2145;
J Immunol. 2015 May 1;194(9):4438-45. doi: 10.4049/jimmunol.1401706. Epub 2015 Apr 3.
Prior HSV-2 infection enhances the acquisition of HIV-1 >3-fold. In genital herpes lesions, the superficial layers of stratified squamous epithelium are disrupted, allowing easier access of HIV-1 to Langerhans cells (LC) in the epidermis and perhaps even dendritic cells (DCs) in the outer dermis, as well as to lesion infiltrating activated T lymphocytes and macrophages. Therefore, we examined the effects of coinfection with HIV-1 and HSV-2 on monocyte-derived DCs (MDDC). With simultaneous coinfection, HSV-2 significantly stimulated HIV-1 DNA production 5-fold compared with HIV-1 infection alone. Because <1% of cells were dually infected, this was a field effect. Virus-stripped supernatants from HSV-2-infected MDDCs were shown to enhance HIV-1 infection, as measured by HIV-1-DNA and p24 Ag in MDDCs. Furthermore these supernatants markedly stimulated CCR5 expression on both MDDCs and LCs. TNF-α was by far the most prominent cytokine in the supernatant and also within HSV-2-infected MDDCs. HSV-2 infection of isolated immature epidermal LCs, but not keratinocytes, also produced TNF-α (and low levels of IFN-β). Neutralizing Ab to TNF-α and its receptor, TNF-R1, on MDDCs markedly inhibited the CCR5-stimulating effect of the supernatant. Therefore, these results suggest that HSV-2 infection of DCs in the skin during primary or recurrent genital herpes may enhance HIV-1 infection of adjacent DCs, thus contributing to acquisition of HIV-1 through herpetic lesions.
既往单纯疱疹病毒2型（HSV-2）感染会使HIV-1的感染几率增加3倍以上。在生殖器疱疹病变中，复层鳞状上皮的表层遭到破坏，使得HIV-1更容易接触到表皮中的朗格汉斯细胞（LC），甚至可能接触到真皮外层的树突状细胞（DC），以及病变部位浸润的活化T淋巴细胞和巨噬细胞。因此，我们研究了HIV-1与HSV-2合并感染对单核细胞来源的DC（MDDC）的影响。同时合并感染时，与单独感染HIV-1相比，HSV-2能显著刺激HIV-1 DNA产生，增加5倍。由于只有不到1%的细胞发生双重感染，这是一种旁分泌效应。HSV-2感染的MDDC去除病毒后的上清液可增强HIV-1感染，这通过MDDC中的HIV-1 DNA和p24抗原得以检测。此外，这些上清液能显著刺激MDDC和LC上CCR5的表达。到目前为止，TNF-α是上清液以及HSV-2感染的MDDC中最显著的细胞因子。对分离出的未成熟表皮LC而非角质形成细胞进行HSV-2感染，也会产生TNF-α（以及低水平的IFN-β）。用针对TNF-α及其受体TNF-R1的中和抗体处理MDDC，可显著抑制上清液对CCR5的刺激作用。因此，这些结果表明，在原发性或复发性生殖器疱疹期间，皮肤中的DC受到HSV-2感染可能会增强相邻DC的HIV-1感染，从而导致通过疱疹病变感染HIV-1。
