title: Herpes simplex virus type 2-infected dendritic cells produce TNF-α, which enhances CCR5 expression and stimulates HIV production from adjacent infected cells.
abstract: 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.
authors.affiliation: 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;
authors.forename: Valerie
authors.initials: V
authors.lastname: Marsden
authors.affiliation: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia 2145;
authors.forename: Heather
authors.initials: H
authors.lastname: Donaghy
authors.affiliation: 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;
authors.forename: Kirstie M
authors.initials: KM
authors.lastname: Bertram
authors.affiliation: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia 2145;
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Harman
authors.affiliation: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales, Australia 2145;
authors.forename: Najla
authors.initials: N
authors.lastname: Nasr
authors.affiliation: Inflammation and Infection Research Centre, Faculty of Medicine, The University of New South Wales, Kensington, New South Wales, Australia 2052; and.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Keoshkerian
authors.affiliation: Pure Aesthetics Plastic Surgery, Sydney, New South Wales, Australia 2000.
authors.forename: Steven
authors.initials: S
authors.lastname: Merten
authors.affiliation: Inflammation and Infection Research Centre, Faculty of Medicine, The University of New South Wales, Kensington, New South Wales, Australia 2052; and.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Lloyd
authors.affiliation: 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; tony.cunningham@sydney.edu.au.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Cunningham
mesh_terms: D060085:Coinfection; D017077:Culture Media, Conditioned / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006558:Herpes Genitalis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018258:Herpesvirus 2, Human / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D008954:Models, Biological; D019713:Receptors, CCR5 / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation; D014779:Virus Replication
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha