Persistence of HIV-1 receptor–positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition

Genital herpes is the most prevalent viral sexually transmitted infection worldwide and is mainly caused by HSV type 2 (HSV-2). HSV-2 infection enhances HIV-1 susceptibility, even in the absence of clinical symptoms. In this study, we investigated the effect of HSV-2 on HIV-1 transmission by mucosal Langerhans cells (LCs). LCs are important in heterosexual transmission because they form a barrier against HIV-1 infection; LCs efficiently capture and degrade HIV-1 through the C-type lectin langerin, thereby preventing HIV-1 transmission. Notably, our data showed that HSV-2 enhanced HIV-1 infection of LCs and subsequent HIV-1 transmission to T cells. HSV-2 interfered with HIV-1 capture by langerin, which allowed efficient HIV-1 infection of LCs. HSV-2 inhibited the antiviral function of langerin at two levels; HSV-2 decreased langerin expression and competed with HIV-1 for langerin binding. HSV-2 replication was not required, because both UV-inactivated HSV-2 and TLR-3 agonist polyinosinic:polycytidylic acid similarly increased HIV-1 transmission by LCs. Therefore, we identified a mechanism by which HSV-2 enhances HIV-1 susceptibility, even in the absence of clinical symptoms. Our data demonstrated that viral coinfections, such as HSV-2, breach the protective function of LCs by abrogating langerin function, which increases HIV-1 susceptibility. These data reinforce the importance of preventing sexually transmitted infections, such as HSV-2, to reduce the transmission of HIV-1.

Section: Discussionmentioning

confidence: 99%

“…HSV-2 also induces inflammation, thereby including T cell influx, even in the absence of clinically apparent lesions. Furthermore, HIV-1-susceptible inflammatory cells can persist for a long period of time after HSV-2 infection has been cleared and the lesions have healed (10).…”

mentioning

confidence: 99%

Herpes Simplex Virus Type 2 Enhances HIV-1 Susceptibility by Affecting Langerhans Cell Function

Jong

Witte

Taylor

et al. 2010

“…Residual dermal DCs, plasmacytoid DCs (pDCs), and CD4 and CD8 T lymphocytes persist in the dermis between lesions. CD8 T lymphocytes are most superficial, with some present at the dermo-epidermal junction (8).…”

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confidence: 99%

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

Kim

Osborne

Zeng

et al. 2012

NK cells infiltrate human herpetic lesions, but their role has been underexplored. HSV can stimulate innate immune responses via surface TLR2, which is expressed on monocyte-derived dendritic cells (DCs) and NK cells. In this study, UV-inactivated HSV1/2 and immunodominant HSV2 glycoprotein D peptides conjugated to the TLR2 agonist dipalmitoyl-S-glyceryl cysteine stimulated CD4 T lymphocyte IFN-γ responses within PBMCs or in coculture with monocyte-derived DCs. NK cells contributed markedly to the PBMC responses. Furthermore, NK cells alone were activated directly by both Ags, also upregulating HLA-DR and HLA-DQ and then they activated autologous CD4 T lymphocytes. Using Transwells, Ag-stimulated NK cells and CD4 T lymphocytes were shown to interact through both cell-to-cell contact and cytokines, differing in relative importance in different donors. A distinct immunological synapse between Ag-stimulated NK cells and CD4 T lymphocytes was observed, indicating the significance of their cell-to-cell contact. A large proportion (57%) of NK cells was also in contact with CD4 T lymphocytes in the dermal infiltrate of human recurrent herpetic lesions. Thus, NK cells stimulated by TLR2-activating HSV Ags can present Ag alone or augment the role of DCs in vitro and perhaps in herpetic lesions or draining lymph nodes. In addition to DCs, NK cells should be considered as targets for adjuvants during HSV vaccine development.

“…For instance, the formation of pustules and ulcers by genital herpes may facilitate HIV-1 entry into mucosal tissues (10,11). Analyses of biopsies of HSV-2 lesions from patients revealed that HSV-2 reactivation resulted in an influx of activated CD4 + T cells, which may facilitate HIV-1 infection and subsequent dissemination (12,13). Immune activation of HIV-1 target cells, including dendritic cells and CD4 + T cells by HSV-2 infection, also likely enhances HIV-1 susceptibility (14).…”

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confidence: 99%

Herpes Simplex Virus Type 2 Infection of Human Epithelial Cells Induces CXCL9 Expression and CD4+ T Cell Migration via Activation of p38-CCAAT/Enhancer-Binding Protein-β Pathway

Huang

Luo

et al. 2012

Recruitment of CD4+ T cells to infection areas after HSV-2 infection may be one of the mechanisms that account for increased HIV-1 sexual transmission. Lymphocytes recruited by chemokine CXCL9 are known to be important in control of HSV-2 infection in mice, although the underlying mechanism remains to be addressed. Based on our observation that CXCL9 expression is augmented in the cervical mucus of HSV-2–positive women, in this study we demonstrate that HSV-2 infection directly induces CXCL9 expression in primary cervical epithelial cells and cell lines, the principal targets of HSV-2, at both mRNA and protein levels. Further studies reveal that the induction of CXCL9 expression by HSV-2 is dependent upon a binding site for C/EBP-β within CXCL9 promoter sequence. Furthermore, CXCL9 expression is promoted at the transcriptional level through phosphorylating C/EBP-β via p38 MAPK pathway, leading to binding of C/EBP-β to the CXCL9 promoter. Chemotaxis assays indicate that upregulation of CXCL9 expression at the protein level by HSV-2 infection enhances the migration of PBLs and CD4+ T cells, whereas neutralization of CXCL9 or inhibition of p38-C/EBP-β pathway can significantly decrease the migration. Our data together demonstrate that HSV-2 induces CXCL9 expression in human cervical epithelial cells by activation of p38-C/EBP-β pathway through promoting the binding of C/EBP-β to CXCL9 promoter, which may recruit activated CD4+ T cells to mucosal HSV-2 infection sites and potentially increase the risk of HIV-1 sexual transmission.