Abstract
Herpes simplex virus type 2 (HSV-2) increases the risk of HIV-1 infection and, although several reports describe the interaction between these two viruses, the exact mechanism for this increased susceptibility remains unclear. Dendritic cells (DCs) at the site of entry of HSV-2 and HIV-1 contribute to viral spread in the mucosa. Specialized DCs present in the gut-associated lymphoid tissues produce retinoic acid (RA), an important immunomodulator, able to influence HIV-1 replication and a key mediator of integrin α4β7 on lymphocytes. α4β7 can be engaged by HIV-1 on the cell-surface and CD4+ T cells expressing high levels of this integrin (α4β7 high) are particularly susceptible to HIV-1 infection. Herein we provide in-vivo data in macaques showing an increased percentage of α4β7 high CD4+ T cells in rectal mucosa, iliac lymph nodes and blood within 6 days of rectal exposure to live (n = 11), but not UV-treated (n = 8), HSV-2. We found that CD11c+ DCs are a major target of HSV-2 infection in in-vitro exposed PBMCs. We determined that immature monocyte-derived DCs (moDCs) express aldehyde dehydrogenase ALDH1A1, an enzyme essential for RA production, which increases upon HSV-2 infection. Moreover, HSV-2-infected moDCs significantly increase α4β7 expression on CD4+ T lymphocytes and HIV-1 infection in DC-T cell mixtures in a RA-dependent manner. Thus, we propose that HSV-2 modulates its microenviroment, influencing DC function, increasing RA production capability and amplifying a α4β7 highCD4+ T cells. These factors may play a role in increasing the susceptibility to HIV-1.
Highlights
Herpes Simplex Virus Type 2 (HSV-2) infects genital and perianal mucosa and its infection is associated with a three-fold increased risk of HIV-1 acquisition among both men and women [1]
We investigated whether human monocytederived DCs (moDCs) express aldehyde dehydrogenase 1A (ALDH1A) and if the expression of a4b7 on T cells in the dendritic cells (DCs)-T cell co-cultures could be related to a de-novo production of retinoic acid (RA) by the DCs
Having shown that HSV-2-infected DCs increase the percentage of a4b7high T cells through an RAdependent mechanism, we evaluated the impact of HSV-2 infection of immature moDCs on HIV-1 replication in DC-T cell mixtures
Summary
Herpes Simplex Virus Type 2 (HSV-2) infects genital and perianal mucosa and its infection is associated with a three-fold increased risk of HIV-1 acquisition among both men and women [1]. Active HSV-2 shedding, inflammation and ulcers during primary infections and virus reactivation certainly contribute, their resolution by suppressive therapy with acyclovir is not effective in reducing HIV-1 acquisition in HSV-2 seropositive individuals [2]. Plasmacytoid and myeloid dendritic cells (DCs), which infiltrate areas of skin infected with HSV-2, persist after lesion healing in the context of acyclovir therapy [3] and may contribute to the increased risk of HIV-1 acquisition associated with HSV-2 infection. HSV-2 infection of DCs in-vitro has been shown to inhibit their maturation and immunostimulatory functions [5,6,8,9] and in-vivo HSV-2 infection reduces HIV-1 specific T cell responses [6,10,11]
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