HSV-2 infection of dendritic cells amplifies a highly susceptible HIV-1 cell target (PDF)
Martinelli,Elena; Tharinger,Hugo; Frank,Ines; Arthos,James; Piatak Jr.,Michael; Lifson,Jeffrey D.; Blanchard,James; Gettie,Agegnehu; Robbiani,Melissa
PLoS Pathogens 7(6): e1002109. doi:10.1371/journal.ppat.1002109-
Publication date: 2011
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 gutassociated lymphoid tissues produce retinoic acid (RA), an important immunomodulator, able to influence HIV-1 replication and a key mediator of integrin a4b7 on lymphocytes. a4b7 can be engaged by HIV-1 on the cell-surface and CD4+ T cells expressing high levels of this integrin (a4b7 ) are particularly susceptible to HIV-1 infection. Herein we provide in-vivo data in macaques showing an increased percentage of a4b7 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 ofHSV-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 a4b7 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 a4b7 CD4+ T cells. These factors may play a role in increasing the susceptibility to HIV-1.