To explore the mechanism behind the association between HSV-2 and HIV-1 acquisition, we performed in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions on and off antiviral therapy. CD4+ and CD8+ T cells, and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even in the context of daily antiviral therapy. The CD4+ T cells that persisted reacted to HSV-2 antigen, were enriched for CCR5 expression, and were also contiguous to DCs expressing CD123 or DC-SIGN. Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed increased concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies as compared to control skin biopsies. The persistence and enrichment of HIV-receptor-positive inflammatory cells in the genitalia help explain the failure of anti-HSV-2 therapy to reduce HIV acquisition.

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