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

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Abstract
Infection with HSV-2 increases the likelihood of HIV acquisition, but suppression of HSV-2 reactivation with antiviral drugs does not seem to reduce the acquisition of HIV. Laurence Corey and colleagues provide a potential mechanism underlying this observation, showing that even after acyclovir treatment for the HSV-2 infection, many inflammatory and immune cells possessing the receptors required for HIV infection persist in the mucosa, making the initial 'spark' of infection more likely. To explore the mechanism by which herpes simplex virus (HSV)-2 infection is related to HIV-1 acquisition, we conducted in situ analysis of the cellular infiltrate from sequential biopsies of HSV-2 lesions from patients on and off antiviral therapy. CD4+ and CD8+ T cells and a mixed population of plasmacytoid and myeloid dendritic cells (DCs), including cells expressing the C-type lectin receptor DC-SIGN, persisted at sites of HSV-2 reactivation for months after healing, even with daily antiviral therapy. The CD4+ T cells that persisted reacted to HSV-2 antigen, were enriched for expression of the chemokine receptor CCR5, and were contiguous to DCs expressing the interleukin-3 receptor CD123 or DC-SIGN. Ex vivo infection with a CCR5-tropic strain of HIV-1 revealed greater concentrations of integrated HIV-1 DNA in cells derived from healed genital lesion biopsies than in cells from control skin biopsies. The persistence and enrichment of HIV receptor–positive inflammatory cells in the genitalia help explain the inability of anti–HSV-2 therapy to reduce HIV acquisition.