Local Determinants of HSV-2 Shedding in Humans

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Recurrent HSV-2 shedding is a major risk factor for HIV-1 transmission. Recent data indicate that HSV-2 is present up to 40% of days in the periphery. The factors that control HSV-2 shedding in the skin are incompletely understood. One contributor is likely HSV-2-specific CDS T-cells, which will be studied in Project 1. This Project will focus on the expression of antiviral genes in the skin and correlating this with shedding of HSV-2. We hypothesize that a net antiviral state, as measured by the mRNA levels of interferon-stimulated genes (ISG), will correlate with the re-appearance of HSV-2 DMA after the healing of symptomatic HSV-2 lesions. Because circulating HSV-2-specific CDS T-cells over-express CXCR3, and mice with lesions in the CXCR3 axis have accelerated HSV-2 pathogenesis, we further hypothesize that the CXCR3 ligand chemokines, CXCL9, 10, and 11, will correlate with the infiltration of HSV-2-specific CDS cells (Project 1) and pDC, and negatively with detection of HSV-2 DMA and mRNA. Plasmacytoid dendritic cells (pDC) infiltrate HSV-2 lesions in animals and humans (our data), react strongly with HSV-2 via TLR9 to secrete IFN-a, and are required for defense against HSV-2 in mice. Substantial heterogeneity in pDC reactivity to HSV-2 has been observed, as have rare patients with pDC numerical or functional deficiencies and severe HSV infections. pDC likely contribute to the net IFN-driven antiviral state in lesions and the anti- HSV drug action of resiquimod. We propose blood-based studies to investigate the hypothesis that pDC number of function correlates with HSV-2 shedding rates, using subjects from the Clinical Core who are studied in Project I. Aim 1 will correlate ISG and interferon-producing cells with HSV-2 DNA/mRNA detection in human skin biopsies. Aim 2 will focus on the chemokine receptor utilization of HSV-2-specific CDS T-cells. Aim 3 will correlate pDC number and function in blood with HSV-2 shedding and clearance rates. The results may assist in designing vaccines for HSV-2 that elicit cells with the appropriate homing strategies, and clarify the mechanism of action of innate immunity modifiers as local therapy for HSV-2.