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

Abstract

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.

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Figure 1: Persistence and localization of CD4+ and CD8+ T cells in genital lesions of immunocompetent subjects.
Figure 2: Persistence of CD4+ and CD8+ T cells in genital skin of subjects on daily acyclovir (ACV) therapy.
Figure 3: HIV co-receptor expression on CD4+ T cells in HSV-2 lesions.
Figure 4: Persistence of DCs in genital lesion biopsies.
Figure 5: Interactions between DCs and CD4+ T cells in biopsies taken after healing during acyclovir treatment.

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Acknowledgements

We thank M. Mack (University Hospital Regensburg, Germany) for the antibody to CCR5 and C. McClurkan, L. Ballweber and H. Xie for technical assistance. We also thank our dedicated study participants. This work was supported by the National Institutes of Health (R37AI042528, P01AI030731, AI50132 and HD51455) and the Tietze Foundation.

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J.Z. designed the study, developed the technologies, conducted the experiments, prepared the figures and wrote the draft. A. Woodward and A.K. performed the staining and quantification. T.P. developed the first data suggesting DCs are part of the inflammatory milieu in the healing biopsy stage. F.H. conducted the ex vivo organ culture studies. C.J. and M.R. enrolled subjects and conducted the biopsies. A. Wald supervised the clinic. D.M.K. designed and analyzed experiments on HSV-2 specificity of skin-derived T cells and HIV co-receptor flow cytometry. A.M. conducted the statistical analyses. L.C. and A. Wald formulated the hypothesis and designed the study. L.C. provided funding for the study and led the writing of the paper. All authors contributed to critical revisions of the paper.

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Correspondence to Lawrence Corey.

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Zhu, J., Hladik, F., Woodward, A. et al. Persistence of HIV-1 receptor–positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nat Med 15, 886–892 (2009). https://doi.org/10.1038/nm.2006

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