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      Persistence of HIV-1 Receptor-Positive Cells after HSV-2 Reactivation: A Potential Mechanism for Increased HIV-1 Acquisition

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          Abstract

          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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          Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies.

          Judith R Glynn, Olivia E. Freeman, Keith R. Hayes … (2006)
          To estimate the sex-specific effect of herpes simplex virus type 2 (HSV-2) on the acquisition of HIV infection. The increased number of longitudinal studies available since the last meta-analysis was published allows for the calculation of age- and sexual behaviour-adjusted relative risks (RR) separately for men and women. Systematic review and meta-analysis of longitudinal studies. PubMed, Embase and relevant conference abstracts were systematically searched to identify longitudinal studies in which the relative timing of HSV-2 infection and HIV infection could be established. Where necessary, authors were contacted for separate estimates in men and women, adjusted for age and a measure of sexual behaviour. Summary adjusted RR were calculated using random-effects meta-analyses where appropriate. Studies on recent HSV-2 incidence as a risk factor for HIV acquisition were also collated. Of 19 eligible studies identified, 18 adjusted for age and at least one measure of sexual behaviour after author contact. Among these, HSV-2 seropositivity was a statistically significant risk factor for HIV acquisition in general population studies of men [summary adjusted RR, 2.7; 95% confidence interval (CI), 1.9-3.9] and women (RR, 3.1; 95% CI, 1.7-5.6), and among men who have sex with men (RR, 1.7; 95% CI, 1.2-2.4). The effect in high-risk women showed significant heterogeneity, with no overall evidence of an association. Prevalent HSV-2 infection is associated with a three-fold increased risk of HIV acquisition among both men and women in the general population, suggesting that, in areas of high HSV-2 prevalence, a high proportion of HIV is attributable to HSV-2.
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            Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding.

            U. O'Doherty, W J Swiggard, M Malim (2000)
            The study of early events in the human immunodeficiency virus type 1 (HIV-1) life cycle can be limited by the relatively low numbers of cells that can be infected synchronously in vitro. Although the efficiency of HIV-1 infection can be substantially improved by centrifugal inoculation (spinoculation or shell vial methods), the underlying mechanism of enhancement has not been defined. To understand spinoculation in greater detail, we have used real-time PCR to quantitate viral particles in suspension, virions that associate with cells, and the ability of those virions to give rise to reverse transcripts. We report that centrifugation of HIV-1(IIIB) virions at 1,200 x g for 2 h at 25 degrees C increases the number of particles that bind to CEM-SS T-cell targets by approximately 40-fold relative to inoculation by simple virus-cell mixing. Following subsequent incubation at 37 degrees C for 5 h to allow membrane fusion and uncoating to occur, the number of reverse transcripts per target cell was similarly enhanced. Indeed, by culturing spinoculated samples for 24 h, approximately 100% of the target cells were reproducibly shown to be productively infected, as judged by the expression of p24(gag). Because the modest g forces employed in this procedure were found to be capable of sedimenting viral particles and because CD4-specific antibodies were effective at blocking virus binding, we propose that spinoculation works by depositing virions on the surfaces of target cells and that diffusion is the major rate-limiting step for viral adsorption under routine in vitro pulsing conditions. Thus, techniques that accelerate the binding of viruses to target cells not only promise to facilitate the experimental investigation of postentry steps of HIV-1 infection but should also help to enhance the efficacy of virus-based genetic therapies.
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              Dendritic cell-induced memory T cell activation in nonlymphoid tissues.

              Linda M Wakim, Jason Waithman, Nico van Rooijen … (2008)
              Secondary lymphoid organs are dominant sites of T cell activation, although many T cells are subsequently retained within peripheral tissues. Currently, these nonlymphoid compartments are viewed as sites only of effector T cell function, without the involvement of renewed induction of immunity via the interactions with professional antigen-presenting cells. We describe a method of reactivation of herpes simplex virus to examine the stimulation of tissue-resident T cells during secondary challenge. The results revealed that memory CD8+ T cell responses can be initiated within peripheral tissues through a tripartite interaction that includes CD4+ T cells and recruited dendritic cells. These findings lend evidence for the existence of a sophisticated T cell response mechanism in extra-lymphoid tissues that can act to control localized infection.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9502015
                Journal ID (pubmed-jr-id): 8791
                Journal ID (nlm-ta): Nat Med
                Title: Nature medicine
                ISSN (Print): 1078-8956
                ISSN (Electronic): 1546-170X
                Publication date Nihms-submitted: 27 June 2009
                Publication date (Electronic): 2 August 2009
                Publication date (Print): August 2009
                Publication date PMC-release: 1 February 2010
                Volume: 15
                Issue: 8
                Pages: 886-892
                Affiliations
                [1 ] Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, USA
                [2 ] Department of Laboratory Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
                [3 ] Department of Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
                [4 ] Department of Epidemiology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
                [5 ] Department of Global Health, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
                [6 ] Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                Manuscript ID: nihpa124698
                DOI: 10.1038/nm.2006
                PMC ID: 2723183
                PubMed ID: 19648930
                SO-VID: dac95261-5843-40e1-bfc7-a8066c7979a1
                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Institute of Child Health & Human Development : NICHD
                Award ID: R37 AI042528-12 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Institute of Child Health & Human Development : NICHD
                Award ID: R01 HD051455-03 ||HD
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Institute of Child Health & Human Development : NICHD
                Award ID: R01 AI050132-05 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Institute of Child Health & Human Development : NICHD
                Award ID: P01 AI030731-18 ||AI
                Categories
                Subject: Article

                ScienceOpen disciplines: Medicine
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                ScienceOpen disciplines: Medicine

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