PMID- 27285483 OWN - NLM STAT- MEDLINE DCOM- 20170710 LR - 20201215 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 6 DP - 2016 TI - Mathematical Modeling Predicts that Increased HSV-2 Shedding in HIV-1 Infected Persons Is Due to Poor Immunologic Control in Ganglia and Genital Mucosa. PG - e0155124 LID - 10.1371/journal.pone.0155124 [doi] LID - e0155124 AB - A signature feature of HIV infection is poor control of herpes virus infections, which reactivate from latency and cause opportunistic infections. While the general mechanism underlying this observation is deficient CD4+T-cell function, it is unknown whether increased severity of herpes virus infections is due primarily to poor immune control in latent or lytic sites of infection, or whether CD4+ immunodeficiency leads to more critical downstream deficits in humoral or cell-mediated immunologic responses. Here we compare genital shedding patterns of herpes simplex virus-2 (HSV-2) in 98 HIV infected and 98 HIV uninfected men matched on length of infection, HSV-1 serostatus and nationality. We demonstrate that high copy HSV-2 shedding is more frequent in HIV positive men, particularly in participants with CD4+ T-cell count <200/muL. Genital shedding is more frequent due to higher rate of shedding episodes, as well as a higher proportion of prolonged shedding episodes. Peak episode viral load was not found to differ between HIV infected and uninfected participants regardless of CD4+ T-cell count. We simulate a mathematical model which recapitulates these findings and identifies that rate of HSV-2 release from neural tissue increases, duration of mucosal cytolytic immune protection decreases, and cell-free viral lifespan increases in HIV infected participants. These results suggest that increased HSV-2 shedding in HIV infected persons may be caused by impaired immune function in both latent and lytic tissue compartments, with deficits in clearance of HSV-2 infected cells and extracellular virus. FAU - Schiffer, Joshua T AU - Schiffer JT AD - Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. AD - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. AD - Department of Medicine, University of Washington, Seattle, Washington, United States of America. FAU - Swan, David A AU - Swan DA AD - Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. FAU - Magaret, Amalia AU - Magaret A AD - Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. AD - Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America. AD - Department of Biostatistics, University of Washington, Seattle, Washington, United States of America. FAU - Schacker, Timothy W AU - Schacker TW AD - Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America. FAU - Wald, Anna AU - Wald A AD - Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. AD - Department of Medicine, University of Washington, Seattle, Washington, United States of America. AD - Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America. AD - Department of Epidemiology, University of Washington, Seattle, Washington, United States of America. FAU - Corey, Lawrence AU - Corey L AD - Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. AD - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. AD - Department of Medicine, University of Washington, Seattle, Washington, United States of America. AD - Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America. LA - eng GR - K23 AI087206/AI/NIAID NIH HHS/United States GR - K24 AI071113/AI/NIAID NIH HHS/United States GR - P01 AI030731/AI/NIAID NIH HHS/United States GR - R01 AI042528/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20160610 PL - United States TA - PLoS One JT - PloS one JID - 101285081 SB - IM MH - AIDS-Related Opportunistic Infections/diagnosis/immunology/virology MH - Adult MH - Aged MH - Case-Control Studies MH - Coinfection/diagnosis/virology MH - *Ganglia/immunology/virology MH - *Genitalia, Male/immunology/virology MH - HIV Infections/diagnosis/immunology/*virology MH - HIV-1 MH - Herpes Simplex/diagnosis/immunology/*virology MH - Herpesvirus 2, Human/*physiology MH - Humans MH - Immunocompromised Host/immunology MH - Male MH - Middle Aged MH - *Models, Theoretical MH - Mucous Membrane/immunology/virology MH - Prognosis MH - Virus Shedding/*physiology PMC - PMC4902308 COIS- Competing Interests: AM received consulting fees from Immune Design and AiCuris. LC sits on the scientific advisory board for and holds stock (>1% of company) in Immune Design Corp. AW received consulting fees from Aicuris, Amgen, and grant support through her institution from Agenus, Genentech, Genocea, Gilead, and Vical. LC holds the following two patents: 1. Koelle DM, Chen H, Corey L. Immunologically significant herpes simplex virus antigens and methods for identifying and using same. US Patent 6,962,709. November 8, 2005. Hosken, McGowan, Fling, Posavad removed from inventorship via Certificate of Correction Sept. 19, 2006. 2. Koelle DM, Corey L. Immunological herpes simplex virus antigens and methods for use thereof. US Patent 8,852,602. October 7, 2014. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no products in development or marketed products to declare. EDAT- 2016/06/11 06:00 MHDA- 2017/07/14 06:00 PMCR- 2016/06/10 CRDT- 2016/06/11 06:00 PHST- 2016/01/29 00:00 [received] PHST- 2016/04/25 00:00 [accepted] PHST- 2016/06/11 06:00 [entrez] PHST- 2016/06/11 06:00 [pubmed] PHST- 2017/07/14 06:00 [medline] PHST- 2016/06/10 00:00 [pmc-release] AID - PONE-D-16-02671 [pii] AID - 10.1371/journal.pone.0155124 [doi] PST - epublish SO - PLoS One. 2016 Jun 10;11(6):e0155124. doi: 10.1371/journal.pone.0155124. eCollection 2016.