Mathematical Modeling Predicts that Increased HSV-2 Shedding in HIV-1 Infected Persons Is Due to Poor Immunologic Control in Ganglia and Genital Mucosa.
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/μL. 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.
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Department of Medicine, University of Washington, Seattle, Washington, United States of America.
Joshua T
JT
Schiffer
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
David A
DA
Swan
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
Amalia
A
Magaret
Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
Timothy W
TW
Schacker
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
Anna
A
Wald
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America.
Lawrence
L
Corey
D017088:AIDS-Related Opportunistic Infections / Q000175:diagnosis / Q000276:immunology / Q000821:virology; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D060085:Coinfection / Q000175:diagnosis / Q000821:virology; D005724:Ganglia / Q000276:immunology / Q000821:virology; D005837:Genitalia, Male / Q000276:immunology / Q000821:virology; D015658:HIV Infections / Q000175:diagnosis / Q000276:immunology / Q000821:virology*; D015497:HIV-1; D006561:Herpes Simplex / Q000175:diagnosis / Q000276:immunology / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000502:physiology*; D006801:Humans; D016867:Immunocompromised Host / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009092:Mucous Membrane / Q000276:immunology / Q000821:virology; D011379:Prognosis; D017201:Virus Shedding / Q000502:physiology*