title: Herpes simplex virus 2 (HSV-2) prevents dendritic cell maturation, induces apoptosis, and triggers release of proinflammatory cytokines: potential links to HSV-HIV synergy.
abstract: Herpes simplex virus 2 (HSV-2) may cause frequent recurrences, highlighting its ability to evade host defense. This study tested the hypothesis that HSV-2 interferes with dendritic cell (DC) function as an escape mechanism, which may contribute to enhanced HIV replication in coinfected populations. Immature monocyte-derived human DCs were exposed to live or UV-inactivated HSV-2 or lipopolysaccharide. Little or no increase in the maturation marker CD83 was observed in response to HSV-2 and HSV-2 exposed DCs were impaired in their ability to present antigen (influenza) to T cells. Exposure to UV-inactivated virus stimulated a modest, but significant increase in CD83, suggesting that viral gene expression contributes to the block in DC maturation. The functional impairment of HSV-2-exposed DCs could be partially attributed to the induction of apoptosis. Live and inactivated HSV-2 triggered an increase in the number of early and late apoptotic cells in both the infected and bystander cell populations; apoptosis was associated with a decrease in cellular FLICE-inhibitory protein (c-FLIP). Paradoxically, HSV-2 induced Akt phosphorylation, which typically promotes DC maturation and survival. Despite these aberrant responses, live and inactivated HSV-2 induced the release of cytokines into culture supernatants, which were sufficient to activate HIV-1 replication in latently infected U1 cells. Together, these findings suggest that in the presence of overt or subclinical HSV-2, the function of mucosal DCs would be impaired. These responses may allow HSV to escape immune surveillance but may also promote HIV infection and contribute to the epidemiological link between HIV and HSV.
authors.affiliation: Departments of Pediatrics and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA. martha.stefanidou@einstein.yu.edu
authors.forename: Martha
authors.initials: M
authors.lastname: Stefanidou
authors.forename: Irene
authors.initials: I
authors.lastname: Ramos
authors.forename: Veronica
authors.initials: V
authors.lastname: Mas Casullo
authors.forename: Janie B
authors.initials: JB
authors.lastname: Trépanier
authors.forename: Sara
authors.initials: S
authors.lastname: Rosenbaum
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez-Sesma
authors.forename: Betsy C
authors.initials: BC
authors.lastname: Herold
mesh_terms: D017951:Antigen Presentation; D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D057131:Immune Evasion; D007136:Immunoglobulins / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D014779:Virus Replication; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D000097802:CD83 Antigen