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

bHerpes 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.

Herpes Simplex Virus Type 2–Infected Dendritic Cells Produce TNF-α, Which Enhances CCR5 Expression and Stimulates HIV Production from Adjacent Infected Cells

“…Luminex analysis confirmed that TNF-a was the major cytokine produced, with minor enhancement of CXCL10 (IP-10) and IL-8. TNF-a production in this setting was consistent with a previous report on HSV-2-infected MDDCs, although we found only low levels of IL-6 (26). Because TNF-a is a soluble trimer, with a total size of 51 kDa, it fits within the identified m.w.…”

“…Our results showing no effect of HSV-2 superinfection on MDDCs, previously infected with HIV-1 for 4 d to increase HIV-1 DNA, are not contradictory to a previous report (26) where supernatants from HSV-2-exposed MDDCs (containing TNF-a and IL-6) were able to induce HIV-1 replication in the transformed U1 monocytoid cell line where the virus is integrated in every cell. This stimulatory effect of TNF-a on monocytoid cell lines such as U937 and U1 is well-known and operates through the NF-kB sites in the LTR (47).…”

“…HSV-2 also inhibits IL-12 production (24,25). These findings have recently been confirmed (26). Apoptotic DCs are then taken up by bystanders and HSV-2 Ag presented to T cells (27).…”

“…This stimulatory effect of TNF-a on monocytoid cell lines such as U937 and U1 is well-known and operates through the NF-kB sites in the LTR (47). However, TNF-a has different effects on DCs infected de novo, for example, it induces maturation in MDDCs, which eventually reduces their susceptibility to productive HIV-1 infection (26,48). The balance between inhibition of HIV-1 production by IFN-b and stimulation by TNF-a after live and UV inactivated HSV-2 stimulation also explains apparent differences from two previous reports (26,46).…”

“…However, TNF-a has different effects on DCs infected de novo, for example, it induces maturation in MDDCs, which eventually reduces their susceptibility to productive HIV-1 infection (26,48). The balance between inhibition of HIV-1 production by IFN-b and stimulation by TNF-a after live and UV inactivated HSV-2 stimulation also explains apparent differences from two previous reports (26,46). One of these reports (46) discounted any effect of TNF-a in enhancing HIV-1 production by LCs, but this is explained by the other, which showed that MDDCs exposed to UV HSV-2 produced greater levels of IFN-b but lower levels of TNF-a than those exposed to infectious HSV-2 (26).…”