Impact of Asymptomatic Herpes Simplex Virus Type 2 Infection on Mucosal Homing and Immune Cell Subsets in the Blood and Female Genital Tract

Abstract

HSV-2 infection is common and generally asymptomatic, but it is associated with increased HIV susceptibility and disease progression. This may relate to herpes-mediated changes in genital and systemic immunology. Cervical cytobrushes and blood were collected from HIV-uninfected African/Caribbean women in Toronto, and immune cell subsets were enumerated blindly by flow cytometry. Immune differences between groups were assessed by univariate analysis and confirmed using a multivariate model. Study participants consisted of 46 women, of whom 54% were infected with HSV-2. T cell activation and expression of the mucosal homing integrin α4β7 (19.60 versus 8.76%; p < 0.001) were increased in the blood of HSV-2–infected women. Furthermore, expression of α4β7 on blood T cells correlated with increased numbers of activated (coexpressing CD38/HLA-DR; p = 0.004) and CCR5+ (p = 0.005) cervical CD4+ T cells. HSV-2–infected women exhibited an increase in the number of cervical CD4+ T cells (715 versus 262 cells/cytobrush; p = 0.016), as well as an increase in the number and proportion of cervical CD4+ T cells that expressed CCR5+ (406 versus 131 cells, p = 0.001; and 50.70 versus 34.90%, p = 0.004) and were activated (112 versus 13 cells, p < 0.001; and 9.84 versus 4.86%, p = 0.009). Mannose receptor expression also was increased on cervical dendritic cell subsets. In conclusion, asymptomatic HSV-2 infection was associated with significant systemic and genital immune changes, including increased immune activation and systemic α4β7 expression; correlation of the latter with highly HIV-susceptible CD4+ T cell subsets in the cervix may provide a mechanism for the increased HIV susceptibility observed in asymptomatic HSV-2–infected women.

Association of HPV infection and clearance with cervicovaginal immunology and the vaginal microbiota

“…We hypothesized that this increased risk might relate to the mucosal recruitment of HIV-susceptible CD4+ target cells, as is seen during chronic HSV-2 infection. 18, 19, 25 Furthermore, we hypothesized that this recruitment might be exaggerated in women who go on to clear HPV, since a Th1 cytokine milieu may predominate during host immune clearance 5 and Th1 CD4+ T cells are highly HIV susceptible. However, we found no association between prevalent HPV infection and genital inflammatory cytokines, nor with endocervical CD4+ T cell numbers or highly susceptible CD4+ T cell subsets such as those expressing CCR5 or CD69.…”

“…Interestingly, although herpes simplex virus type-2 (HSV-2) is not associated with elevated pro-inflammatory genital cytokines, 17 HSV-2 infection has been consistently associated with elevated levels of activated CD4+ T cells in the genital mucosa 18, 19 and also with a three-fold increase in HIV acquisition risk. 17 Even in the absence of classical STIs, HIV risk is increased 60% in the context of bacterial vaginosis (BV), defined as the absence of vaginal Lactobacillus spp.…”

Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding

“…The biological basis of increased susceptibility is due to both increased ulceration and increased inflammation present in the skin and mucosa of persons who are HSV-2 infected. Increased numbers of activated CD4 ϩ T cells are seen in cervical secretions from HSV-2-seropositive women (105,106), and increased inflammation is seen in foreskins of HSV-2-seropositive men, compared to those who are HSV-2 seronegative (107,108). Importantly, this is seen in the absence of genital lesions, suggesting that HSV-2 infection, likely through the immune response to subclinical shedding, fundamentally alters the inflammatory infiltrate to the genital skin and mucosa.…”

Inflammation and HIV Transmission in Sub-Saharan Africa

“…The prevalence of this life-long infection is up to threefold higher among adults in SSA than in the general population from North America or Europe [53], and although only a minority (10-20 %) of infected individuals have any genital symptoms [54], HSV-2 seropositivity is associated with an approximately threefold increase in HIV acquisition [55]. In addition to barrier disruption during symptomatic genital ulceration, this likely relates to the mucosal immune alterations induced by intermittent asymptomatic HSV-2 reactivation, which include increased numbers of genital CD4+ T cells as well as a substantial increase in their CCR5 expression and levels of immune activation [56][57][58]. Unfortunately, HSV-2 suppressive therapy is not able to reverse these immune alterations [59] or HIV transmission [60,61], perhaps because HSV-2-induced mucosal immune alterations are long lived and current therapy can only partially reduce asymptomatic reactivation [62].…”