Effects of HIV-1 and Herpes Simplex Virus Type 2 Infection on Lymphocyte and Dendritic Cell Density in Adult Foreskins from Rakai, Uganda

Johnson, Kristine E.; Redd, Andrew D.; Quinn, Thomas C.; Collinson-Streng, Aleisha; Cornish, Toby C.; Kong, Xiangrong; Sharma, Rajni; Tobian, Aaron A.R.; Tsai, Benjamin; Sherman, Mark E.; Kigozi, Godfrey; Serwadda, David; Wawer, Maria J.; Gray, Ronald H.

doi:10.1093/infdis/jiq091

Cited by 55 publications

(47 citation statements)

References 26 publications

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“…Both incident and prevalent HSV-2 infection are associated with an increased risk of HIV acquisition (3), and CD4 ϩ T cells found at the sites of HSV lesions bear the HIV coreceptors CCR5 and CXCR4 (17,34). We found HSV-specific CD4 ϩ T cells that produce proinflammatory cytokines in response to HSV stimula- ϩ T cells from the asymptomatic biopsy specimen produce IFN-␥ in response to whole HSV-2 antigen.…”

Section: Discussionmentioning

confidence: 72%

Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

Johnston

Zhu

Jing

et al. 2014

J Virol

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Genital herpes simplex virus (HSV) reactivation is thought to be anatomically and temporally localized, coincident with limited ganglionic infection. Short, subclinical shedding episodes are the most common form of HSV-2 reactivation, with host clearance mechanisms leading to rapid containment. The anatomic distribution of shedding episodes has not been characterized. To precisely define patterns of anatomic reactivation, we divided the genital tract into a 22-region grid and obtained daily swabs for 20 days from each region in 28 immunocompetent, HSV-2-seropositive persons. HSV was detected via PCR, and sites of asymptomatic HSV shedding were subjected to a biopsy procedure within 24 h. CD4؉ and CD8 ؉ T cells were quantified by immunofluorescence, and HSV-specific CD4 ؉ T cells were identified by intracellular cytokine cytometry. HSV was detected in 868 (7%) of 11,603 genital swabs at a median of 12 sites per person (range, 0 to 22). Bilateral HSV detection occurred on 83 (67%) days with shedding, and the median quantity of virus detected/day was associated with the number of sites positive (P < 0.001). In biopsy specimens of asymptomatic shedding sites, we found increased numbers of CD8 ؉ T cells compared to control tissue (27 versus 13 cells/mm 2 , P ‫؍‬ 0.03) and identified HSV-specific CD4 ؉ T cells. HSV reactivations emanate from widely separated anatomic regions of the genital tract and are associated with a localized cellular infiltrate that was demonstrated to be HSV specific in 3 cases. These data provide evidence that asymptomatic HSV-2 shedding contributes to chronic inflammation throughout the genital tract. IMPORTANCEThis detailed report of the anatomic patterns of genital HSV-2 shedding demonstrates that HSV-2 reactivation can be detected at multiple bilateral sites in the genital tract, suggesting that HSV establishes latency throughout the sacral ganglia. In addition, genital biopsy specimens from sites of asymptomatic HSV shedding have increased numbers of CD8 ؉ T cells compared to control tissue, and HSV-specific CD4 ؉ T cells are found at sites of asymptomatic shedding. These findings suggest that widespread asymptomatic genital HSV-2 shedding is associated with a targeted host immune response and contributes to chronic inflammation throughout the genital tract. H erpes simplex virus 2 (HSV-2) infects over 500 million people worldwide (1) and is the leading cause of genital ulcer disease (2) and increases the risk of HIV acquisition (3). Herpetic genital ulcers in the immunocompetent person are localized with respect to time and anatomic site (4), consistent with reactivation of virus from the ganglion innervating this region. However, most HSV genital shedding is subclinical, with rapid onset and clearance (5, 6). Such subclinical reactivation may be more widespread in the genital area (7), consistent with frequent leakage of virus into the genital skin and mucosa with localized host containment (8, 9). Mathematical models suggest that observed shedding patterns are the result of ove...

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Section: Discussionmentioning

confidence: 72%

Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

Johnston

Zhu

Jing

et al. 2014

J Virol

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“…HSV lesions are associated with persistent infiltrate of CD4 + and CD8 + T cells in the mucosa (21,38) and at nerve endings (38) that may contribute to a chronic inflammatory state in genital skin and mucosa. In support of this hypothesis, histopathologic studies of foreskin in HIV-seronegative men after adult circumcision have shown a higher concentration of CD4 + and CD8 + T cells in HSV-2-seropositive compared with HSV-2-seronegative men (39). Thus, even persons with established infection and a functional immune system can experience both subclinical genital HSV shedding and lesional recurrences, which suggests that the virus can evade even mature host immune responses.…”

Section: Introductionmentioning

confidence: 92%

HSV-2: in pursuit of a vaccine

Johnston

Koelle²,

Wald³

2011

J. Clin. Invest.

127

111

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Herpes simplex virus type 2 (HSV-2) is one of the most prevalent sexually transmitted infections worldwide. In addition to recurrent genital ulcers, HSV-2 causes neonatal herpes, and it is associated with a 3-fold increased risk for HIV acquisition. Although many HSV-2 vaccines have been studied in animal models, few have reached clinical trials, and those that have been tested in humans were not consistently effective. Here, we review HSV-2 pathogenesis, with a focus on novel understanding of mucosal immunobiology of HSV-2, and vaccine efforts to date, in an attempt to stimulate thinking about future directions for development of effective prophylactic and therapeutic HSV-2 vaccines.

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“…Asymptomatic HSV-2 infection is also associated with T cell alterations in the genital mucosa (3,5,6), an increased expression of CD69 and CCR5 by endocervical CD4 + T cells (3), and increased CD4 + T cell density (7) and CCR5 expression by CD4 + T cells (6) in the foreskin. Because CCR5 + T cells are the primary target for sexually transmitted R5-tropic strains of HIV (8), this increased density of target cells in the genital mucosa may be an important contributor to the increased HIV susceptibility observed in asymptomatic HSV-2 infection.…”

mentioning

confidence: 99%

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

Shannon

Thomas-Pavanel

et al. 2014

The Journal of Immunology

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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.

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Effects of HIV-1 and Herpes Simplex Virus Type 2 Infection on Lymphocyte and Dendritic Cell Density in Adult Foreskins from Rakai, Uganda

Cited by 55 publications

References 26 publications

Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

HSV-2: in pursuit of a vaccine

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

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