Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract

Rebbapragada, Anu; Wachihi, Charles; Pettengell, Christopher; Sunderji, Sherzana; Huibner, Sanja; Jaoko, Walter; Ball, Blake; Fowke, Keith R.; Mazzulli, Tony; Plummer, Francis A.; Kaul, Rupert

doi:10.1097/qad.0b013e328012b896

Cited by 165 publications

(152 citation statements)

References 48 publications

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“…Given the breadth of the study populations examined and consistent results, it is unlikely that residual confounding associated with sexual behaviors accounts for the association between HSV-2 and HIV-1 acquisition, suggesting that other mechanisms, possibly immunological susceptibility, may partially explain the observed relationships (Corey et al 2004). In a recent study, HSV-2 +/HIV− women showed an increase in genital mucosal target cells populations that are known to enhance HIV infection, even in the absence of genital ulceration or HSV2 reactivation (Rebbapragada et al 2007). Kaul et al has reviewed the evidence for negative mucosal synergy between HIV and HSV-2 (Kaul et al 2007).…”

Section: Stress and Acquisition Of Hivmentioning

confidence: 97%

Population Levels of Psychological Stress, Herpesvirus Reactivation and HIV

2008

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Nearly 40,000 Americans are newly infected with Human Immunodeficiency Virus (HIV) each year. Recently, studies have demonstrated associations between group-level characteristics and the prevalence and incidence of HIV/Acquired Immune Deficiency Syndrome (AIDS) and other sexually transmitted diseases. Two mechanisms previously posited to explain these associations are neighborhood effects on risk behaviors and social or institutional policies. In this paper, we hypothesize that adversity at the population level, such as neighborhood poverty, also influences HIV risk through stress-mediated aberrations in immunological susceptibility by reviewing existing data examining each of these pathways. In particular, we review the evidence showing that: (1) Neighborhood ecologic stressors influence neighborhood-and individual-levels of mental health, psychosocial stress, and HIV/AIDS risk, (2) Individual-level psychosocial stressors influence progression from HIV to AIDS through stress-related hormonal changes, and (3) Individual-level psychosocial stressors influence HIV acquisition via stress-related reactivation of latent herpesviruses, specifically EBV and HSV-2. Our review indicates that further studies are needed to examine the joint pathways linking neighborhood-level sources of psychosocial stress, stress-related reactivation of HSV-2 and EBV, and increased acquisition rates of HIV. We suggest using a multi-level framework for targeting HIV prevention efforts that address not only behavioral risk factors, but structural, political, and institutional factors associated with neighborhood disadvantage, levels of psychosocial stress, and prevention or treatment of HSV-2 and EBV.

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Section: Stress and Acquisition Of Hivmentioning

confidence: 97%

Population Levels of Psychological Stress, Herpesvirus Reactivation and HIV

2008

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“…Cytobrush samples were obtained as described in ref. 31 under a study protocol approved by the Research Ethics Boards at the University of Toronto and the Kenyatta National Hospital (Nairobi, Kenya). Retinoic acid was obtained from Sigma Chemical.…”

Section: Methodsmentioning

confidence: 99%

The integrin α ₄ β ₇ forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1

Cicala¹,

Martinelli²,

McNally³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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258

290

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Both activated and resting CD4 ؉ T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. HIV-1 gp120 binds to integrin ␣4␤7 (␣4␤7), the gut mucosal homing receptor. We find that ␣4␤7 high CD4 ؉ T cells are more susceptible to productive infection than are ␣4␤7 low-neg CD4 ؉ T cells in part because this cellular subset is enriched with metabolically active CD4 ؉ T cells. ␣4␤7 high CD4 ؉ T cells are CCR5 high and CXCR4 low ; on these cells, ␣4␤7 appears in a complex with CD4. The specific affinity of gp120 for ␣4␤7 provides a mechanism for HIV-1 to target activated cells that are critical for efficient virus propagation and dissemination following sexual transmission.integrin receptor ͉ transmission ͉ gut-associated lymphoid tissues (GALT)

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“…Also, activated CD4 T lymphocytes and macrophages, which act as target cells for HIV-1 attachment and entry, infiltrate genital herpes lesions in epidermis and/or dermis (11)(12)(13). Increases in these HIV-1 target cell populations are evident in the genital mucosa even in the absence of clinical HSV-2 disease, during asymptomatic shedding, and also persist between lesions (14), suggesting that a persistent state of increased mucosal susceptibility is induced by HSV-2 infection. Indeed, HIV-1 has been shown to replicate to much higher levels in cells extracted from mucosa between lesions than from control mucosa.…”

mentioning

confidence: 99%

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

Marsden

Donaghy

Bertram

et al. 2015

The Journal of Immunology

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Prior HSV-2 infection enhances the acquisition of HIV-1 >3-fold. In genital herpes lesions, the superficial layers of stratified squamous epithelium are disrupted, allowing easier access of HIV-1 to Langerhans cells (LC) in the epidermis and perhaps even dendritic cells (DCs) in the outer dermis, as well as to lesion infiltrating activated T lymphocytes and macrophages. Therefore, we examined the effects of coinfection with HIV-1 and HSV-2 on monocyte-derived DCs (MDDC). With simultaneous coinfection, HSV-2 significantly stimulated HIV-1 DNA production 5-fold compared with HIV-1 infection alone. Because <1% of cells were dually infected, this was a field effect. Virus-stripped supernatants from HSV-2–infected MDDCs were shown to enhance HIV-1 infection, as measured by HIV-1–DNA and p24 Ag in MDDCs. Furthermore these supernatants markedly stimulated CCR5 expression on both MDDCs and LCs. TNF-α was by far the most prominent cytokine in the supernatant and also within HSV-2–infected MDDCs. HSV-2 infection of isolated immature epidermal LCs, but not keratinocytes, also produced TNF-α (and low levels of IFN-β). Neutralizing Ab to TNF-α and its receptor, TNF-R1, on MDDCs markedly inhibited the CCR5-stimulating effect of the supernatant. Therefore, these results suggest that HSV-2 infection of DCs in the skin during primary or recurrent genital herpes may enhance HIV-1 infection of adjacent DCs, thus contributing to acquisition of HIV-1 through herpetic lesions.

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Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract

Abstract: The findings suggest a mucosal vicious circle in which HSV2 infection increases HIV target cells in the genital mucosa, subsequent HIV infection impairs HSV2 mucosal immune control, and local HSV2 reactivation enhances both HSV2 and HIV transmission.

Cited by 165 publications

References 48 publications

Population Levels of Psychological Stress, Herpesvirus Reactivation and HIV

Population Levels of Psychological Stress, Herpesvirus Reactivation and HIV

The integrin α ₄ β ₇ forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1

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

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Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract

Abstract: The findings suggest a mucosal vicious circle in which HSV2 infection increases HIV target cells in the genital mucosa, subsequent HIV infection impairs HSV2 mucosal immune control, and local HSV2 reactivation enhances both HSV2 and HIV transmission.

Cited by 165 publications

References 48 publications

Population Levels of Psychological Stress, Herpesvirus Reactivation and HIV

Population Levels of Psychological Stress, Herpesvirus Reactivation and HIV

The integrin α 4 β 7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1

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

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The integrin α ₄ β ₇ forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1