Genital Inflammation Research Articles

Comparable mRNA expression of inflammatory markers but lower claudin-1 mRNA levels in foreskin tissue of HSV-2 seropositive versus seronegative asymptomatic Kenyan young men

ObjectivesSkin biopsies from local sites of herpes simplex virus 2 (HSV-2)-induced ulcers can show infiltrates of inflammatory cells several months after macroscopic healing. We hypothesise that foreskin tissue samples of...

Adolescent girls and young women: key populations for HIV epidemic control.

IntroductionAt the epicentre of the HIV epidemic in southern Africa, adolescent girls and young women aged 15–24 contribute a disproportionate ~30% of all new infections and seroconvert 5–7 years earlier than their male peers. This age–sex disparity in HIV acquisition continues to sustain unprecedentedly high incidence rates, and preventing HIV infection in this age group is a pre-requisite for achieving an AIDS-free generation and attaining epidemic control.DiscussionAdolescent girls and young women in southern Africa are uniquely vulnerable to HIV and have up to eight times more infection than their male peers. While the cause of this vulnerability has not been fully elucidated, it is compounded by structural, social and biological factors. These factors include but are not limited to: engagement in age-disparate and/or transactional relationships, few years of schooling, experience of food insecurity, experience of gender-based violence, increased genital inflammation, and amplification of effects of transmission co-factors. Despite the large and immediate HIV prevention need of adolescent girls and young women, there is a dearth of evidence-based interventions to reduce their risk. The exclusion of adolescents in biomedical research is a huge barrier. School and community-based education programmes are commonplace in many settings, yet few have been evaluated and none have demonstrated efficacy in preventing HIV infection. Promising data are emerging on prophylactic use of anti-retrovirals and conditional cash transfers for HIV prevention in these populations.ConclusionsThere is an urgent need to meet the HIV prevention needs of adolescent girls and young women, particularly those who are unable to negotiate monogamy, condom use and/or male circumcision. Concerted efforts to expand the prevention options available to these young women in terms of the development of novel HIV-specific biomedical, structural and behavioural interventions are urgently needed for epidemic control. In the interim, a pragmatic approach of integrating existing HIV prevention efforts into broader sexual reproductive health services is a public health imperative.

Clinical features analysis of 36 cases of intestinal Behcet's disease

Objective To improve the knowledge of intestinal Behcet's disease. Methods From October 2012 to January 2014, 36 patients with intestinal Behcet's disease were collected. The general information of the patients, manifestation of Behcet's disease, digestive symptoms, lab findings, imaging findings, endoscopic examination results, treatment and prognosis of Behcet's disease were analyzed. Chi square test and Fisher exact probability test were performed for count data analysis. Single factor and multi factors of efficacy were analyzed by Logistic regression analysis. Results Among 36 patients with Behcet's disease (male 19 and female 17), the mean onset age was 26.5 years old and the average course of disease was (8.2±6.8) years. Symptoms of digestive system of 91.7% (33/36) patients showed up later than system manifestations of Behcet's disease appeared. All 36 patients had oral ulcer. The rates of genital ulcers, skin diseases, inflammation and joint disease were 63.9% (23/36), 58.3% (21/36), 25.0% (9/36) and 25.0% (9/36), respectively. The main symptoms of digestive system were abdominal pain, diarrhea, bloating and hemafecia, of which abdominal pain was the predominant symptom and the incidence rate was 75.0% (27/36). Gastrointestinal bleeding, intestinal perforation, intestinal obstruction and arteriovenous fistula were the common complications of Behcet's disease and the incidence rates were 36.1% (13/36), 2.8% (1/36), 2.8% (1/36) and 2.8% (1/36), respectively. Among patients with ocular lesions, male patients were more than female patients (male six and female three), and the difference was statistically significant (χ2=0.111, P<0.05). Erythrocyte sedimentation rate increased in 55.6% (20/36) patients. C–reactive protein was positive in 27.8% (10/36) patients. Nine patients received computed tomography (CT) examination, there were five cases with thickened bowel wall and one case with proliferative lesions at ileocecal valve. Ileocecum was the predilection site, and accounted for 36.1% of the disease (13/36). Endoscopic appearance was mainly ulcers. Pathological examination indicated non–specific acute and chronic gastrointestinal mucosal inflammation and the formation of inflammatory granulation tissue. Twerty–two patients received sulfasalazine (SASP) treatment and 24 patients accepted glucocorticoid therapy. After Behcet's disease recurrence, five patients received combined immunosuppressive therapy, five patients received immunosuppressive therapy and tumor necrosis factor (TNF) antagonist treatment, and nine patients received TNF antagonist treatment. All the patients treated together with proton pump inhibitor (PPI). Twelve patients without glucocorticoid treatment took thalidomide and immunosuppressive therapy. The efficacy was good in patients with immunosuppressive therapy or TNF antagonist treatment and the recurrence rate was low (r=3.984, P<0.05). Conclusions Most patients with intestinal Behcet's disease are young adults. Symptoms of digestive system show up later than system manifestations of Behcet's disease appeared. Ileocecum is the predilection site of digestive system. The common endoscopic appearance is ulcers. Corticosteroids and sulfasalazine are the main therapy, which could be much more effective when combined with tumor necrosis factor antagonists or immunosuppressive therapy. Key words: Intestinal Behcet's disease; Clinical features; Endoscopes

Rush to judgment: the STI-treatment trials and HIV in sub-Saharan Africa.

IntroductionThe extraordinarily high incidence of HIV in sub-Saharan Africa led to the search for cofactor infections that could explain the high rates of transmission in the region. Genital inflammation and lesions caused by sexually transmitted infections (STIs) were a probable mechanism, and numerous observational studies indicated several STI cofactors. Nine out of the ten randomized controlled trials (RCTs), however, failed to demonstrate that treating STIs could lower HIV incidence. We evaluate all 10 trials to determine if their design permits the conclusion, widely believed, that STI treatment is ineffective in reducing HIV incidence.DiscussionExamination of the trials reveals critical methodological problems sufficient to account for statistically insignificant outcomes in nine of the ten trials. Shortcomings of the trials include weak exposure contrast, confounding, non-differential misclassification, contamination and effect modification, all of which consistently bias the results toward the null. In any future STI-HIV trial, ethical considerations will again require weak exposure contrast. The complexity posed by HIV transmission in the genital microbial environment means that any future STI-HIV trial will face confounding, non-differential misclassification and effect modification. As a result, it is unlikely that additional trials would be able to answer the question of whether STI control reduces HIV incidence.ConclusionsShortcomings in published RCTs render invalid the conclusion that treating STIs and other cofactor infections is ineffective in HIV prevention. Meta-analyses of observational studies conclude that STIs can raise HIV transmission efficiency two- to fourfold. Health policy is always implemented under uncertainty. Given the known benefits of STI control, the irreparable harm from not treating STIs and the likely decline in HIV incidence resulting from STI control, it is appropriate to expand STI control programmes and to use funds earmarked for HIV prevention to finance those programmes.

Interpregnancy Interval and Anti-inflammatory Cervical Cytokines among Women with Previous Spontaneous Preterm Birth.

Both history of spontaneous preterm birth (sPTB) and shorter interpregnancy intervals (IPIs) increase the risk of recurrent sPTB. Mechanisms underlying the association between IPI and recurrent sPTB are unknown. We have previously demonstrated that higher concentrations of cervical anti-inflammatory cytokines are a risk factor for sPTB and upper genital tract inflammation. Here, we examine the association between IPI and cervical anti-inflammatory cytokines among women with previous sPTB. A prospective cohort of 73 women with previous sPTB and cervical interleukins (IL-4, IL-10, and IL-13) measured at < 16 weeks. Using the published principal factor analysis, the anti-inflammatory (ANTI) score was calculated. From our previous work, higher ANTI scores increase the subsequent risk of sPTB. IPI was the time from the previous birth to the conception of current pregnancy. Confounders included education level, marital status, gonorrhea, chlamydia, body mass index, race, and cigarette smoking. IPI and ANTI score were analyzed using univariable and multivariable analyses. There was a significant negative linear relation between IPI and ANTI score (β = -0.075, p = 0.017). This persisted after adjustment for confounders (p = 0.02). As IPI decreases by 1 month, the ANTI-score-associated risk of sPTB increases approximately by 4%. Among women with previous sPTB, there was a significant negative linear relation between IPI and ANTI score.

Strategies for preventing mucosal cell-associated HIV transmission.

Human immunodeficiency virus (HIV) may be transmitted through either cell-free virions or leukocytes harboring intracellular HIV in bodily fluids. In recent years, the early initiation of combination antiretroviral therapy leading to virological suppression has resulted in decreased HIV transmission to uninfected partners. Additionally, the efficacy of primary chemoprophylaxis with oral or topical antiretroviral regimens containing tenofovir (with or without emtricitabine) has been demonstrated. However, the efficacy of these approaches may be compromised by suboptimal adherence, decreased drug concentrations in mucosal compartments in women, and genital inflammation. Furthermore, in vitro studies on the effects of tenofovir on cell-associated HIV transmission have produced conflicting results. Preclinical studies suggest that combination preventive approaches may be most effective in stopping the transmission of HIV after mucosal exposure. Since the development of antibodies were found to correlate with protection in the only effective HIV vaccine trial, the administration of preformed mucosal and systemic antibodies may inform the development of safe and effective antibody-based oral, topical, and/or systemic preexposure prophylaxis agents and provide guidance in the development of HIV vaccines that effectively block cell-associated HIV transmission.

Neonatal testicular cell transplantation restores murine spermatogenesis damaged in the course of herpes simplex virus-induced orchitis.

Genital tract infection and inflammation may affect male fertility, causing germ and Sertoli cell loss. We determined if testicular cell transplantation is effective at repairing testicular injury induced by herpes simplex virus (HSV) orchitis. ROSA26 mice were used as donors and the recipients were C57BL/6 mice after HSV testicular inoculation; some of the recipients were treated with the antiviral drug acyclovir (ACV). ACV reduced the amount of HSV antigen in testes on Day 3 after transplantation and enhanced the efficacy of transplantation at Day 30. In recipient testes, donor Sertoli cells formed new seminiferous tubules; significantly more new tubules were observed in the testes of ACV-treated mice compared with mice not treated with ACV (17.8% vs 3.6%). Over half (50.4%) of new tubules in ACV-treated testes contained germ cells and round spermatids were detected in 14.2% of new tubules compared with 15.9% and 5.3% in testes not treated with ACV, respectively. At Day 150 the seminiferous epithelium was completely recovered in some donor tubules and elongated spermatids were observed inside it. Thus, our findings reveal the effectiveness of the combination of antiviral therapy with neonatal testis-cell transplantation for the restoration of spermatogenesis damaged by viral infection.

Effect of Bacterial Vaginosis on Markers of Genital Tract Inflammation and Mucosal Immunity: Mechanisms for Susceptibility to HIV Infection

AIDS Research and Human RetrovirusesVol. 30, No. S1 Bacterial Vaginosis and HSV-2: Impact on Genital ImmunityEffect of Bacterial Vaginosis on Markers of Genital Tract Inflammation and Mucosal Immunity: Mechanisms for Susceptibility to HIV InfectionAndrea Ries Thurman, Thomas D. Kimble, Tina D. Cunningham, Betsy C. Herold, Pedro Mesquita, Ashley Huber, Raina N. Fichorova, Hassan Y. Dawood, Titilayo Fashemi, Neelima Chandra, Jill L. Schwartz, and Gustavo F. DoncelAndrea Ries ThurmanCONRAD, Eastern Virginia Medical School, Norfolk, VA, United StatesSearch for more papers by this author, Thomas D. KimbleCONRAD, Eastern Virginia Medical School, Norfolk, VA, United StatesSearch for more papers by this author, Tina D. CunninghamEastern Virginia Medical School, School of Public Health, Norfolk, VA, United StatesSearch for more papers by this author, Betsy C. HeroldAlbert Einstein College of Medicine, Infectious Diseases and Pediatrics, Bronx, NY, United StatesSearch for more papers by this author, Pedro MesquitaAlbert Einstein College of Medicine, Infectious Diseases and Pediatrics, Bronx, NY, United StatesSearch for more papers by this author, Ashley HuberAlbert Einstein College of Medicine, Infectious Diseases and Pediatrics, Bronx, NY, United StatesSearch for more papers by this author, Raina N. FichorovaBrigham and Women's Hospital, Harvard Medical School, Laboratory of Genital Tract Biology, Boston, MA, United StatesSearch for more papers by this author, Hassan Y. DawoodBrigham and Women's Hospital, Harvard Medical School, Laboratory of Genital Tract Biology, Boston, MA, United StatesSearch for more papers by this author, Titilayo FashemiBrigham and Women's Hospital, Harvard Medical School, Laboratory of Genital Tract Biology, Boston, MA, United StatesSearch for more papers by this author, Neelima ChandraCONRAD, Eastern Virginia Medical School, Norfolk, VA, United StatesSearch for more papers by this author, Jill L. SchwartzCONRAD, Eastern Virginia Medical School, Norfolk, VA, United StatesSearch for more papers by this author, and Gustavo F. DoncelCONRAD, Eastern Virginia Medical School, Norfolk, VA, United StatesSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5047.abstractAboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Effect of Bacterial Vaginosis on Markers of Genital Tract Inflammation and Mucosal Immunity: Mechanisms for Susceptibility to HIV Infection." AIDS Research and Human Retroviruses, 30(S1), p. A30FiguresReferencesRelatedDetails Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Andrea Ries Thurman, Thomas D. Kimble, Tina D. Cunningham, Betsy C. Herold, Pedro Mesquita, Ashley Huber, Raina N. Fichorova, Hassan Y. Dawood, Titilayo Fashemi, Neelima Chandra, Jill L. Schwartz, and Gustavo F. Doncel.Effect of Bacterial Vaginosis on Markers of Genital Tract Inflammation and Mucosal Immunity: Mechanisms for Susceptibility to HIV Infection.AIDS Research and Human Retroviruses.Oct 2014.A30-A30.http://doi.org/10.1089/aid.2014.5047.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Genital IRIS, Immune Activation and Inflammation in the Female Genital Tract Influences HIV Shedding in HIV-infected Women Starting HAART

AIDS Research and Human RetrovirusesVol. 30, No. S1 Mucosal Immune Activation and InflammationGenital IRIS, Immune Activation and Inflammation in the Female Genital Tract Influences HIV Shedding in HIV-infected Women Starting HAARTSmritee Dabee, Jean-Mari Kriek, David Lewis, Maseko Venessa, Mkhize Nonhlanhla, Pamela P. Gumbi, Zizipho Mbulawa, Anna-Lise Williamson, Heather B. Jaspan, and Jo-Ann S. PassmoreSmritee DabeeInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Department of Clinical Laboratory Sciences, Cape Town, South AfricaSearch for more papers by this author, Jean-Mari KriekInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Department of Clinical Laboratory Sciences, Cape Town, South AfricaSearch for more papers by this author, David LewisNational Institute for Communicable Diseases, Johannesburg, South AfricaInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South AfricaSearch for more papers by this author, Maseko VenessaNational Institute for Communicable Diseases, Johannesburg, South AfricaSearch for more papers by this author, Mkhize NonhlanhlaNational Institute for Communicable Diseases, Johannesburg, South AfricaSearch for more papers by this author, Pamela P. GumbiInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South AfricaSearch for more papers by this author, Zizipho MbulawaInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Department of Clinical Laboratory Sciences, Cape Town, South AfricaSearch for more papers by this author, Anna-Lise WilliamsonInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Department of Clinical Laboratory Sciences, Cape Town, South AfricaNational Health Laboratory Services, Cape Town, South AfricaSearch for more papers by this author, Heather B. JaspanInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Department of Clinical Laboratory Sciences, Cape Town, South AfricaNational Health Laboratory Services, Cape Town, South AfricaSearch for more papers by this author, and Jo-Ann S. PassmoreInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Department of Clinical Laboratory Sciences, Cape Town, South AfricaNational Health Laboratory Services, Cape Town, South AfricaSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5505.abstractAboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Genital IRIS, Immune Activation and Inflammation in the Female Genital Tract Influences HIV Shedding in HIV-infected Women Starting HAART." AIDS Research and Human Retroviruses, 30(S1), p. A230FiguresReferencesRelatedDetails Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Smritee Dabee, Jean-Mari Kriek, David Lewis, Maseko Venessa, Mkhize Nonhlanhla, Pamela P. Gumbi, Zizipho Mbulawa, Anna-Lise Williamson, Heather B. Jaspan, and Jo-Ann S. Passmore.Genital IRIS, Immune Activation and Inflammation in the Female Genital Tract Influences HIV Shedding in HIV-infected Women Starting HAART.AIDS Research and Human Retroviruses.Oct 2014.A230-A230.http://doi.org/10.1089/aid.2014.5505.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Mucosal Proteomic Profiles Associated with Female Genital Tract Inflammation

AIDS Research and Human RetrovirusesVol. 30, No. S1 Mucosal Immune Activation and InflammationMucosal Proteomic Profiles Associated with Female Genital Tract InflammationKelly Arnold, Adam Burgener, Kenzie Birse, Laura Dunphy, Kamnoosh Shahabi, Max Abou, Jessie Kwatampora, Billy Nyanga, Joshua Kimani, Lenine Liebenberg, Lindi Masson, Salim S. Abdool Karim, Jo-Ann S. Passmore, Douglas A. Lauffenburger, Rupert Kaul, and Lyle R. McKinnonKelly ArnoldMIT, Boston, MA, United StatesSearch for more papers by this author, Adam BurgenerUniversity of Manitoba, Winnipeg, MB, CanadaSearch for more papers by this author, Kenzie BirseUniversity of Manitoba, Winnipeg, MB, CanadaSearch for more papers by this author, Laura DunphyMIT, Boston, MA, United StatesSearch for more papers by this author, Kamnoosh ShahabiUniversity of Toronto, Toronto, ON, CanadaSearch for more papers by this author, Max AbouPublic Health Agency of Canada, Winnipeg, MB, CanadaSearch for more papers by this author, Jessie KwatamporaUniversity of Nairobi, Nairobi, KenyaSearch for more papers by this author, Billy NyangaUniversity of Nairobi, Nairobi, KenyaSearch for more papers by this author, Joshua KimaniUniversity of Manitoba, Winnipeg, MB, CanadaSearch for more papers by this author, Lenine LiebenbergCAPRISA, Durban, South AfricaSearch for more papers by this author, Lindi MassonUniversity of Cape Town, Cape Town, South AfricaSearch for more papers by this author, Salim S. Abdool KarimCAPRISA, Durban, South AfricaSearch for more papers by this author, Jo-Ann S. PassmoreUniversity of Cape Town, Cape Town, South AfricaSearch for more papers by this author, Douglas A. LauffenburgerMIT, Boston, MA, United StatesSearch for more papers by this author, Rupert KaulUniversity of Toronto, Toronto, ON, CanadaSearch for more papers by this author, and Lyle R. McKinnonCAPRISA, Durban, South AfricaSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5517.abstractAboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Mucosal Proteomic Profiles Associated with Female Genital Tract Inflammation." AIDS Research and Human Retroviruses, 30(S1), p. A235FiguresReferencesRelatedDetails Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Kelly Arnold, Adam Burgener, Kenzie Birse, Laura Dunphy, Kamnoosh Shahabi, Max Abou, Jessie Kwatampora, Billy Nyanga, Joshua Kimani, Lenine Liebenberg, Lindi Masson, Salim S. Abdool Karim, Jo-Ann S. Passmore, Douglas A. Lauffenburger, Rupert Kaul, and Lyle R. McKinnon.Mucosal Proteomic Profiles Associated with Female Genital Tract Inflammation.AIDS Research and Human Retroviruses.Oct 2014.A235-A235.http://doi.org/10.1089/aid.2014.5517.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Hormonal Contraception Use and Risk of Female-to-Male HIV Transmission Risk in a Zambian Cohort

Background: The association between hormonal contraception (HC) use and risk of both male-to-female and female-to-male transmission HIV transmission is highly debated. Very little data exists related to female-to-male transmission risk and HC use. USAID FHI360 and the World Health Organization have called for more evaluations of this association. Methods: HIV discordant couples in which the man was negative and the woman was positive (M-F+) were identified after couples voluntary HIV counseling and testing from 1995-2012 in Lusaka Zambia. Discordant couples were followed longitudinally and demographic behavioral clinical and family planning measures were collected at baseline and 3-monthly. Men were re-tested for HIV every three months. Multivariate Cox models evaluated time to HIV acquisition among men. Results: Among 1654 M-F+couples 226 incident infections occurred over 3366 couple-years (6.71/100 couple-years; 95%CI: 5.87-7.65). 171 (76%) infections were genetically linked to the study partner. No interaction between genital ulceration/inflammation and contraception was observed. Use of injectables (HR=0.7; 95%CI:0.4-1.4) OCPs (HR=1.3; 95%CI:0.7-2.1) or implants (HR=0.8; 95%CI:0.2-2.8) in the past three months was not associated with genetically linked HIV transmission from women to men relative to non-HC controlling for: womans age number of previous pregnancies womans log viral load at baseline male circumcision status pregnancy status sex frequency with and without a condom sperm on a wet mount male and female genital inflammation and ulceration and time interval since enrollment. Conclusions: Our results add to a small and inconclusive body of literature. Over 17 years of follow-up we found no statistically significant association between HC use and female-to-male HIV transmission. These findings support the continued use of HC methods for pregnancy prevention and Prong 2 of PMTCT.

Herpes simplex virus 2 ICP34.5 confers neurovirulence by regulating the type I interferon response

The γ34.5 gene of herpes simplex virus (HSV) 2 encodes ICP34.5, which enhances HSV-2 neurovirulence by an unknown mechanism. We found that an HSV-2 γ34.5-null mutant (γ34.5−/−) replicated less robustly than its rescue virus (γ34.5R) in wild-type mouse embryo fibroblasts (MEFs), and in cells primed with IFNβ. Increased eIF2α phosphorylation correlated with γ34.5−/− attenuation. However, γ34.5−/− achieved titers equivalent to γ34.5R in MEFs lacking the type I IFN receptor (IFNα/βR−/−) or lacking protein kinase R. γ34.5−/− also replicated poorly in the vaginal mucosa of wild-type mice, caused little genital inflammation, and spread to the nervous system at lower levels compared to γ34.5R. In IFNα/βR−/− mice, however, γ34.5−/− regained the capacity to replicate and cause disease equivalent to γ34.5R after intravaginal infection or direct inoculation into the central nervous system. Thus, the capacity of HSV-2 ICP34.5 to interdict the type I IFN response in vivo largely determines its neurovirulence.

Autoantibodies against protein disulfide isomerase ER-60 are a diagnostic marker for low-grade testicular inflammation.

Is there a non-invasive biomarker for the diagnosis of testicular inflammatory lesions? In sera from infertile azoospermic patients with histologically confirmed low-grade testicular inflammation, significantly elevated titers of autoantibodies against disulfide isomerase family A, member 3 (ER-60) were found. Infection and inflammation of the genital tract are supposed to be responsible for up to 15% of cases among infertile males. However, specific seminal or serological markers are not available to assess subacute or chronic inflammatory conditions in the testis. This study consisted of the identification of autoantibodies for testicular antigens in sera of patients with low-grade testicular inflammation, validation of candidates, development of an ELISA for the most promising target antigen and measurement of autoantibodies titers in healthy normozoospermic men (n = 20); male blood donors (n = 14); men with impaired semen quality without (n = 14) or with (n = 26) symptoms of genital tract infection/inflammation; azoospermic men with histologically confirmed testicular inflammatory lesions (n = 16); men after pharmacotherapy of genital tract infection/inflammation (n = 15) and men with acute epididymo-orchitis (n = 30). Proteins in lysates of normal testicular tissue were separated by high-resolution 2D gel electrophoresis and probed with sera of 13 patients with histologically confirmed chronic testicular inflammation. There were 14 proteins that immunoreacted with a majority of these sera and could be identified by mass spectrometry. Of these 14 proteins, disulfide isomerase family A, member 3 (ER-60), transferrin and chaperonin containing TCP1 complex, subunit 5 (epsilon) (CCT5) were considered as specific. Since ER-60 reacted with 92% of patient sera, an ER-60-autoantibody ELISA was developed. The newly established ELISA detected significantly elevated titers of autoantibodies against ER-60 in the sera from infertile men with histologically confirmed chronic testicular inflammation (median 8.6; P < 0.01) compared with the control groups. Moreover, elevated levels of anti-ER-60 titers were detected in patients suffering from acute epididymo-orchitis (median 3.3; P < 0.05) as compared with healthy normozoospermic men (median 2.13; P < 0.001), male blood donors with unknown fertility status (median 2.72; P < 0.01), patients with impaired semen quality but no infection/inflammation (median 2.59; P < 0.001) and patients with symptoms of genital tract infections and/or inflammation (median 2.18; P < 0.001). Significantly lower levels of anti-ER-60 antibodies were measured in sera from patients after application of anti-inflammatory pharmacotherapy (median 1.9; P < 0.01) compared with those with histologically confirmed chronic testicular inflammation. The cut-off value of the assay was set to 6.6 U/ml based on a calculated sensitivity of 100% and a specificity of 81.2%. The results obtained in this study showed statistically significant elevated titers of ER-60 antibodies in sera from patients with histologically confirmed testicular inflammatory lesions and from a few patients with acute epididymo-orchitis. However, the number of serum samples tested was limited. Severe testicular damage seen in azoospermic patients could represent a bias towards ER-60 reactivity, while the assay does not allow for different etiologies of the lesions to be distinguished. Due to ethical reasons, the prevalence of testicular inflammatory lesions among controls and non-azoospermic men cannot be studied at the histological level. Measurement of ER-60 autoantibody titers in serum could be a novel non-invasive marker for the diagnosis of asymptomatic testicular inflammation causing male fertility disturbances. This study was supported by a grant of the Deutsche Forschungsgemeinschaft (ME 1323/4-4) and the Translational Science Fund (Wirtschafts-und Strukturbank Hessen-WI Bank). M.F., A.P., W.W., H.-C.S. and A.M. are supported by the LOEWE focus group 'MIBIE' (Male infertility during infection and inflammation). The ER-60 ELISA is protected by a patent to the Justus-Liebig-University of Giessen with A.M. and M.F. as inventors (patent no. DE 10 2008 053 503). T.Z. as employee of the DRG Company was responsible for the ELISA development.

Defining genital tract cytokine signatures of sexually transmitted infections and bacterial vaginosis in women at high risk of HIV infection: a cross-sectional study

ObjectivesSexually transmitted infections (STI) and bacterial vaginosis (BV) cause female genital tract inflammation. This inflammation, which is often present in the absence of symptoms, is associated with increased susceptibility to...

HIV transmission. Selection bias at the heterosexual HIV-1 transmission bottleneck.

Heterosexual transmission of HIV-1 typically results in one genetic variant establishing systemic infection. We compared, for 137 linked transmission pairs, the amino acid sequences encoded by non-envelope genes of viruses in both partners and demonstrate a selection bias for transmission of residues that are predicted to confer increased in vivo fitness on viruses in the newly infected, immunologically naïve recipient. Although tempered by transmission risk factors, such as donor viral load, genital inflammation, and recipient gender, this selection bias provides an overall transmission advantage for viral quasispecies that are dominated by viruses with high in vivo fitness. Thus, preventative or therapeutic approaches that even marginally reduce viral fitness may lower the overall transmission rates and offer long-term benefits even upon successful transmission.

Elevated urinary leukocyte esterase as a potential surrogate marker for HIV sexual transmission risks in men receiving antiretroviral therapy.

Local genital tract inflammation stimulates leukocyte activity and causes HIV shedding, potentially increasing HIV sexual infectiousness. Although there are available clinical markers for genital tract inflammation, such as urinary leukocyte esterase, none have yet been examined in relation to HIV sexual risk behaviours. We sought to examine the association between urinary leukocyte esterase and sexual practices. Sexually active men living with HIV and receiving antiretroviral therapy (ART, N = 290) provided urine specimens and completed behavioural health assessments. HIV RNA tests and CD4 cell counts were abstracted from medical records. Urine specimens were analysed for leukocyte esterase using a standard point-of-care dipstick test. Thirty-one (10.6%) participants tested positive for leukocyte esterase. Logistic regression models did not indicate differences between men with elevated and un-elevated leukocyte activity on demographic, health, recent sexually transmitted infection symptoms and diagnoses or substance use. However, men with elevated leukocyte activity indicated significantly greater sexual behaviour in the previous three months, including more recent unprotected sexual intercourse. A simple over-the-counter urine test may serve as an indicator of sexual HIV infectiousness to inform further evaluation and treatment of genital tract inflammation, as well as condom use decisions during times of increased genital tract inflammation.

Association between symptomatic vulvovaginal candidiasis and HIV RNA levels in plasma and genital secretions among women on HAART

Background. Genital tract (GT) inflammation plays a major role in HIV transmission. We aimed to determine the association between symptomatic vulvovaginal candidiasis (VVC) and HIV RNA levels in plasma and GTs of HIV-infected women on highly active antiretroviral therapy (HAART). Method. Women with VVC on HAART were recruited from a primary healthcare clinic in KwaZulu-Natal Province, South Africa, between June 2011 and December 2011. VVC was diagnosed clinically, supported by Gram staining and culture of genital secretions. HIV RNA load was determined by reverse transcription polymerase chain reaction. CD4+ counts were obtained from patients’ medical records.Results. Plasma HIV RNA was detected in 42 of 60 (70%) patients on HAART. The mean duration (± standard deviation) on HAART for these patients was 4.2 (±1.6) months v. 10.7 (±1.4) months for the remaining 18 patients (p&lt;0.0001). Of the 42 women with detectable plasma HIV RNA, 12 (28.6%) had detectable genital HIV RNA. Plasma HIV RNA levels ranged from 2.5 (±0.8) to 4.1 (±0.8) log10 copies/ml. Genital HIV RNA levels ranged from 1.4 to 2.5 (±1.1) log10 copies/ml. The adjusted odds ratios of plasma HIV RNA levels increased for patients &lt;35 years (p=0.039) and in those with VVC (p=0.008). Detectability of HIV in genital secretions was significantly increased in patients with a plasma HIV load ≥10 000 copies/ml (p=0.032) and genital absolute counts of neutrophils &gt;10 cells/5 high microscopic fields (p=0.007). Conclusion. Given that the majority of women had recently initiated HAART (allowing a high rate of detectable plasma HIV RNA), there was insufficient evidence to conclude that VVC was predictive of high plasma HIV RNA levels. It is more likely that this cohort of immunosuppressed women were prone to develop VVC. Plasma HIV loads and local genital inflammation were predictors of genital HIV detectability.

Association between symptomatic vulvovaginal candidiasis and HIV RNA levels in plasma and genital secretions among women on HAART

Background. Genital tract (GT) inflammation plays a major role in HIV transmission. We aimed to determine the association between symptomatic vulvovaginal candidiasis (VVC) and HIV RNA levels in plasma and GTs of HIV-infected women on highly active antiretroviral therapy (HAART). Method. Women with VVC on HAART were recruited from a primary healthcare clinic in KwaZulu-Natal Province, South Africa, between June 2011 and December 2011. VVC was diagnosed clinically, supported by Gram staining and culture of genital secretions. HIV RNA load was determined by reverse transcription polymerase chain reaction. CD4+ counts were obtained from patients' medical records. Results. Plasma HIV RNA was detected in 42 of 60 (70%) patients on HAART. The mean duration (± standard deviation) on HAART for these patients was 4.2 (±1.6) months v. 10.7 (±1.4) months for the remaining 18 patients (p 10 cells/5 high microscopic fields (p=0.007). Conclusion. Given that the majority of women had recently initiated HAART (allowing a high rate of detectable plasma HIV RNA), there was insufficient evidence to conclude that VVC was predictive of high plasma HIV RNA levels. It is more likely that this cohort of immunosuppressed women were prone to develop VVC. Plasma HIV loads and local genital inflammation were predictors of genital HIV detectability.

Increased susceptibility to vaginal simian/human immunodeficiency virus transmission in pig-tailed macaques coinfected with Chlamydia trachomatis and Trichomonas vaginalis.

Sexually transmitted infections (STIs) are associated with an increased risk of human immunodeficiency virus (HIV) infection, but their biological effect on HIV susceptibility is not fully understood. Female pig-tailed macaques inoculated with Chlamydia trachomatis and Trichomonas vaginalis (n = 9) or medium (controls; n = 7) were repeatedly challenged intravaginally with SHIVSF162p3. Virus levels were evaluated by real-time polymerase chain reaction, plasma and genital cytokine levels by Luminex assays, and STI clinical signs by colposcopy. Simian/HIV (SHIV) susceptibility was enhanced in STI-positive macaques (P = .04, by the log-rank test; relative risk, 2.5 [95% confidence interval, 1.1-5.6]). All STI-positive macaques were SHIV infected, whereas 3 controls (43%) remained uninfected. Moreover, relative to STI-negative animals, SHIV infections occurred earlier in the menstrual cycle in STI-positive macaques (P = .01, by the Wilcoxon test). Levels of inflammatory cytokines (interferon γ, interleukin 6, and granulocyte colony-stimulating factor [G-CSF]) were higher in STI-positive macaques during STI inoculation and SHIV exposure periods (P ≤ .05, by the Wilcoxon test). C. trachomatis and T. vaginalis infection increase the susceptibility to SHIV, likely because of prolonged genital tract inflammation. These novel data demonstrate a biological link between these nonulcerative STIs and the risk of SHIV infection, supporting epidemiological associations of HIV and STIs. This study establishes a macaque model for studies of high-risk HIV transmission and prevention.

Quotidian changes of genital tract cytokines in human immunodeficiency virus-1-infected women during the menstrual cycle.

The role of hormonal changes throughout the menstrual cycle on genital tract inflammation during chronic human immunodeficiency virus (HIV) infection is not well defined, but it has implications for HIV prevention. We assessed daily levels of 26 vaginal cytokines and chemokines from 15 women infected with HIV-1. Taking into account coexisting sexually transmitted infections, behavioral factors, and menstruation, this study illustrates cyclic patterns of granulocyte macrophage colony-stimulating factor, interferon-α2, interleukin (IL)-6, IL-10, macrophage inflammatory protein (MIP)-1α, MIP-1β, and tumor necrosis factor (TNF)-α. Progesterone was associated with levels of granulocyte colony-stimulating factor, IL-1α, and monocyte chemoattractant protein-1. Interferon-α2, IL-6, MIP-1α, MIP-1β, and TNF-α levels predicted HIV shedding, but these associations were heavily influenced by the menstrual cycle.