1,721,089 research outputs found
Depo-provera treatment does not abrogate protection from intravenous SIV challenge in female macaques immunized with an attenuated AIDS virus.
Get PDFIn a previous study, progesterone treatment of female monkeys immunized with live, attenuated SHIV89.6 abrogated the generally consistent protection from vaginal simian immunodeficiency virus (SIV) challenge. The mechanisms responsible for the loss of protection remain to be defined. The objective of the present study was to determine whether Depo-Provera administration alters protection from intravenous SIV challenge in SHIV-immunized female macaques.Two groups of female macaques were immunized with attenuated SHIV89.6 and then challenged intravenously with SIVmac239. Four weeks before challenge, one animal group was treated with Depo-Provera, a commonly used injectable contraceptive progestin. As expected, SHIV-immunized monkeys had significantly lower peak and set-point plasma viral RNA levels compared to naïve controls, but in contrast to previously published findings with vaginal SIV challenge, the Depo-Provera SHIV-immunized animals controlled SIV replication to a similar, or even slightly greater, degree than did the untreated SHIV-immunized animals. Control of viral replication from week 4 to week 20 after challenge was more consistent in the progesterone-treated, SHIV-immunized animals than in untreated, SHIV-immunized animals. Although levels of interferon-gamma production were similar, the SIV-specific CD8(+) T cells of progesterone-treated animals expressed more functions than the anti-viral CD8(+) T cells from untreated animals.Depo-Provera did not diminish the control of viral replication after intravenous SIV challenge in female macaques immunized with a live-attenuated lentivirus. This result contrasts with the previously reported effect of Depo-Provera(R) on protection from vaginal SIV challenge and strongly implies that the decreased protection from vaginal challenge is due to effects of progesterone on the genital tract rather than to systemic effects. Further, these results demonstrate that the effects of hormonal contraceptives on vaccine efficacy need to be considered in the context of testing and use of an AIDS vaccine
Unexpected Inflammatory Effects of Intravaginal Gels (Universal Placebo Gel and Nonoxynol-9) on the Upper Female Reproductive Tract: A Randomized Crossover Study.
Get PDFIntravaginal anti-HIV microbicides could provide women with a self-controlled means for HIV prevention, but results from clinical trials have been largely disappointing. We postulated that unrecognized effects of intravaginal gels on the upper female reproductive tract might contribute to the lower-than-expected efficacy of HIV microbicides. Our objective was to study the effects of intravaginal gels on the immune microenvironment of the cervix and uterus. In this randomized crossover study, 27 healthy female volunteers used a nightly application of intravaginal nonoxynol-9 (N9) gel as a "failed" microbicide or the universal placebo gel (UPG) as a "safe" gel (intervention cycles), or nothing (control cycle) from the end of menses to the mid-luteal phase. At a specific time-point following ovulation, all participants underwent sample collection for measurements of T-cell phenotypes, gene expression, and cytokine/chemokine protein concentrations from 3 anatomic sites above the vagina: the cervical transformation zone, the endocervix and the endometrium. We used hierarchical statistical models to estimate mean (95% CI) intervention effects, for N9 and UPG relative to control. Exposure to N9 gel and UPG generated a common "harm signal" that included transcriptional up-regulation of inflammatory genes chemokine (C-C motif) ligand 20 (macrophage inflammatory factor-3alpha) and interleukin 8 in the cervix, decreased protein concentrations of secretory leukocyte protease inhibitor, and transcriptional up-regulation of inflammatory mediators glycodelin-A and osteopontin in the endometrium. These results need to be replicated with a larger sample, but underscore the need to consider the effects of microbicide agents and gel excipients on the upper female reproductive tract in studies of vaginal microbicides
Impact of Penile-Vaginal Sex on the Microbiome and Immunology of the Penile Urethra
Get PDFInflammation and microbiome composition affect HIV acquisition risk and are both affected by penile-vaginal sex. Despite being a key acquisition site in men, the penile urethra and the impact of sex on its microenvironment is poorly understood. First-void urine was collected to characterize the penile urethra microbiome (through 16S sequencing and qPCR) and immune milieu (through a multiplex chemiluminescent immunoassay) before and after penile-vaginal sex with an established partner (immediately, 1, 7 and 72 hours after). Sex induced immediate urethral inflammation, and enrichment of common vaginal species Lactobacillus crispatus and L. jensenii, which were resolved within 1 and 7 hours respectively. Interestingly, non-optimal bacterial species which contribute to inflammation and HIV risk in the vagina – L. iners and Gardnerella vaginalis – were commonly found in the urethra and remained unaffected after sex. These results highlight how sex shapes the urethral microenvironment, with potential implications for the genital health of sexual partners.M.Sc
Defining Immune Correlates of HIV Susceptibility in the Foreskin
Get PDFHIV is a predominantly sexually transmitted infection that has infected over 60 million people and been responsible for 60 million deaths. To date, non-antiretroviral microbicides have failed to prevent HIV acquisition, or even increased it. This is likely because HIV preferentially infects activated immune cells (CD4+ T cells), taking advantage of the body’s attempts to defend itself. Therefore, relative immunoquiescence, as opposed to immune activation, may be protective. I hypothesized that men who are biologically more susceptible to HIV would have increased foreskin CD4 T cell activation, while the opposite would be true of men who are relatively resistant. The foreskin has recently been identified as a major site of HIV acquisition, but little previous research has been performed on this tissue. I therefore developed novel techniques to isolate viable, immunologically functional T cells from foreskin tissue. I then worked with the Rakai Health Sciences Program in Uganda to identify men undergoing elective circumcision who are HIV-Exposed but have remained SeroNegative (HESN, relatively resistant to HIV), and men with Herpes Simple Virus-2 infection (HSV-2+, relatively susceptible to HIV). I collected sub-preputial swabs and foreskin tissue from these men, and characterized numerous immune parameters in their samples. I found that HSV-2+ men had an increased relative abundance of CD4 T cells co-expressing the HIV receptor CCR5. In contrast, I found that HESN men had a decreased relative abundance of activated T cells (CD4/8 T cells producing TNFα) and Th17 cells (a pro-inflammatory T cell subset known to be particularly susceptible to HIV). Additionally, foreskin secretions from HESN men were more likely to have antibodies (IgA) able to neutralize HIV, and had more innate anti-viral peptides. I therefore propose HIV resistance may be driven by decreased T cell activation in genital tissue, in combination with increased secretion of anti-HIV immune proteins.Ph
The Role of Gut Mucosal Immunology in HIV Immunopathogenesis
No full textProgressive HIV infection is characterized by a rapid and profound depletion of CD4 T cells from the gut, structural deterioration of the intestinal epithelium, and microbial translocation into the gut mucosa and bloodstream. Circulating microbes are potent immune activators and the resulting inflammation is linked to HIV disease progression, serious non-AIDS events, and death. The gut is normally enriched with bacteria-specific Th17 cells and tissue protective Th22 cells that provide mucosal immune defense against invading microbes, however these cells may be preferential targets of HIV. Although HIV-infected elite controllers (ECs) suppress HIV to undetectable levels without antiretroviral therapy (ART), microbial translocation and chronic inflammation may increase serious non-AIDS occurrences and mortality.My PhD work aims to elucidate the role of gut mucosal immunology in its protection against microbial translocation and immune activation in treated and untreated HIV infection. During chronic HIV infection, IL-22 producing gut lymphocytes, including Th22 cells, were profoundly depleted, epithelial integrity was compromised, and microbial translocation was increased. However, early infection was uniquely associated with increased IL-22 production by non-T cells and the preservation of epithelial integrity. The tissue protective role of Th22 cells was supported by in vitro studies demonstrating the capacity of IL-22 to prevent HIV-induced epithelial damage. Sigmoid Th17 cells were also depleted during chronic HIV infection, but their pro-inflammatory polyfunctional capacity (co-production of IL-22, TNF-α and/or IFN-γ) was lost from the earliest stages. Although ART rapidly restored gut Th17 numbers, their functional reconstitution and resolution of microbial translocation was much delayed. ART-naïve ECs had normal levels of gut CD4 T cells, microbial translocation and immune activation, but soluble biomarkers of serious non-AIDS events (IL-6 and D-dimer) were elevated and a trial of short-term ART did not reduce these biomarkers.These findings emphasize that gut immune changes during HIV infection are important contributors to microbial translocation and systemic inflammation, however gut independent mechanisms may also be involved. Novel therapeutic strategies to accelerate the restoration of gut immune function and to reduce chronic inflammation may have important benefit in people living with HIV.Ph.D
Exploring the Effects of Endemic East African Co-infections on HIV Susceptibility in the Female Genital Tract
No full textRATIONALE: Human immunodeficiency virus (HIV) remains a leading cause of global morbidity with the highest burden in Sub-Saharan Africa (SSA). For reasons that are incompletely understood, the likelihood of HIV transmission is several fold higher in SSA than in higher income countries, and most of these infections are acquired by women. Residents of SSA are also exposed to a variety of endemic infections that could elevate HIV susceptibility through effects on mucosal and systemic immunology. In the East African Lake Victoria region high HIV transmission geographically overlaps with endemic malaria and Schistosoma mansoni infections. Therefore in this thesis I aimed to explore the impact of these infections on HIV susceptibility in the female genital tract. MAIN FINDINGS: The prevalence of malaria in adult women from Entebbe, Uganda was much lower than expected, but this low prevalence was masked by high rates of over-diagnosis in public health facilities. The prevalence of S. mansoni infection approached 50% and was associated with systemic immune alterations and several socio-behavioral HIV risk factors, emphasizing the importance of controlling these confounders in mucosal studies. A longitudinal clinical trial of S. mansoni treatment effects [ClinicalTrials.gov ID: NCT02878564] demonstrated a substantial anthelminthic treatment-induced reduction of HIV entry into both genital and blood CD4 T cells for two months after standard therapy, despite transient mucosal and systemic immune activation. Furthermore, schistosomiasis treatment was associated with the induction of Type I Interferon pathways, providing a possible mechanism for the reduced HIV entry seen in the trial. CONCLUSIONS: Collectively, the findings presented in this thesis i) highlight the importance of understanding the epidemiology of endemic infections and associated socio-behavioral factors that could confound studies of mucosal HIV susceptibility, and ii) suggest that S. mansoni treatment may lead to new HIV prevention strategies in SSA.
ОБОСНОВАНИЕ: Вирус иммунодефицита человека (ВИЧ) является ведущей причиной глобальной заболеваемости с самым высоким уровнем инфекций в Африке к Югу от Сахары (АЮС). По причинам, которые не полностью изучены, вероятность передачи ВИЧ в несколько раз выше в АЮС, чем в странах с более высоким уровнем дохода, и большинство ВИЧ инфекций наблюдается у женщин. Жители АЮС также подвергаются воздействию множества эндемичных инфекций, которые могут влиять на восприимчивость к ВИЧ на иммунитет слизистой и на общесистемном уровне. В Восточно-Африканском регионе, в районе озера Виктория, высокая передача ВИЧ географически перекрывается с эндемичной малярией и шистосомой Мэнсона (Schistosoma mansoni). Цель этой диссертации- изучить влияние этих инфекций на восприимчивость к ВИЧ в женском половом пути. ОСНОВНЫЕ РЕЗУЛЬТАТЫ: Распространенность малярии у взрослых женщин из Энтеббе, Уганда, была намного ниже по сравнению с ожидаемым уровнем, но эта низкая распространенность была замаскирована высокими показателями чрезмерного диагноза малярии в медицинских учреждениях. Распространенность инфекции S. mansoni достигала 50% и была связана с иммунными изменениями в крови и несколькими социально-поведенческими факторами связанными с риском ВИЧ инфекции, что указало на необходимость принятия во внимание эти факторов в дальнейших клинических исследованиях. Проспективное клиническое исследование эффектов лечения S. mansoni [ClinicalTrials.gov ID: NCT02878564] продемонстрировало существенное снижение уровня ВИЧ инфекции CD4 Т-клеток изолированных из эндошейки матки и крови в течение двух месяцев после стандартной терапии шистосомоза, несмотря на временную иммунную активацию. Кроме того, лечение шистосомоза было связано с индукцией антивирусного интерферона типа I, что объясняет возможный механизм снижения уровня ВИЧ-инфекции. ВЫВОДЫ: В совокупности результаты, представленные в этом тезисе, i) подчеркивают важность понимания эпидемиологии эндемических инфекций и связанных с ними социально-поведенческих факторов в исследованиях восприимчивости к ВИЧ ii) указывают на то, что лечение S. mansoni может быть включено в стратегическую профилактику ВИЧ в АЮС.Ph.D
Exploring the Effects of Endemic East African Co-infections on HIV Susceptibility in the Female Genital Tract
Get PDFRATIONALE: Human immunodeficiency virus (HIV) remains a leading cause of global morbidity with the highest burden in Sub-Saharan Africa (SSA). For reasons that are incompletely understood, the likelihood of HIV transmission is several fold higher in SSA than in higher income countries, and most of these infections are acquired by women. Residents of SSA are also exposed to a variety of endemic infections that could elevate HIV susceptibility through effects on mucosal and systemic immunology. In the East African Lake Victoria region high HIV transmission geographically overlaps with endemic malaria and Schistosoma mansoni infections. Therefore in this thesis I aimed to explore the impact of these infections on HIV susceptibility in the female genital tract. MAIN FINDINGS: The prevalence of malaria in adult women from Entebbe, Uganda was much lower than expected, but this low prevalence was masked by high rates of over-diagnosis in public health facilities. The prevalence of S. mansoni infection approached 50% and was associated with systemic immune alterations and several socio-behavioral HIV risk factors, emphasizing the importance of controlling these confounders in mucosal studies. A longitudinal clinical trial of S. mansoni treatment effects [ClinicalTrials.gov ID: NCT02878564] demonstrated a substantial anthelminthic treatment-induced reduction of HIV entry into both genital and blood CD4 T cells for two months after standard therapy, despite transient mucosal and systemic immune activation. Furthermore, schistosomiasis treatment was associated with the induction of Type I Interferon pathways, providing a possible mechanism for the reduced HIV entry seen in the trial. CONCLUSIONS: Collectively, the findings presented in this thesis i) highlight the importance of understanding the epidemiology of endemic infections and associated socio-behavioral factors that could confound studies of mucosal HIV susceptibility, and ii) suggest that S. mansoni treatment may lead to new HIV prevention strategies in SSA.
ОБОСНОВАНИЕ: Вирус иммунодефицита человека (ВИЧ) является ведущей причиной глобальной заболеваемости с самым высоким уровнем инфекций в Африке к Югу от Сахары (АЮС). По причинам, которые не полностью изучены, вероятность передачи ВИЧ в несколько раз выше в АЮС, чем в странах с более высоким уровнем дохода, и большинство ВИЧ инфекций наблюдается у женщин. Жители АЮС также подвергаются воздействию множества эндемичных инфекций, которые могут влиять на восприимчивость к ВИЧ на иммунитет слизистой и на общесистемном уровне. В Восточно-Африканском регионе, в районе озера Виктория, высокая передача ВИЧ географически перекрывается с эндемичной малярией и шистосомой Мэнсона (Schistosoma mansoni). Цель этой диссертации- изучить влияние этих инфекций на восприимчивость к ВИЧ в женском половом пути. ОСНОВНЫЕ РЕЗУЛЬТАТЫ: Распространенность малярии у взрослых женщин из Энтеббе, Уганда, была намного ниже по сравнению с ожидаемым уровнем, но эта низкая распространенность была замаскирована высокими показателями чрезмерного диагноза малярии в медицинских учреждениях. Распространенность инфекции S. mansoni достигала 50% и была связана с иммунными изменениями в крови и несколькими социально-поведенческими факторами связанными с риском ВИЧ инфекции, что указало на необходимость принятия во внимание эти факторов в дальнейших клинических исследованиях. Проспективное клиническое исследование эффектов лечения S. mansoni [ClinicalTrials.gov ID: NCT02878564] продемонстрировало существенное снижение уровня ВИЧ инфекции CD4 Т-клеток изолированных из эндошейки матки и крови в течение двух месяцев после стандартной терапии шистосомоза, несмотря на временную иммунную активацию. Кроме того, лечение шистосомоза было связано с индукцией антивирусного интерферона типа I, что объясняет возможный механизм снижения уровня ВИЧ-инфекции. ВЫВОДЫ: В совокупности результаты, представленные в этом тезисе, i) подчеркивают важность понимания эпидемиологии эндемических инфекций и связанных с ними социально-поведенческих факторов в исследованиях восприимчивости к ВИЧ ii) указывают на то, что лечение S. mansoni может быть включено в стратегическую профилактику ВИЧ в АЮС.Ph.D
The Impact of Herpes Therapy on Genital and Systemic immunology
No full textHIV infects more than 34 million people globally. Herpes simplex virus type 2 (HSV-2)
has been associated with a 3-fold increase in the rate of HIV acquisition, which may be due to physical breaks in the mucosal barrier during symptomatic episodes and/or an increased number of HIV target cells being exposed in the genital tract. Although clinical trials have demonstrated that herpes suppression in HIV uninfected individuals had no impact on HIV incidence,
acyclovir was associated with a decrease in plasma HIV viral load and delayed disease
progression in HSV-2 co-infected individuals. In addition, many HIV infected individuals display persistent systemic immune activation, which correlates with disease progression, despite successful antiretroviral therapy (ART). It is hypothesized that HSV could be one of the drivers of this activation. To further assess these relationships, my thesis focused on examining the impact of herpes therapy on genital tract immunology and systemic immune activation in HIV uninfected women and a comparison of systemic immune activation in individuals co-infected with HIV and HSV-2 on ART randomized to valacyclovir or placebo.
A randomized, placebo-controlled, double-blinded, cross-over trial was conducted in
HSV-2 infected, HIV uninfected, women using valacyclovir. No differences were observed in
the number of various HIV target cells in the endocervix between valacyclovir and placebo phases. Further, valacyclovir had no impact on systemic immune activation in the same cohort.
In a second clinical trial, the role of herpes therapy on systemic immune activation and inflammation in HIV and HSV-2 co-infected individuals on ART was evaluated. It was concluded that valacyclovir therapy had no impact on these parameters in this population.
In summary, we were unable to demonstrate that herpes therapy was able to reduce the
number of HIV target cells in the endocervix of HSV-2 infected, HIV uninfected women or
systemic immune activation in either HIV uninfected or HIV infected individuals. These findings demonstrate that currently available herpes therapy in standard doses does not appear to reverse the immunological changes associated with HSV-2 infection.Ph
Development and clinical application of a novel ex vivo assay to assess genital HIV susceptibility
No full textA better understanding of the biological factors that promote heterosexual HIV acquisition in the female genital tract (FGT) may inform HIV prevention efforts. The mucosal cellular targets of HIV are not well defined and proposed cellular and molecular correlates include the HIV co-receptor CCR5 and markers of immune activation, including CD69. I established a novel ex vivo HIV entry assay for mucosal studies to enable assessment of ex vivo HIV infection in freshly isolated and unstimulated endocervical CD4+ T cells. HIV susceptibility was enhanced in cervix-derived CD4+ T cells compared to blood. Cervical CCR5+, CD69+, α4β7+ or α4β1+ CD4+ T cells were preferential HIV targets, however, the homing integrins α4β7 or α4β1 did not mediate direct binding to the HIV env or HIV entry into CD4+ T cells, suggesting that α4β7 and α4β1 are unlikely to be HIV entry receptors.
Next, I tested whether ex vivo HIV entry predicts subsequent heterosexual HIV acquisition. Ideally, this would be done using fresh genital samples, but these are usually not available. Hence, I performed a nested, retrospective, blinded, case-control study in blood CD4+ T cells obtained from HIV-uninfected South African female participants enrolled in the CAPRISA 004 clinical trial. Virus entry into blood CD4+ T cell subsets did not predict subsequent HIV acquisition, possibly due to the compartmentalization of immune factors in the genital mucosa.
One such compartmentalized factor in the FGT is the bacterial microbiota, which is dominated in the majority of women by lactobacilli, while a shift towards diverse gram-negative anaerobic species, defined (based on Gram stain) as bacterial vaginosis (BV), is associated with increased HIV acquisition in women. To investigate underlying biological mechanisms that may increase HIV acquisition risk in women with BV, I assessed the impact of BV treatment using the current standard of care, oral metronidazole, on genital immunology and HIV susceptibility. BV treatment reduced endocervical CD4+ T cell susceptibility to HIV and genital IL-1 levels; however, an unexpected increase in several chemokines previously associated with increased HIV risk suggests that more studies are needed before the treatment and/or prevention of asymptomatic BV can be recommended for HIV prevention.Ph.D
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