Remaking the Technosubject: Kenyan Men Contextualizing HIV Self-Testing Technologies.

The Kenyan government offers free HIV self-testing kits to men who have sex with men. The value of self-testing is based on the imaginary of an autonomous technosubject empowered to independently control testing services, thereby "freed," through technology, from the social conditions that might inhibit health services utilization. Following a community-centered collaborative approach, community researchers interviewed their peers who examined and reacted to the technology. Participants reframed the technosubject as intertwined with the social world and the testing kit itself as an object that exerts agency and possesses affective potential. Attending to these socio-material relationalities offers insights into program planning.

Healthcare utilization among persons living with HIV in Manitoba, Canada, prior to HIV diagnosis: A case-control analysis.

BACKGROUND: Understanding care patterns of persons living with HIV prior to diagnosis can inform prevention opportunities, earlier diagnosis, and engagement strategies. We examined healthcare utilization among HIV-positive individuals and compared them to HIV-negative controls. METHODS: Data were from a retrospective cohort from Manitoba, Canada. Participants included individuals living with HIV presenting to care between 2007 and 2011, and HIV-negative controls, matched (1:5) by age, sex, and region. Data from population-based administrative databases included physician visits, hospitalizations, drug dispensation, and chlamydia and gonorrhea testing. Diagnoses associated with physician visits were classified according to International Classification of Diseases chapters. Conditional logistic regression models were used to compare cases/controls, with adjusted odds ratios (AORs) and their 95% confidence intervals (95% CI) reported. RESULTS: A total of 193 cases and 965 controls were included. Physician visits and hospitalizations were higher for cases, compared to controls. In the 2 years prior to case date, cases were more likely to be diagnosed with "blood disorders" (AOR: 4.2, 95% CI: 2.0-9.0), be treated for mood disorders (AOR: 2.4, 95% CI: 1.6-3.4), and to have 1+ visits to a hospital (AOR: 2.2, 95% CI: 1.4-3.6). CONCLUSION: Opportunities exist for prevention, screening, and earlier diagnosis. There is a need for better integration of healthcare services with public health.

Invaplex functions as an intranasal adjuvant for subunit and DNA vaccines co-delivered in the nasal cavity of nonhuman primates.

Development of intranasal vaccines for HIV-1 and other mucosal pathogens has been hampered by the lack of adjuvants that can be given safely to humans. We have found that an intranasal Shigella vaccine (Invaplex) which is well tolerated in humans can also function as an adjuvant for intranasal protein and DNA vaccines in mice. To determine whether Invaplex could potentially adjuvant similar vaccines in humans, we simultaneously administered a simian immunodeficiency virus (SIV) envelope (Env) protein and DNA encoding simian-human immunodeficiency virus (SHIV) with or without Invaplex in the nasal cavity of female rhesus macaques. Animals were intranasally boosted with adenoviral vectors expressing SIV env or gag,pol to evaluate memory responses. Anti-SIV antibodies in sera and nasal, genital tract and rectal secretions were quantitated by ELISA. Intracellular cytokine staining was used to measure Th1-type T cells in blood. Macaques given DNA/protein immunizations with 0.5 mg Invaplex developed greater serum IgG, nasal IgA and cervicovaginal IgA responses to SIV Env and SHIV Gag,Pol proteins when compared to non-adjuvanted controls. Rectal IgA responses to Env were only briefly elevated and not observed to Gag,Pol. Invaplex increased frequencies of IFNγ-producing CD4 and CD8 T cells to the Env protein, but not T cell responses induced by the DNA. Ad-SIV boosting increased Env-specific polyfunctional T cells and Env- and Gag,Pol-specific antibodies in serum and all secretions. The data suggest that Invaplex could be highly effective as an adjuvant for intranasal protein vaccines in humans, especially those intended to prevent infections in the genital or respiratory tract.

Nanoscale Probing of Liposome Encapsulating Drug Nanocrystal Using Atomic Force Microscopy-Infrared Spectroscopy.

Use of liposomes encapsulating drug nanocrystals for the treatment of diseases like cancer and pulmonary infections is gaining attention. The potential therapeutic benefit of these engineered formulations relies on maintaining the physical integrity of the liposomes and the stability of the encapsulated drug. With the significant advancement in the microscopic and analytical techniques, analysis of the size and size distribution of these nanosized vesicles is possible. However, due to the limited spatial resolution of conventional vibrational spectroscopy techniques, the chemical composition of individual nanosized liposome cannot be resolved. To address this limitation, we applied atomic force microscopy infrared spectroscopy (AFM-IR) to assess the chemical composition of individual liposomes encapsulating ciprofloxacin in dissolved and nanocrystalline form. Spatially resolved AFM-IR spectra acquired from individual liposomes confirmed the presence of peaks related to N-H bending vibration, C-N stretching and symmetric, and asymmetric vibration of the carboxyl group present in the ciprofloxacin. Our results further demonstrated the effectiveness of AFM-IR in differentiating the liposome containing ciprofloxacin in dissolved or nanocrystalline form. Spectra acquired from dissolved ciprofloxacin had peaks related to the ionised carboxyl group, i.e., at 1576 and 1392 cm-1, which were either absent or far weaker in intensity in the spectra of liposomal sample containing ciprofloxacin nanocrystals. These findings are highly significant for pharmaceutical scientists to ascertain the stability and physicochemical composition of individual liposomes and will facilitate the design and development of liposomes with greater therapeutic benefits.

Geographical Variation and Factors Associated With Inflammatory Bowel Disease in a Central Canadian Province.

BACKGROUND: We investigated temporal trends, geographical variation, and geographical risk factors for incidence of inflammatory bowel disease (IBD). METHODS: We used the University of Manitoba IBD Epidemiology Database to identify incident IBD cases diagnosed between 1990 and 2012, which were then geocoded to 296 small geographic areas (SGAs). Sociodemographic characteristics of the SGAs (proportions of immigrants, visible minorities, Indigenous people, and average household income) were obtained from the 2006 Canadian Census. The geographical variation of IBD incidence was modeled using a Bayesian spatial Poisson model. Time trends of IBD incidence were plotted using Joinpoint regression. RESULTS: The incidence of IBD decreased over the study years from 23.6 (per 100,000 population) in 1990 to 16.3 (per 100,000 population) in 2012. For both Crohn's disease (CD) and ulcerative colitis (UC), the highest incidence was in Winnipeg and the southern and central regions of Manitoba, whereas most of northern Manitoba had lower incidence. There was no effect of sociodemographic characteristics of SGAs, other than the proportion of Indigenous people, which was associated with lower IBD incidence. CONCLUSIONS: Although the incidence of IBD in Manitoba is decreasing over time, we have identified geographic areas with persistently higher IBD incidence that warrant further study for etiologic clues.

Evaluation of community-based HIV self-testing delivery strategies on reducing undiagnosed HIV infection, and improving linkage to prevention and treatment services, among men who have sex with men in Kenya: a programme science study protocol.

BACKGROUND: HIV prevalence among men having sex with men (MSM) in Kenya is 18.2%. Despite scale-up of HIV testing services, many MSM remain unaware of their HIV status and thus do not benefit from accessing HIV treatment or prevention services. HIV self-testing (HIVST) may help address this gap. However, evidence is limited on how, when, and in what contexts the delivery of HIVST to MSM could increase awareness of HIV status and lead to early linkage to HIV treatment and prevention. METHODS: The study will be embedded within existing MSM-focused community-based HIV prevention and treatment programmes in 3 counties in Kenya (Kisumu, Mombasa, Kiambu). The study is designed to assess three HIV testing outcomes among MSM, namely a) coverage b) frequency of testing and c) early uptake of testing. The study will adopt a mixed methods programme science approach to the implementation and evaluation of HIVST strategies via: (i) a baseline and endline bio-behavioural survey with 1400 MSM; (ii) a socio-sexual network study with 351 MSM; (iii) a longitudinal qualitative cohort study with 72 MSM; (iv) routine programme monitoring in three sites; (v) a programme-specific costing exercise; and (vi) mathematical modelling. This protocol evaluates the impact of community-based implementation of HIV self-testing delivery strategies among MSM in Kenya on reducing the undiagnosed MSM population, and time for linkage to prevention, treatment and care following HIV self-testing. Baseline data collection started in April 2019 and the endline data collection will start in July 2020. DISCUSSION: This study is one of the first programme science studies in Sub-Saharan Africa exploring the effectiveness of integrating HIVST interventions within already existing HIV prevention and treatment programmes for MSM in Kenya at scale. Findings from this study will inform national best approaches to scale up HIVST among MSM in Kenya.

Mapping and size estimates of female sex workers in Cameroon: Toward informed policy for design and implementation in the national HIV program.

BACKGROUND: Due to high HIV prevalence among Female Sex Workers (FSWs) in Cameroon (36.5%), this population is especially vulnerable to HIV acquisition and transmission nationwide. Though being prioritized in the national HIV response, it would be relevant to generate statistics on the number of FSWs in order to guide HIV interventions among FSWs. Our objective was to estimate the size of FSWs within hotspots of Cameroon. METHODS: A cross-sectional study was conducted from September-November 2015 in selected cities in Cameroon: Bafoussam, Bamenda, Bertoua, Buea, Douala, Kribi, Limbé, and Yaoundé. A programmatic mapping was used, consisting of interviews with secondary key informants (KI) to identify hotspots of FSWs and their respective estimated numbers. Validation of size estimates was done by interviews with FSW at each hotspot. Size estimations in the councils mapped were extended to others not mapped using a Poisson regression model. RESULTS: A total of 2,194 hotspots were identified: Douala (760), Yaoundé (622), Bamenda (263), Bafoussam (194), Kribi (154), Bertoua (140), Limbé (35), and Buea (26). The estimated total number (range) of FSWs was 21,124 (16,079-26,170), distributed per city as follows: Douala 7,557 (5,550-9,364), Yaoundé 6,596 (4,712-8,480), Bafoussam 2,458 (1,994-2,923), Bamenda 1,975 (1,605-2,345), Kribi 1,121 (832-1,408), Bertoua 1,044 (891-1,198), Buea 225 (185-266), and Limbé 148 (110-148). The variability of estimates among cities was also observed within the councils of each city. The national predicted estimate of FSW population was 112,580 (103,436-121,723), covering all councils of Cameroon. An estimate of 1.91% (112,580/5,881,526; 0.47%-3.36%) adult female population in Cameroon could be sex workers. CONCLUSION: There are considerable numbers of FSW in major cities in Cameroon. There is a need to prioritize interventions for HIV prevention toward this population in order to limit the burden of HIV sexual transmission nationwide.

Changes in HIV prevention programme outcomes among key populations in Kenya: Data from periodic surveys.

The Kenya National AIDS and STI Control Programme (NASCOP) conducted annual polling booth surveys (PBS) in 2014 and 2015 to measure outcomes from the national HIV prevention programme for key populations (KPs), comprising behavioural, biomedical and structural interventions. KPs included female sex workers (FSWs), men who have sex with men (MSM) and people who inject drugs (PWID). We compared survey results from the first and second rounds. Comparing the second to the first round, significantly more FSWs (93% vs. 88%, p<0.001) and MSM (77% vs. 58%, p<0.001) reported condom use at last sex with a paying client, and at last anal sex among MSM (80% vs. 77%, p<0.05) and PWID (48% vs. 27%, p<0.01). However, condom use with regular partners remained low, at less than 53% for FSWs and 69% for MSM. Among PWID, there was a significant increase in use of new needles and syringes at last injection (93% vs. 88%, p<0.001), and a significant decrease in reported non-availability of clean needles (23% vs. 36%, p<0.001). The number of overdoses in the past six months reduced significantly but remained high (40% vs. 51%, p<0.001). FSWs and MSM reported significantly higher HIV testing, and in all KP groups, over 93% reported ever having been tested for HIV. Among the respondents self-reporting to have tested HIV positive (24% of FSW, 22% of MSM and 19% of PWID), 80% of FSWs, 70% of MSM, and 73% of PWID reported currently taking antiretroviral therapy (ART). While the experience of forced intercourse by partners declined among FSWs (18% vs. 22%, p<0.01) and MSM (13% vs. 17%, p<0.01), more FSWs reported violence by law enforcement personnel (49% vs. 44%, p<0.001). These findings provide valuable information on the programme's progress, and a signpost for the integrated behavioural, biomedical and structural interventions to achieve their HIV prevention targets.

Griffithsin carrageenan fast dissolving inserts prevent SHIV HSV-2 and HPV infections in vivo.

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) strategies with proven in vivo efficacy rely on antiretroviral drugs, creating the potential for drug resistance and complicated treatment options in individuals who become infected. Moreover, on-demand products are currently missing from the PrEP development portfolio. Griffithsin (GRFT) is a non-antiretroviral HIV entry inhibitor derived from red algae with an excellent safety profile and potent activity in vitro. When combined with carrageenan (CG), GRFT has strong activity against herpes simplex virus-2 (HSV-2) and human papillomavirus (HPV) in vitro and in vivo. Here, we report that GRFT/CG in a freeze-dried fast dissolving insert (FDI) formulation for on-demand use protects rhesus macaques from a high dose vaginal SHIV SF162P3 challenge 4 h after FDI insertion. Furthermore, the GRFT/CG FDI also protects mice vaginally against HSV-2 and HPV pseudovirus. As a safe, potent, broad-spectrum, on-demand non-antiretroviral product, the GRFT/CG FDI warrants clinical development.

Effective Treatment of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus Species Infections in Macrophages, Biofilm, and Mice by Using Liposomal Ciprofloxacin.

Nontuberculous mycobacteria (NTM) affect an increasing number of individuals worldwide. Infection with these organisms is more common in patients with chronic lung conditions, and treatment is challenging. Quinolones, such as ciprofloxacin, have been used to treat patients, but the results have not been encouraging. In this report, we evaluate novel formulations of liposome-encapsulated ciprofloxacin (liposomal ciprofloxacin) in vitro and in vivo Its efficacy against Mycobacterium avium and Mycobacterium abscessus was examined in macrophages, in biofilms, and in vivo using intranasal instillation mouse models. Liposomal ciprofloxacin was significantly more active than free ciprofloxacin against both pathogens in macrophages and biofilms. When evaluated in vivo, treatment with the liposomal ciprofloxacin formulations was associated with significant decreases in the bacterial loads in the lungs of animals infected with M. avium and M. abscessus In summary, topical delivery of liposomal ciprofloxacin in the lung at concentrations greater than those achieved in the serum can be effective in the treatment of NTM, and further evaluation is warranted.

Effects of exposure to an intensive HIV-prevention programme on behavioural changes among female sex workers in Nairobi, Kenya.

While Kenya has had a long-standing national HIV-prevention programme, evidence on the level of exposure to its interventions and related effects on behavioural changes among female sex workers (FSWs) is limited. Using cross-sectional behavioural data collected in 2013 from 1 357 FSWs aged 18 years and above in Nairobi, Kenya, this study explores the relationship between FSW programme exposure levels and behavioural outcomes including condom use, sexually transmitted infection (STI)-treatment, and empowerment measures like disclosure of self-identity and violence reporting. We categorised programme exposure levels as none, moderate and intensive. Multivariate logistic regression was used for analysis. Overall, 35% of the FSWs were not exposed to any HIV prevention programme, whereas about 24% had moderate and 41% had intensive exposure. FSWs having intensive programme exposure had a higher likelihood of using condoms consistently with occasional clients (AOR: 1.57; 95% CI: 1.08-2.31) and seeking treatment for STIs (AOR: 3.37; 95% CI: 1.63-7.02) compared to FSWs with no or moderate exposure. Intensive programme exposure was also associated with higher self-disclosure of sex-work identity (AOR: 1.63; 95% CI: 1.19-2.24), reporting of violence to police (AOR: 2.45; 95% CI: 1.03-5.84), and negotiation of condom use at last sex when the client was under the influence of alcohol (AOR: 1.63; 95% CI: 0.94-2.82). Although HIV prevention programmes in Kenya have been underway for over a decade, programme efforts were largely focused on saturating the coverage (intervention breadth). Strategies should now focus on ensuring improved quality of contacts through intensified programme exposure (intervention depth) to enhance gains in behavioural change among FSWs and preventing the burden of HIV infection among them.

In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of Mycobacterium tuberculosis.

Mycobacterium tuberculosis continues to cause devastating levels of mortality due to tuberculosis (TB). The failure to control TB stems from an incomplete understanding of the highly specialized strategies that M. tuberculosis utilizes to modulate host immunity and thereby persist in host lungs. Here, we show that M. tuberculosis induced the expression of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan catabolism, in macrophages and in the lungs of animals (mice and macaque) with active disease. In a macaque model of inhalation TB, suppression of IDO activity reduced bacterial burden, pathology, and clinical signs of TB disease, leading to increased host survival. This increased protection was accompanied by increased lung T cell proliferation, induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing, reduced checkpoint signaling, and the relocation of effector T cells to the center of the granulomata. The enhanced killing of M. tuberculosis in macrophages in vivo by CD4+ T cells was also replicated in vitro, in cocultures of macaque macrophages and CD4+ T cells. Collectively, these results suggest that there exists a potential for using IDO inhibition as an effective and clinically relevant host-directed therapy for TB.

An intravaginal ring that releases three antiviral agents and a contraceptive blocks SHIV-RT infection, reduces HSV-2 shedding, and suppresses hormonal cycling in rhesus macaques.

Women globally need access to multipurpose prevention technologies (MPTs) that prevent human immunodeficiency virus (HIV), sexually transmitted infections that increase HIV acquisition/transmission risk, and unintended pregnancy. Seeking an MPT with activity against HIV, herpes simplex virus-2 (HSV-2), and human papillomavirus (HPV), we developed a prototype intravaginal ring (IVR), the MZCL IVR, which released the antiviral agents MIV-150, zinc acetate, and carrageenan (MZC for short) and the contraceptive levonorgestrel (LNG). Previously, we showed that an MZC gel has potent activity against immunodeficiency viruses, HSV-2, and HPV and that the MZCL (MZC with LNG) IVR releases all four components in macaques in vivo at levels associated with efficacy. Vaginal fluid from treated macaques has in vitro activity against HIV, HSV-2, and HPV. Herein, we assessed the ability of the MZCL IVR to protect macaques against repeated co-challenge with HSV-2 and SHIV-RT (simian immunodeficiency virus [SIV] containing the reverse transcriptase gene from HIV) and prevent hormonal cycling. We evaluated in vivo drug release in co-challenged macaques by measuring drug levels in blood and vaginal fluid and residual drug levels in used IVRs. The MZCL IVR significantly prevented SHIV-RT infection, reduced HSV-2 vaginal shedding, and prevented cycling. No non-nucleoside HIV reverse transcriptase inhibitor (NNRTI)-resistant SHIV was detected in macaques that became infected after continuous exposure to MZC from the IVR. Macaques wearing the MZCL IVR also had carrageenan levels in vaginal fluid expected to protect from HPV (extrapolated from mice) and LNG levels in blood associated with contraceptive efficacy. The MZCL IVR is a promising MPT candidate that warrants further development.

Estimates of Disease Course in Inflammatory Bowel Disease Using Administrative Data: A Population-level Study.

BACKGROUND AND AIMS: We sought develop a predictive model of disease course in inflammatory bowel disease [IBD] using health care utilization measures from administrative health data, and to apply this model to estimate disease course at a population level over time. METHODS: Study participants were IBD patients who were prospectively followed for a 1-year period between 2009 and 2010 in a Canadian clinic setting to assess their IBD disease course [i.e. remission, mild, moderate, severe]. Clinic data were linked with population-based administrative health data. A multivariable partial proportional odds model tested health care utilization measures that discriminated disease course groups. The model was applied to project the distribution of disease course for the Manitoba IBD population for 1995-2013. RESULTS: There were 407 participants (54.3% females, 64.4% Crohn's disease [CD]) with mean age at diagnosis of 29.8 years [SD 14.9]. Forty-one per cent of participants were clinically in remission, while 14.0% had severe IBD. Mild, moderate or severe disease was associated with three or more gastroenterologist visits (odds ratio [OR] = 3.33, 95% confidence interval [CI]: 2.03-5.54) or three or more general practitioner visits [OR = 2.97, 95% CI: 1.44-6.37] with an IBD diagnosis and ≥1 radiology test [OR = 2.22, 95% CI: 1.31-3.80]. The percentages of the Manitoba IBD population in remission rose steadily from 1995 to 2013 [43.6 to 59.9%], while the percentages of individuals with mild, moderate or severe disease declined. CONCLUSION: This study demonstrated that health care utilization measures from administrative data can be used to predict disease course in the IBD population.

Mucosal Vaccination with Heterologous Viral Vectored Vaccine Targeting Subdominant SIV Accessory Antigens Strongly Inhibits Early Viral Replication.

Conventional HIV T cell vaccine strategies have not been successful in containing acute peak viremia, nor in providing long-term control. We immunized rhesus macaques intramuscularly and rectally using a heterologous adenovirus vectored SIV vaccine regimen encoding normally weakly immunogenic tat, vif, rev and vpr antigens fused to the MHC class II associated invariant chain. Immunizations induced broad T cell responses in all vaccinees. Following up to 10 repeated low-dose intrarectal challenges, vaccinees suppressed early viral replication (P=0.01) and prevented the peak viremia in 5/6 animals. Despite consistently undetectable viremia in 2 out of 6 vaccinees, all animals showed evidence of infection induced immune responses indicating that infection had taken place. Vaccinees, with and without detectable viremia better preserved their rectal CD4+ T cell population and had reduced immune hyperactivation as measured by naïve T cell depletion, Ki-67 and PD-1 expression on T cells. These results indicate that vaccination towards SIV accessory antigens vaccine can provide a level of acute control of SIV replication with a suggestion of beneficial immunological consequences in infected animals of unknown long-term significance. In conclusion, our studies demonstrate that a vaccine encoding subdominant antigens not normally associated with virus control can exert a significant impact on acute peak viremia.

MZC Gel Inhibits SHIV-RT and HSV-2 in Macaque Vaginal Mucosa and SHIV-RT in Rectal Mucosa.

The Population Council's microbicide gel MZC (also known as PC-1005) containing MIV-150 and zinc acetate dihydrate (ZA) in carrageenan (CG) has shown promise as a broad-spectrum microbicide against HIV, herpes simplex virus (HSV), and human papillomavirus. Previous data show antiviral activity against these viruses in cell-based assays, prevention of vaginal and rectal simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) infection, and reduction of vaginal HSV shedding in rhesus macaques and also excellent antiviral activity against HSV and human papillomavirus in murine models. Recently, we demonstrated that MZC is safe and effective against SHIV-RT in macaque vaginal explants. Here we established models of ex vivo SHIV-RT/HSV-2 coinfection of vaginal mucosa and SHIV-RT infection of rectal mucosa in macaques (challenge of rectal mucosa with HSV-2 did not result in reproducible tissue infection), evaluated antiviral activity of MZC, and compared quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay readouts for monitoring SHIV-RT infection. MZC (at nontoxic dilutions) significantly inhibited SHIV-RT in vaginal and rectal mucosas and HSV-2 in vaginal mucosa when present during viral challenge. Analysis of SHIV-RT infection and MZC activity by 1-step simian immunodeficiency virus gag quantitative RT-PCR and p27 enzyme-linked immunosorbent assay demonstrated similar virus growth dynamics and MZC activity by both methods and higher sensitivity of quantitative RT-PCR. Our data provide more evidence that MZC is a promising dual compartment multipurpose prevention technology candidate.

CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection.

The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4(+) T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4(+) T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8(+) memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.

A Novel Microbicide/Contraceptive Intravaginal Ring Protects Macaque Genital Mucosa against SHIV-RT Infection Ex Vivo.

Women need multipurpose prevention products (MPTs) that protect against sexually transmitted infections (STIs) and provide contraception. The Population Council has developed a prototype intravaginal ring (IVR) releasing the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 (M), zinc acetate (ZA), carrageenan (CG) and levonorgestrel (LNG) (MZCL IVR) to protect against HIV, HSV-2, HPV and unintended pregnancy. Our objective was to evaluate the anti-SHIV-RT activity of MZCL IVR in genital mucosa. First, macaque vaginal tissues were challenged with SHIV-RT in the presence of (i) MIV-150 ± LNG or (ii) vaginal fluids (VF); available from studies completed earlier) collected at various time points post insertion of MZCL and MZC IVRs. Then, (iii) MZCL IVRs (vs. LNG IVRs) were inserted in non-Depo Provera-treated macaques for 24h and VF, genital biopsies, and blood were collected and tissues were challenged with SHIV-RT. Infection was monitored with one step SIV gag qRT-PCR or p27 ELISA. MIV-150 (LCMS/MS, RIA), LNG (RIA) and CG (ELISA) were measured in different compartments. Log-normal generalized mixed linear models were used for analysis. LNG did not affect the anti-SHIV-RT activity of MIV-150 in vitro. MIV-150 in VF from MZC/MZCL IVR-treated macaques inhibited SHIV-RT in vaginal mucosa in a dose-dependent manner (p<0.05). MIV-150 in vaginal tissue from MZCL IVR-treated animals inhibited ex vivo infection relative to baseline (96%; p<0.0001) and post LNG IVR group (90%, p<0.001). No MIV-150 dose-dependent protection was observed, likely because of high MIV-150 concentrations in all vaginal tissue samples. In cervical tissue, MIV-150 inhibited infection vs. baseline (99%; p<0.05). No cervical tissue was available for MIV-150 measurement. Exposure to LNG IVR did not change tissue infection level. These observations support further development of MZCL IVR as a multipurpose prevention technology to improve women's sexual and reproductive health.

Increasing incidence of anogenital warts with an urban-rural divide among males in Manitoba, Canada, 1990-2011.

BACKGROUND: Anogenital warts (AGW) are caused by the most common sexually transmitted infection, human papillomavirus. The objective of this study was to examine AGW incidence from 1990 to 2011 by sex, age, income quintile, and residential area category (urban/rural). The study period included the initiation of school-based HPV vaccination for girls in the sixth grade, which began in 2008. The data presented in this paper may also be useful for establishing baseline rates of AGW incidence which may be used to evaluate the success of the school-based HPV immunization program. METHODS: Cases of anogenital warts were identified using Manitoba's administrative databases of Physician Claims and Hospital Discharge Abstracts. Annual age-standardized incidence in Manitoba from 1990 to 2011 was calculated. Incident AGW rates were compared by sex, age group, residential area category (urban/rural), and household income quintile using logistic regression. Joinpoint regression analyses were used to evaluate the time trends of AGW. RESULTS: Prior to 2000, AGW incidence was higher among females than males. However, from 2000 to 2011 the incidence was higher among males and increased steadily over time. AGW incidence tended to peak in younger age groups among females compared to males. Females and males living in urban areas had nearly twice the odds of AGW occurrence compared to those in rural areas. CONCLUSIONS: There is a need for education about AGW in male population. The upcoming initiation of HPV vaccination among boys may reduce the incidence and should be evaluated.

Mucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis.

Tuberculosis (TB) is a global pandaemic, partially due to the failure of vaccination approaches. Novel anti-TB vaccines are therefore urgently required. Here we show that aerosol immunization of macaques with the Mtb mutant in SigH (MtbΔsigH) results in significant recruitment of inducible bronchus-associated lymphoid tissue (iBALT) as well as CD4(+) and CD8(+) T cells expressing activation and proliferation markers to the lungs. Further, the findings indicate that pulmonary vaccination with MtbΔsigH elicited strong central memory CD4(+) and CD8(+) T-cell responses in the lung. Vaccination with MtbΔsigH results in significant protection against a lethal TB challenge, as evidenced by an approximately three log reduction in bacterial burdens, significantly diminished clinical manifestations and granulomatous pathology and characterized by the presence of profound iBALT. This highly protective response is virtually absent in unvaccinated and BCG-vaccinated animals after challenge. These results suggest that future TB vaccine candidates can be developed on the basis of MtbΔsigH.