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1.  Validation of the Modes of Transmission Model as a Tool to Prioritize HIV Prevention Targets: A Comparative Modelling Analysis 
PLoS ONE  2014;9(7):e101690.
Background
The static Modes of Transmission (MOT) model predicts the annual fraction of new HIV infections acquired across subgroups (MOT metric), and is used to focus HIV prevention. Using synthetic epidemics via a dynamical model, we assessed the validity of the MOT metric for identifying epidemic drivers (behaviours or subgroups that are sufficient and necessary for HIV to establish and persist), and the potential consequence of MOT-guided policies.
Methods and Findings
To generate benchmark MOT metrics for comparison, we simulated three synthetic epidemics (concentrated, mixed, and generalized) with different epidemic drivers using a dynamical model of heterosexual HIV transmission. MOT metrics from generic and complex MOT models were compared against the benchmark, and to the contribution of epidemic drivers to overall HIV transmission (cumulative population attributable fraction over t years, PAFt). The complex MOT metric was similar to the benchmark, but the generic MOT underestimated the fraction of infections in epidemic drivers. The benchmark MOT metric identified epidemic drivers early in the epidemics. Over time, the MOT metric did not identify epidemic drivers. This was not due to simplified MOT models or biased parameters but occurred because the MOT metric (irrespective of the model used to generate it) underestimates the contribution of epidemic drivers to HIV transmission over time (PAF5–30). MOT-directed policies that fail to reach epidemic drivers could undermine long-term impact on HIV incidence, and achieve a similar impact as random allocation of additional resources.
Conclusions
Irrespective of how it is obtained, the MOT metric is not a valid stand-alone tool to identify epidemic drivers, and has limited additional value in guiding the prioritization of HIV prevention targets. Policy-makers should use the MOT model judiciously, in combination with other approaches, to identify epidemic drivers.
doi:10.1371/journal.pone.0101690
PMCID: PMC4090151  PMID: 25014543
2.  Sex Hormones Selectively Impact the Endocervical Mucosal Microenvironment: Implications for HIV Transmission 
PLoS ONE  2014;9(5):e97767.
Several studies suggest that progesterone and estrogens may affect HIV transmission in different, possibly opposing ways. Nonetheless, a direct comparison of their effects on the mucosal immune system has never been done. We hypothesize that sex hormones might impact the availability of cells and immune factors important in early stages of mucosal transmission, and, in doing so influence the risk of HIV acquisition. To test this hypothesis, we employed 15 ovarectomized rhesus macaques: 5 were treated with Depot Medroxy Progesterone Acetate (DMPA), 6 with 17-β estradiol (E2) and 4 were left untreated. All animals were euthanized 5 weeks after the initiation of hormone treatment, a time post-DMPA injection associated with high susceptibility to SIV infection. We found that DMPA-treated macaques exhibited higher expression of integrin α4β7 (α4β7) on CD4+ T cells, the gut homing receptor and a marker of cells highly susceptible to HIV, in the endocervix than did the E2-treated animals. In contrast, the frequency of CCR5+ CD4+ T cells in DMPA-treated macaques was higher than in the E2-treated group in vaginal tissue, but lower in endocervix. α4β7 expression on dendritic cells (DCs) was higher in the DMPA-treated group in the endocervical tissue, but lower in vaginal tissue and on blood DCs compared with the E2-treated animals. Soluble MAdCAM-1, the α4β7 ligand, was present in the vaginal fluids of the control and E2-treated groups, but absent in the fluids from DMPA-treated animals. Both hormones modulated the expression and release of inflammatory factors and modified the distribution of sialomucins in the endocervix. In summary, we found that sex hormones profoundly impact mucosal immune factors that are directly implicated in HIV transmission. The effect is particularly significant in the endocervix. This may increase our understanding of the potential hormone-driven modulation of HIV susceptibility and potentially guide contraceptive policies in high-risk settings.
doi:10.1371/journal.pone.0097767
PMCID: PMC4022654  PMID: 24830732
3.  A Potent Combination Microbicide that Targets SHIV-RT, HSV-2 and HPV 
PLoS ONE  2014;9(4):e94547.
Prevalent infection with human herpes simplex 2 (HSV-2) or human papillomavirus (HPV) is associated with increased human immunodeficiency virus (HIV) acquisition. Microbicides that target HIV as well as these sexually transmitted infections (STIs) may more effectively limit HIV incidence. Previously, we showed that a microbicide gel (MZC) containing MIV-150, zinc acetate (ZA) and carrageenan (CG) protected macaques against simian-human immunodeficiency virus (SHIV-RT) infection and that a ZC gel protected mice against HSV-2 infection. Here we evaluated a modified MZC gel (containing different buffers, co-solvents, and preservatives suitable for clinical testing) against both vaginal and rectal challenge of animals with SHIV-RT, HSV-2 or HPV. MZC was stable and safe in vitro (cell viability and monolayer integrity) and in vivo (histology). MZC protected macaques against vaginal (p<0.0001) SHIV-RT infection when applied up to 8 hours (h) prior to challenge. When used close to the time of challenge, MZC prevented rectal SHIV-RT infection of macaques similar to the CG control. MZC significantly reduced vaginal (p<0.0001) and anorectal (p = 0.0187) infection of mice when 106 pfu HSV-2 were applied immediately after vaginal challenge and also when 5×103 pfu were applied between 8 h before and 4 h after vaginal challenge (p<0.0248). Protection of mice against 8×106 HPV16 pseudovirus particles (HPV16 PsV) was significant for MZC applied up to 24 h before and 2 h after vaginal challenge (p<0.0001) and also if applied 2 h before or after anorectal challenge (p<0.0006). MZC provides a durable window of protection against vaginal infection with these three viruses and, against HSV-2 and HPV making it an excellent candidate microbicide for clinical use.
doi:10.1371/journal.pone.0094547
PMCID: PMC3989196  PMID: 24740100
4.  Efficient mucosal transmissibility but limited pathogenicity of R5 SHIVSF162P3N in Chinese origin rhesus macaques 
Background
Infection of rhesus macaques (RMs) of Indian origin with SIV or SHIV provided powerful tools to study HIV-1 transmission and disease, and for testing the efficacy of novel drugs, vaccines and prevention strategies. In developing alternative nonhuman primate AIDS models for the CCR5 (R5)-tropic SHIVSF162P3N, we characterized virus transmission and infection in Chinese origin RMs.
Methods
Virologic, immunologic and pathogenic evaluations of R5 SHIVSF162P3N infection in Chinese RMs challenged intrarectally (ir) or intravaginally (ivg) were performed and compared to those previously observed in Indian origin rhesus exposed to the same inoculum dose and via similar route.
Results
R5 SHIVSF162P3N transmits efficiently across mucosal surfaces in Chinese RMs. The magnitude and kinetics of early virus dissemination following intrarectal inoculation in the Chinese macaques were similar to those observed in Indian rhesus, but a trend towards increased SHIVSF162P3N vaginal infectivity and rapid virus spread was seen in the Chinese macaques compared to the Indian origin animals. Once infected, however, set-point viremia in the ir- and ivg-infected Chinese rhesus was significantly lower and the animals survived longer compared with infected Indian rhesus.
Conclusions
The R5 SHIVSF162P3N/Chinese rhesus macaque infection model is suitable for studies of mucosal HIV-1 transmission and protection, but the high frequency of spontaneous control of chronic viremia and reduced virulence with SHIVSF162P3N in this macaque subspecies may limit its utility in studying HIV-1 pathogenesis and in evaluating vaccines and antiretrovirals that rely on reduction in chronic viral load or AIDS development as an experimental endpoint.
doi:10.1097/QAI.0b013e31827f1c11
PMCID: PMC3622143  PMID: 23221980
SHIV; rhesus macaque subspecies; mucosal transmission; AIDS
5.  Granuloma Correlates of Protection Against Tuberculosis and Mechanisms of Immune Modulation by Mycobacterium tuberculosis 
The Journal of Infectious Diseases  2012;207(7):1115-1127.
Background. The BCG vaccine is ineffective against adult tuberculosis. Hence, new antituberculosis vaccines are needed. Correlates of protection against tuberculosis are not known. We studied the effects of BCG vaccination on gene expression in tuberculosis granulomas using macaques.
Methods. Macaques were BCG-vaccinated or sham-vaccinated and then challenged with virulent Mycobacterium tuberculosis. Lung lesions were used for comparative transcriptomics.
Results. Vaccinated macaques were protected with lower bacterial burden and immunopathology. Lesions from BCG-vaccinated nonhuman primates (NHPs) showed a better balance of α- and β-chemokine gene expression with higher levels of β-chemokine expression relative to nonvaccinated animals. Consistent with this, sham-vaccinated macaques recruited fewer macrophages relative to neutrophils in their lungs. The expression of indoleamine 2,3-dioxygenase (IDO), a known immunosuppressor, was significantly higher in both week 5 and 10 lesions from sham-vaccinated, relative to BCG-vaccinated, NHPs. IDO expression was primarily limited to the nonlymphocytic region of the lesions, within the inner ring structure surrounding the central necrosis.
Conclusions. Our study defines lung gene expression correlates of protective response against tuberculosis, relative to disease, which can potentially be employed to assess the efficacy of candidate antituberculosis vaccines. Mycobacterium tuberculosis may modulate protective immune responses using diverse mechanisms, including increased recruitment of inflammatory neutrophils and the concomitant use of IDO to modulate inflammation.
doi:10.1093/infdis/jis778
PMCID: PMC3633457  PMID: 23255564
Mycobacterium tuberculosis; transcriptomics; IDO
6.  Estimating the Size of the Female Sex Worker Population in Kenya to Inform HIV Prevention Programming 
PLoS ONE  2014;9(3):e89180.
Background
The high burden of HIV infections among female sex workers (FSW) in sub-Saharan Africa has been long recognised, but effective preventive interventions have largely not been taken to scale. We undertook a national geographical mapping exercise in 2011/2012 to assess the locations and population size of FSW in Kenya, to facilitate targeted HIV prevention services for this population.
Methods and Findings
We used a geographical mapping approach, consisting of interviews with secondary key informants to identify “hot” spots frequented by FSW, their operational dynamics and the estimated numbers of FSW in those spots. This was followed by validation of the estimates through interviews with FSW at each spot identified. The mapping covered Nairobi, the capital city of Kenya, and 50 other major urban centres. In total, 11,609 secondary key informant interviews were conducted to identify FSW spots. Further, a total of 6,360 FSW were interviewed for spot validation purposes. A total of 10,670 spots where FSW congregate were identified. The estimated FSW population in all the towns mapped was 103,298 (range 77,878 to 128, 717). Size estimates in the towns mapped were extended to smaller towns that were not mapped, using a statistical model. The national urban FSW population estimate was 138,420 (range 107, 552 to 169, 288), covering all towns of over 5,000 population. We estimated that approximately 5% of the urban female population of reproductive age in Kenya could be sex workers, which is consistent with previous estimates from other sub-Saharan African countries.
Conclusions
This study provides the first national level data on the size of the FSW population in Kenya. These data can be used to enhance HIV prevention programme planning and implementation for FSW, to form the basis for impact evaluations, and to improve programme coverage by directing efforts to locations with the greatest need.
doi:10.1371/journal.pone.0089180
PMCID: PMC3940432  PMID: 24595029
7.  Exposure to MIV-150 from a High-Dose Intravaginal Ring Results in Limited Emergence of Drug Resistance Mutations in SHIV-RT Infected Rhesus Macaques 
PLoS ONE  2014;9(2):e89300.
When microbicides used for HIV prevention contain antiretroviral drugs, there is concern for the potential emergence of drug-resistant HIV following use in infected individuals who are either unaware of their HIV infection status or who are aware but still choose to use the microbicide. Resistant virus could ultimately impact their responsiveness to treatment and/or result in subsequent transmission of drug-resistant virus. We tested whether drug resistance mutations (DRMs) would emerge in macaques infected with simian immunodeficiency virus expressing HIV reverse transcriptase (SHIV-RT) after sustained exposure to the potent non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 delivered via an intravaginal ring (IVR). We first treated 4 SHIV-RT-infected animals with daily intramuscular injections of MIV-150 over two 21 day (d) intervals separated by a 7 d drug hiatus. In all 4 animals, NNRTI DRMs (single and combinations) were detected within 14 d and expanded in proportion and diversity with time. Knowing that we could detect in vivo emergence of NNRTI DRMs in response to MIV-150, we then tested whether a high-dose MIV-150 IVR (loaded with >10 times the amount being used in a combination microbicide IVR in development) would select for resistance in 6 infected animals, modeling use of this prevention method by an HIV-infected woman. We previously demonstrated that this MIV-150 IVR provides significant protection against vaginal SHIV-RT challenge. Wearing the MIV-150 IVR for 56 d led to only 2 single DRMs in 2 of 6 animals (430 RT sequences analyzed total, 0.46%) from plasma and lymph nodes despite MIV-150 persisting in the plasma, vaginal fluids, and genital tissues. Only wild type virus sequences were detected in the genital tissues. These findings indicate a low probability for the emergence of DRMs after topical MIV-150 exposure and support the advancement of MIV-150-containing microbicides.
doi:10.1371/journal.pone.0089300
PMCID: PMC3937329  PMID: 24586674
8.  Modelling the interactions between Herpes simplex virus type-2 (HSV-2) and HIV: implications for the HIV epidemic in Southern India 
Background
The role of HSV-2 in the HIV epidemic, and the potential impact of HSV-2 suppressive therapy, have been previously explored only within the context of sub-Saharan Africa. In this analysis, modelling is used to estimate: (1) the contribution of herpes simplex virus type-2 (HSV-2) to HIV transmission from clients to female sex workers (FSWs) in a Southern Indian setting; and (2) the maximum potential impact of ‘perfect’ HSV-2 suppressive therapy on HIV incidence.
Methods
A dynamic HSV-2/HIV model was developed, parameterised and fitted to Mysore data. The model estimated the attributable fractions (AFs) of HIV infections due to HSV-2. Multivariate sensitivity analyses and regression analyses were conducted.
Results
The model suggests that 36% (95% CI: 22-62%) of FSW HIV infections were due to HSV-2, mostly through HSV-2 asymptomatic shedding. Even if HSV-2 suppressive therapy could eliminate the effect of HSV-2 on HIV infectivity among all coinfected clients, only 15% (95% CI: 3-41%) of HIV infections among FSWs would have been averted. 36% (95% CI: 18-61%) of HIV infections among HSV-2-infected FSWs could have been averted if suppressive therapy reduced their risk of HIV acquisition to that of the HSV-2-uninfected FSWs.
Conclusions
HSV-2 contributes substantially to HIV in this Southern Indian context. However, even in the best case scenario, HSV-2 suppressive therapy is unlikely to reduce HIV transmission or acquisition by more than 50% (as aimed for in recent trials), because of the limited strength of the interaction effect between HSV-2 and HIV.
doi:10.1136/sti.2009.041699
PMCID: PMC3920054  PMID: 21059838
HIV; Herpes simplex virus type-2; mathematical modelling; India; female sex work
9.  A Combination Microbicide Gel Protects Macaques Against Vaginal Simian Human Immunodeficiency Virus-Reverse Transcriptase Infection, But Only Partially Reduces Herpes Simplex Virus-2 Infection After a Single High-Dose Cochallenge 
Abstract
Herpes simplex virus-2 (HSV-2) infection increases HIV susceptibility. We previously established a rhesus macaque model of vaginal HSV-2 preexposure followed by cochallenge with HSV-2 and simian/human immunodeficiency virus-reverse transcriptase (SHIV-RT). Using this model, we showed that a gel containing the nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 in carrageenan (CG) reduced SHIV-RT infection. To evaluate the efficacy of new generation microbicides against both viruses, we first established dual infection after single vaginal cochallenge with SHIV-RT and HSV-2 in HSV-2-naive macaques. All animals (6/6) became HSV-2 infected, with 4/6 coinfected with SHIV-RT. In a control group cochallenged with SHIV-RT and UV-inactivated HSV-2, 2/4 became SHIV-RT infected, and none had detectable HSV-2. Low-level HSV-2-specific antibody and T cell responses were detected in some HSV-2-infected animals. To test a CG gel containing MIV-150 and zinc acetate (MZC), which provided naive animals full protection from SHIV-RT for at least 8 h, MZC (vs. CG) was applied daily for 14 days followed by cochallenge 8 h later. MZC prevented SHIV-RT infection (0/9 infected, p=0.04 vs. 3/6 in CG controls), but only reduced HSV-2 infection by 20% (6/9 infected vs. 5/6 in CG, p=0.6). In HSV-2-infected animals, none of the gel-treated animals seroconverted, and only the CG controls had measurable HSV-2-specific T cell responses. This study shows the promise of MZC to prevent immunodeficiency virus infection (even in the presence of HSV-2) and reduce HSV-2 infection after exposure to a high-dose inoculum. Additionally, it demonstrates the potential of a macaque coinfection model to evaluate broad-spectrum microbicides.
doi:10.1089/aid.2013.0165
PMCID: PMC3910668  PMID: 24117013
10.  The potential of liposome–encapsulated ciprofloxacin as a tularemia therapy 
Liposome-encapsulation has been suggested as method to improve the efficacy of ciprofloxacin against the intracellular pathogen, Francisella tularensis. Early work with a prototype formulation, evaluated for use against the F. tularensis live vaccine strain, showed that a single dose of liposomal ciprofloxacin given by the intranasal or inhalational route could provide protection in a mouse model of pneumonic tularemia. Liposomal ciprofloxacin offered better protection than ciprofloxacin given by the same routes. Liposomal ciprofloxacin has been further developed by Aradigm Corporation for Pseudomonas aeruginosa infections in patients with cystic fibrosis and non-cystic fibrosis bronchiectasis. This advanced development formulation is safe, effective and well tolerated in human clinical trials. Further evaluation of the advanced liposomal ciprofloxacin formulation against the highly virulent F. tularensis Schu S4 strain has shown that aerosolized CFI (Ciprofloxacin encapsulated in liposomes for inhalation) provides significantly better protection than oral ciprofloxacin. Thus, liposomal ciprofloxacin is a promising treatment for tularemia and further research with the aim of enabling licensure under the animal rule is warranted.
doi:10.3389/fcimb.2014.00079
PMCID: PMC4062069  PMID: 24995163
tularemia; liposomal; ciprofloxacin; Francisella tularensis
11.  Generation of Lineage-Related, Mucosally Transmissible Subtype C R5 Simian-Human Immunodeficiency Viruses Capable of AIDS Development, Induction of Neurological Disease, and Coreceptor Switching in Rhesus Macaques 
Journal of Virology  2013;87(11):6137-6149.
Most human immunodeficiency virus (HIV) transmissions are initiated with CCR5 (R5)-using viruses across mucosal surfaces, with the majority in regions where HIV type 1 (HIV-1) clade C predominates. Mucosally transmissible, highly replication competent, pathogenic R5 simian-human immunodeficiency viruses (SHIVs) encoding biologically relevant clade C envelopes are therefore needed as challenge viruses in vaccine efficacy studies with nonhuman primates. Here we describe the generation of three lineage-related subtype C SHIVs through four successive rapid transfers in rhesus macaques of SHIVC109F.PB4, a molecular clone expressing the soluble-CD4 (sCD4)-sensitive CCR5-tropic clade C envelope of a recently infected subject in Zambia. The viruses differed in their monkey passage histories and neutralization sensitivities but remained R5 tropic. SHIVC109P3 and SHIVC109P3N were recovered from a passage-3 rapid-progressor animal during chronic infection (24 weeks postinfection [wpi]) and at end-stage disease (34 wpi), respectively, and are classified as tier 1B strains, whereas SHIVC109P4 was recovered from a passage-4 normal-progressor macaque at 22 wpi and is a tier 2 virus, more difficult to neutralize. All three viruses were transmitted efficiently via intrarectal inoculation, reaching peak viral loads of 107 to 109 RNA copies/ml plasma and establishing viremia at various set points. Notably, one of seven (GC98) and two of six (CL31, FI08) SHIVC109P3- and SHIVC109P3N-infected macaques, respectively, progressed to AIDS, with neuropathologies observed in GC98 and FI08, as well as coreceptor switching in the latter. These findings support the use of these new SHIVC109F.PB4-derived viruses to study the immunopathology of HIV-1 clade C infection and to evaluate envelope-based AIDS vaccines in nonhuman primates.
doi:10.1128/JVI.00178-13
PMCID: PMC3648099  PMID: 23514895
12.  Understanding out-migration among female sex workers in South India 
Sexually transmitted diseases  2012;39(10):776-783.
BACKGROUND
Migrant sex workers are known to be vulnerable to HIV. There is substantial female sex worker (FSW) mobility between the borders of Maharashtra and Karnataka, but little programming emphasis on migrant FSWs in India. We sought to understand the individual/cultural, structural and contextual determinants of migration among FSWs from Karnataka.
METHODS
A cross sectional face-to-face interview of 1567FSWs from 142 villages in 3 districts of northern Karnataka, India was conducted from January–June 2008. Villages having 10+FSWs, a large number of whom were migrant, were selected following mapping of FSWs. Multinomial logistic regression was conducted to identify characteristics associated with migrant (travelled for ≥2weeks outside the district past year) and mobile (travelled for <2weeks outside the district past year) FSWs; adjusting for age and district.
RESULTS
Compared to non-migrants, migrant FSWs were more likely to be brothel than street-based (AOR 5.7; 95%CI 1.6–20.0), have higher income from sex work (AOR 42.2; 12.6–142.1), speak >2languages (AOR 5.6%; 2.6–12.0), have more clients (AORper client 2.9; 1.2–7.2) and have more sex acts/day (AORper sex act 3.5; 1.3–9.3). Mobile FSWs had higher income from sex work (AOR=13.2; 3.9–44.6) relative to non-migrants, but not as strongly as for migrant FSWs.
CONCLUSION
Out-migration of FSWs in Karnataka was strongly tied to sex work characteristics; thus, the structure inherent in sex work should be capitalized on when developing HIV preventive interventions. The important role of FSWs in HIV epidemics, coupled with the potential for rapid spread of HIV with migration, requires the most effective interventions possible for mobile and migrant FSWs.
doi:10.1097/OLQ.0b013e3182641d90
PMCID: PMC3457025  PMID: 23001264
Migration; HIV; India; Female sex worker
13.  Myocarditis, Disseminated Infection, and Early Viral Persistence Following Experimental Coxsackievirus B Infection of Cynomolgus Monkeys 
PLoS ONE  2013;8(9):e74569.
Coxsackievirus B (CVB) infection is a common cause of acute viral myocarditis. The clinical presentation of myocarditis caused by this enterovirus is highly variable, ranging from mildly symptoms to complete hemodynamic collapse. These variations in initial symptoms and in the immediate and long term outcomes of this disease have impeded development of effective treatment strategies. Nine cynomolgus monkeys were inoculated with myocarditic strains of CVB. Virological studies performed up to 28 days post-inoculation demonstrated the development of neutralizing antibody in all animals, and the presence of CVB in plasma. High dose intravenous inoculation (n = 2) resulted in severe disseminated disease, while low dose intravenous (n = 6) or oral infection (1 animal) resulted in clinically unapparent infection. Transient, minor, echocardiographic abnormalities were noted in several animals, but no animals displayed signs of significant acute cardiac failure. Although viremia rapidly resolved, signs of myocardial inflammation and injury were observed in all animals at the time of necropsy, and CVB was detected in postmortem myocardial specimens up to 28 days PI. This non-human primate system replicates many features of illness in acute coxsackievirus myocarditis and demonstrates that myocardial involvement may be common in enteroviral infection; it may provide a model system for testing of treatment strategies for enteroviral infections and acute coxsackievirus myocarditis.
doi:10.1371/journal.pone.0074569
PMCID: PMC3767629  PMID: 24040287
14.  A Modified Zinc Acetate Gel, a Potential Nonantiretroviral Microbicide, Is Safe and Effective against Simian-Human Immunodeficiency Virus and Herpes Simplex Virus 2 Infection In Vivo 
We previously showed that a prototype gel comprising zinc acetate (ZA) in carrageenan (CG) protected mice against vaginal and rectal herpes simplex virus 2 (HSV-2) challenge as well as macaques against vaginal simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) challenge. In this work, we modified buffers and cosolvents to obtain a stable, nearly iso-osmolal formulation and evaluated its safety and efficacy against SHIV-RT and HSV-2. In vitro toxicity to lactobacilli and Candida albicans was determined. Macaques were given daily doses of ZA and CG (ZA/CG) or CG alone vaginally for 14 days and challenged with SHIV-RT 24 h later. Mice were challenged vaginally or rectally with HSV-2 immediately after a single gel treatment to measure efficacy or vaginally 12 h after daily gel treatment for 7 days to evaluate the gel's impact on susceptibility to HSV-2 infection. The modified ZA/CG neither affected the viability of lactobacilli or C. albicans nor enhanced vaginal HSV-2 infection after daily ZA/CG treatment. Vaginal SHIV-RT infection of macaques was reduced by 66% (P = 0.006) when macaques were challenged 24 h after the last dose of gel. We observed 60% to 80% uninfected mice after vaginal (P < 0.0001) and rectal (P = 0.008) high-dose HSV-2 challenge. The modified ZA/CG gel is safe and effective in animal models and represents a potential candidate to limit the transmission of HIV and HSV-2.
doi:10.1128/AAC.00796-13
PMCID: PMC3719770  PMID: 23752515
15.  Serological survey of the novel influenza A H1N1 in inner city Winnipeg, Manitoba, 2009 
INTRODUCTION:
Little is known about the determinants of pandemic H1N1 (pH1N1) infection in Canada among low-income, inner city populations. To inform future influenza planning, the seroprevalence of pH1N1 antibodies among inner city clinic attendees in Winnipeg (Manitoba) according to sociodemographic and risk factor characteristics were estimated and vaccination rates were explored.
METHODS:
Adults presenting to three inner city community clinics in Winnipeg from October 2009 to December 2009 were recruited as study participants (n=458). A questionnaire was administered to collect demographic, risk factor and symptom information, and a venous blood sample was collected for hemagglutination inhibition assay testing to detect the presence of antibodies against pH1N1.
RESULTS:
Approximately one-half (53%) of the study participants reported an annual household income of <$10,000/year, and 65% identified as Aboriginal. pH1N1 positivity was 5.7% among those enrolled early in the study and 15.5% among those enrolled later in the study. Positivity was higher among participants who were female, Aboriginal and in contact with children ≤5 years of age. The overall pH1N1 vaccination rate was 28%.
DISCUSSION:
pH1N1 positivity was high among low-income adults accessing clinics in Winnipeg’s inner city compared with the general population. Of further concern were the low rates of uptake of both seasonal and pH1N1 influenza vaccinations. When planning for future influenza outbreaks, it is important to incorporate strategies for the prevention, control, and care of influenza among low-income and inner city adults.
PMCID: PMC3403663  PMID: 23730311
Epidemiology; Hemagglutination inhibition assay; Inner city; Pandemic Influenza A H1N1; pH1N1; Serological survey
16.  Availability and Distribution of Emergency Obstetric Care Services in Karnataka State, South India: Access and Equity Considerations 
PLoS ONE  2013;8(5):e64126.
Background
As part of efforts to reduce maternal deaths in Karnataka state, India, there has been a concerted effort to increase institutional deliveries. However, little is known about the quality of care in these healthcare facilities. We investigated the availability and distribution of emergency obstetric care (EmOC) services in eight northern districts of Karnataka state in south India.
Methods & Findings
We undertook a cross-sectional study of 444 government and 422 private health facilities, functional 24-hours-a-day 7-days-a-week. EmOC availability and distribution were evaluated for 8 districts and 42 taluks (sub-districts) during the year 2010, based on a combination of self-reporting, record review and direct observation. Overall, the availability of EmOC services at the sub-state level [EmOC = 5.9/500,000; comprehensive EmOC (CEmOC) = 4.5/500,000 and basic EmOC (BEmOC) = 1.4/500,000] was seen to meet the benchmark. These services however were largely located in the private sector (90% of CEmOC and 70% of BemOC facilities). Thirty six percent of private facilities and six percent of government facilities were EmOC centres. Although half of eight districts had a sufficient number of EmOC facilities and all eight districts had a sufficient number of CEmOC facilities, only two-fifths of the 42 taluks had a sufficient number of EmOC facilities. With the private facilities being largely located in select towns only, the ‘non-headquarter’ taluks and ‘backward’ taluks suffered from a marked lack of coverage of these services. Spatial mapping further helped identify the clustering of a large number of contiguous taluks without adequate government EmOC facilities in northeastern Karnataka.
Conclusions
In conclusion, disaggregating information on emergency obstetric care service availability at district and subdistrict levels is critical for health policy and planning in the Indian setting. Reducing maternal deaths will require greater attention by the government in addressing inequities in the distribution of emergency obstetric care services.
doi:10.1371/journal.pone.0064126
PMCID: PMC3661461  PMID: 23717547
17.  UV-inactivated vaccinia virus (VV) in a multi-envelope DNA-VV-protein (DVP) HIV-1 vaccine protects macaques from lethal challenge with heterologous SHIV 
Vaccine  2012;30(21):3188-3195.
The pandemic of HIV-1 has continued for decades, yet there remains no licensed vaccine. Previous research has demonstrated the effectiveness of a multi-envelope, multi-vectored HIV-1 vaccine in a macaque-SHIV model, illustrating a potential means of combating HIV-1. Specifically, recombinant DNA, vaccinia virus (VV) and purified protein (DVP) delivery systems were used to vaccinate animals with dozens of antigenically-distinct HIV-1 envelopes for induction of immune breadth. The vaccinated animals controlled disease following challenge with a heterologous SHIV. This demonstration suggested that the antigenic cocktail vaccine strategy, which has succeeded in several other vaccine fields (e.g. pneumococcus), might also succeed against HIV-1. The strategy remains untested in an advanced clinical study, in part due to safety concerns associated with the use of replication-competent VV. To address this concern, we designed a macaque study in which psoralen/ultraviolet light-inactivated VV (UV VV) was substituted for replication-competent VV in the multi-envelope DVP protocol. Control animals received a vaccine encompassing no VV, or no vaccine. All VV vaccinated animals generated an immune response toward VV, and all vaccinated animals generated an immune response toward HIV-1 envelope. After challenge with heterologous SHIV 89.6P, animals that received replication-competent VV or UV VV experienced similar outcomes. They exhibited reduced peak viral loads, maintenance of CD4+ T cell counts and improved survival compared to control animals that received no VV or no vaccine; there were 0/15 deaths among all animals that received VV and 5/9 deaths among controls. Results define a practical means of improving VV safety, and encourage advancement of a promising multi-envelope DVP HIV-1 vaccine candidate.
doi:10.1016/j.vaccine.2012.03.001
PMCID: PMC3386644  PMID: 22425790
HIV-1 vaccine; pathogenic SHIV; non-human primate; envelope cocktail; ultra violet-inactived vaccinia virus
18.  The Mycobacterium tuberculosis Stress Response Factor SigH Is Required for Bacterial Burden as Well as Immunopathology in Primate Lungs 
The Journal of Infectious Diseases  2012;205(8):1203-1213.
(See the editorial commentary by Kernodle, on pages 1186–8.)
Background. Sigma H (sigH) is a major Mycobacterium tuberculosis (Mtb) stress response factor. It is induced in response to heat, oxidative stress, cell wall damage, and hypoxia. Infection of macrophages with the Δ-sigH mutant generates more potent innate immune response than does infection with Mtb. The mutant is attenuated for pathology in mice.
Methods. We used a nonhuman primate (NHP) model of acute tuberculosis, to better understand the phenotype of the Δ-sigH mutant in vivo. NHPs were infected with high doses of Mtb or the mutant, and the progression of tuberculosis was analyzed in both groups using clinical, pathological, microbiological, and immunological parameters.
Results. Animals exposed to Mtb rapidly progressed to acute pulmonary tuberculosis as indicated by worsening clinical correlates, high lung bacterial burden, and granulomatous immunopathology. All the animals rapidly succumbed to tuberculosis. On the other hand, the NHPs exposed to the Mtb:Δ-sigH mutant did not exhibit acute tuberculosis, instead showing significantly blunted disease. These NHPs survived the entire duration of the study.
Conclusions. The Mtb:Δ-sigH mutant is completely attenuated for bacterial burden as well as immunopathology in NHPs. SigH and its regulon are required for complete virulence in primates. Further studies are needed to identify the molecular mechanism of this attenuation.
doi:10.1093/infdis/jis102
PMCID: PMC3308902  PMID: 22402035
19.  Inhalation of Nebulized Perfluorochemical Enhances Recombinant Adenovirus and Adeno-Associated Virus-Mediated Gene Expression in Lung Epithelium 
Human Gene Therapy Methods  2012;23(2):98-110.
Abstract
Use of perfluorochemical liquids during intratracheal vector administration enhances recombinant adenovirus and adeno-associated virus (AAV)-mediated lung epithelial gene expression. We hypothesized that inhalation of nebulized perfluorochemical vapor would also enhance epithelial gene expression after subsequent intratracheal vector administration. Freely breathing adult C57BL/6 mice were exposed for selected times to nebulized perflubron or sterile saline in a sealed Plexiglas chamber. Recombinant adenoviral vector was administered by transtracheal puncture at selected times afterward and mice were killed 3 days after vector administration to assess transgene expression. Mice tolerated the nebulized perflubron without obvious ill effects. Vector administration 6 hr after nebulized perflubron exposure resulted in an average 540% increase in gene expression in airway and alveolar epithelium, compared with that with vector alone or saline plus vector control (p<0.05). However, vector administration 1 hr, 1 day, or 3 days after perflubron exposure was not different from either nebulized saline with vector or vector alone and a 60-min exposure to nebulized perflubron is required. In parallel pilot studies in macaques, inhalation of nebulized perflubron enhanced recombinant AAV2/5 vector expression throughout the lung. Serial chest radiographs, bronchoalveolar lavages, and results of complete blood counts and serum biochemistries demonstrated no obvious adverse effects of nebulized perflubron. Further, one macaque receiving nebulized perflubron only was monitored for 1 year with no obvious adverse effects of exposure. These results demonstrate that inhalation of nebulized perflubron, a simple, clinically more feasible technique than intratracheal administration of liquid perflubron, safely enhances lung gene expression.
Beckett and colleagues show that inhalation of a nebulized perfluorochemical (perflubron) vapor 6 hours before transtracheal administration of recombinant adenoviral vector results in a substantial increase in gene expression in mouse airway and alveolar epithelium. Pilot studies in macaques performed in parallel show that nebulized perflubron enhances recombinant adeno-associated vector serotype 5 expression throughout the lung, with no obvious adverse effects.
doi:10.1089/hgtb.2012.014
PMCID: PMC4015222  PMID: 22568624
20.  Community mobilization, empowerment and HIV prevention among female sex workers in south India 
BMC Public Health  2013;13:234.
Background
While community mobilization has been widely endorsed as an important component of HIV prevention among vulnerable populations such as female sex workers (FSWs), there is uncertainty as to the mechanism through which it impacts upon HIV risk. We explored the hypothesis that individual and collective empowerment of FSW is an outcome of community mobilization, and we examined the means through which HIV risk and vulnerability reduction as well as personal and social transformation are achieved.
Methods
This study was conducted in five districts in south India, where community mobilization programs are implemented as part of the Avahan program (India AIDS Initiative) of the Bill & Melinda Gates Foundation. We used a theoretically derived “integrated empowerment framework” to conduct a secondary analysis of a representative behavioural tracking survey conducted among 1,750 FSWs. We explored the associations between involvement with community mobilization programs, self-reported empowerment (defined as three domains including power within to represent self-esteem and confidence, power with as a measure of collective identity and solidarity, and power over as access to social entitlements, which were created using Principal Components analysis), and outcomes of HIV risk reduction and social transformation.
Results
In multivariate analysis, we found that engagement with HIV programs and community mobilization activities was associated with the domains of empowerment. Power within and power with were positively associated with more program contact (p < .01 and p < .001 respectively). These measures of empowerment were also associated with outcomes of “personal transformation” in terms of self-efficacy for condom and health service use (p < .001). Collective empowerment (power with others) was most strongly associated with “social transformation” variables including higher autonomy and reduced violence and coercion, particularly in districts with programs of longer duration (p < .05). Condom use with clients was associated with power with others (p < .001), while power within was associated with more condom use with regular partners (p < .01) and higher service utilization (p < .05).
Conclusion
These findings support the hypothesis that community mobilization has benefits for empowering FSWs both individually and collectively. HIV prevention is strengthened by improving their ability to address different psycho-social and community-level sources of their vulnerability. Future challenges include the need to develop social, political and legal contexts that support community mobilization of FSWs, and to prospectively measure the impact of combined community-level interventions on measures of empowerment as a means to HIV prevention.
doi:10.1186/1471-2458-13-234
PMCID: PMC3621162  PMID: 23496972
21.  Pathogenic Consequences of Vaginal Infection with CCR5-Tropic Simian-Human Immunodeficiency Virus SHIVSF162P3N 
Journal of Virology  2012;86(17):9432-9442.
We previously reported efficient transmission of the pathogenic R5 simian-human immunodeficiency virus SHIVSF162P3N isolate in Indian rhesus macaques by intravenous and intrarectal inoculations, with a switch to CXCR4 coreceptor usage in ∼50% of infected animals that progressed rapidly to disease. Since women continue to be disproportionately affected by HIV, we developed an animal model based on the intravaginal challenge of female rhesus monkeys with SHIVSF162P3N and sought to validate the utility of this model to study relevant aspects of HIV transmission and pathogenesis. The effect of viral dose on infection outcome was evaluated to determine the optimal conditions for the evaluation of HIV-1 preventive and therapeutic strategies. We found that the virus can successfully cross the vaginal mucosal surface to establish infection and induce disease with coreceptor switch, but with lower efficiencies compared to intravenous and rectal transmissions. In contrast to intrarectal infection, peak and cumulative viral load over a 1 year-infection period were significantly greater in macaques exposed intravaginally to lower rather than higher inoculum doses. Moreover, low and transient viremia was observed only in macaques that were challenged intravaginally twice within the same day with a high dose of virus, which can be seen as doubling the dose. Taken together, these results show that SHIVSF162P3N can successfully transmit across the genital mucosa, undergo coreceptor switch, and induce disease. However, the administered dose appears to impact SHIVSF162P3N vaginal infection outcome in an unexpected manner.
doi:10.1128/JVI.00852-12
PMCID: PMC3416103  PMID: 22740397
22.  Mental comorbidity and multiple sclerosis: validating administrative data to support population-based surveillance 
BMC Neurology  2013;13:16.
Background
While mental comorbidity is considered common in multiple sclerosis (MS), its impact is poorly defined; methods are needed to support studies of mental comorbidity. We validated and applied administrative case definitions for any mental comorbidities in MS.
Methods
Using administrative health data we identified persons with MS and a matched general population cohort. Administrative case definitions for any mental comorbidity, any mood disorder, depression, anxiety, bipolar disorder and schizophrenia were developed and validated against medical records using a a kappa statistic (k). Using these definitions we estimated the prevalence of these comorbidities in the study populations.
Results
Compared to medical records, administrative definitions showed moderate agreement for any mental comorbidity, mood disorders and depression (all k ≥ 0.49), fair agreement for anxiety (k = 0.23) and bipolar disorder (k = 0.30), and near perfect agreement for schizophrenia (k = 1.0). The age-standardized prevalence of all mental comorbidities was higher in the MS than in the general populations: depression (31.7% vs. 20.5%), anxiety (35.6% vs. 29.6%), and bipolar disorder (5.83% vs. 3.45%), except for schizophrenia (0.93% vs. 0.93%).
Conclusions
Administrative data are a valid means of surveillance of mental comorbidity in MS. The prevalence of mental comorbidities, except schizophrenia, is increased in MS compared to the general population.
doi:10.1186/1471-2377-13-16
PMCID: PMC3599013  PMID: 23388102
Multiple sclerosis; Administrative data; Validation; Prevalence; Depression; Anxiety; Bipolar disorder; Schizophrenia
23.  Mucosal transmissibility, disease induction and coreceptor switching of R5 SHIVSF162P3N molecular clones in rhesus macaques 
Retrovirology  2013;10:9.
Background
Mucosally transmissible and pathogenic CCR5 (R5)-tropic simian-human immunodeficiency virus (SHIV) molecular clones are useful reagents to identity neutralization escape in HIV-1 vaccine experiments and to study the envelope evolutionary process and mechanistic basis for coreceptor switch during the course of natural infection.
Results
We observed progression to AIDS in rhesus macaques infected intrarectally with molecular clones of the pathogenic R5 SHIVSF162P3N isolate. Expansion to CXCR4 usage was documented in one diseased macaque that mounted a neutralizing antibody response and in another that failed to do so, with the latter displaying a rapid progressor phenotype. V3 loop envelop glycoprotein gp120 sequence changes that are predictive of a CXCR4 (X4)-using phenotype in HIV-1 subtype B primary isolates, specifically basic amino acid substations at positions 11 (S11R), 24 (G24R) and 25 (D25K) of the loop were detected in the two infected macaques. Functional assays showed that envelopes with V3 S11R or D25K mutation were dual-tropic, infecting CD4+ target cells that expressed either the CCR5 or CXCR4 coreceptor. And, consistent with findings of coreceptor switching in macaques infected with the pathogenic isolate, CXCR4-using variant was first detected in the lymph node of the chronically infected rhesus monkey several weeks prior to its presence in peripheral blood. Moreover, X4 emergence in this macaque coincided with persistent peripheral CD4+ T cell loss and a decline in neutralizing antibody titer that are suggestive of immune deterioration, with macrophages as the major virus-producing cells at the end-stage of disease.
Conclusions
The data showed that molecular clones derived from the R5 SHIVSF162P3N isolate are mucosally transmissible and induced disease in a manner similar to that observed in HIV-1 infected individuals, providing a relevant and useful animal infection model for in-depth analyses of host selection pressures and the env evolutionary changes that influence disease outcome, coreceptor switching and vaccine escape.
doi:10.1186/1742-4690-10-9
PMCID: PMC3571932  PMID: 23369442
R5 SHIV molecular clone; Coreceptor switch; Antiviral antibody response; Macrophage infection
24.  Risky Behaviors among HIV-Positive Female Sex Workers in Northern Karnataka, India 
AIDS Research and Treatment  2013;2013:878151.
Purpose. Little is known about the risky sexual behaviors of HIV-positive female sex workers (FSWs) in the developing world, which is critical for programmatic purposes. This study aims to shed light on their condom use with regular clients as well as husband/cohabiting partner, a first in India. Methods. Multivariate logistic regression analyses for consistent condom use with regular clients and husband/cohabiting partner are conducted for the sample of 606 HIV-positive FSWs. Results. Older FSWs are 90% less likely and nonmobile FSWs are 70% less likely to consistently use condoms. FSWs on ART are 3.84 times more likely to use condoms. Additionally, FSWs who changed their occupation after HIV diagnosis are 70% less likely to use condoms. FSWs who are currently cohabiting are more likely to consistently use condoms with repeat clients and are 3.22 times more likely to do so if they have felt stigma associated with being HIV-positive. FSWs who have multiple repeat clients, and who do not know the sexual behavior of these clients, are more likely to use condoms consistently. Conclusion. This study would help inform programs to target the following particularly vulnerable HIV-positive FSWs: those who are older, those who changed their occupation post-HIV diagnosis, and those who are nonmobile.
doi:10.1155/2013/878151
PMCID: PMC3556430  PMID: 23365728
25.  The Intersection between Sex Work and Reproductive Health in Northern Karnataka, India: Identifying Gaps and Opportunities in the Context of HIV Prevention 
AIDS Research and Treatment  2012;2012:842576.
Objective. To examine the reproductive health practices of female sex workers (FSWs) in the context of an HIV prevention program in Karnataka, India. Methods. Data obtained from a survey of 1,011 FSWs registered with an HIV prevention program. We examined reproductive health indicators, and performed multivariate logistic regression among primiparous FSWs to assess sex work during pregnancy and antenatal HIV testing. Results. Among primiparous FSWs (N = 251), 92.0% continued sex work during pregnancy, and 55.4% received antenatal HIV testing. A longer duration in sex work (AOR 2.7, 95% CI: 1.0–7.5), rural residence (AOR 3.3, 95% CI: 1.2–8.9), and antenatal HIV testing (AOR 6.3, 95% CI: 2.0–20.1) were associated with continued sex work during pregnancy. Older FSWs (age >25 years, AOR 0.12, 95% CI: 0.05–0.33), who delivered at home (AOR 0.14, 95% CI: 0.09–0.34), were least likely to receive antenatal HIV testing. Antenatal HIV testing was associated with awareness of methods to prevent vertical HIV transmission (AOR 3.9, 95% CI: 1.9–14.1). Conclusions. Antenatal HIV testing remains low in the context of ongoing sex work during pregnancy. Existing HIV prevention programs are well positioned to immediately integrate reproductive health care with HIV interventions targeted to FSWs.
doi:10.1155/2012/842576
PMCID: PMC3546443  PMID: 23346390

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