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1.  Bacterial vaginosis and the risk of Trichomonas vaginalis acquisition among HIV-1 negative women 
Sexually transmitted diseases  2014;41(2):123-128.
Background
The vaginal microbiota may play a role in mediating susceptibility to sexually transmitted infections, including Trichomonas vaginalis (TV).
Methods
Data were analyzed from HIV-1 seronegative women participating in HIV Prevention Trials Network Protocol 035. At quarterly visits for up to 30 months, participants completed structured interviews and specimens were collected for genital tract infection testing. TV was detected by saline microscopy. BV was characterized by Gram stain using the Nugent score (BV=7-10; intermediate=4-6; normal=0-3 [reference group]). Cox proportional hazards models stratified by study site were used to assess the association between Nugent score category at the prior quarterly visit and TV acquisition.
Results
In this secondary analysis, 2,920 participants from Malawi, South Africa, USA, Zambia and Zimbabwe contributed 16,259 follow-up visits. BV was detected at 5,680 (35%) visits and TV was detected at 400 (2.5%) visits. Adjusting for age, marital status, hormonal contraceptive use, unprotected sex in the last week and TV at baseline, intermediate Nugent score and BV at the prior visit were associated with an increased risk of TV (intermediate score: adjusted hazard ratio [aHR]=1.73, 95% confidence interval [CI] 1.21-2.19; BV: aHR=2.40, 95% CI 1.92-3.00). Sensitivity analyses excluding 211 participants with TV at baseline were similar to those from the full study population (intermediate score: aHR=1.54, 95% CI 1.10-2.14; BV: aHR=2.23, 95% CI 1.75-2.84)
Conclusions
Women with a Nugent score >3 were at an increased risk of acquiring TV. If this relationship is causal, interventions that improve the vaginal microbiota could contribute to reductions in TV incidence.
doi:10.1097/OLQ.0000000000000075
PMCID: PMC4128240  PMID: 24413493
Bacterial vaginosis; Trichomonas vaginalis; vaginal microbiota; sexually transmitted disease acquisition; prospective cohort
2.  Assessing the implementation effectiveness and safety of 1% tenofovir gel provision through family planning services in KwaZulu-Natal, South Africa: study protocol for an open-label randomized controlled trial 
Trials  2014;15(1):496.
Background
The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide post-trial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial.
Methods/design
This is a two-arm, open-label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously participated in an antiretroviral prevention study will be enrolled from an urban and rural site in KwaZulu-Natal, South Africa. The anticipated study duration is 30 months, with active accrual requiring approximately 12 months (following which an open cohort will be maintained) and follow-up continuing for approximately 18 months. At each of the two sites, eligible participants will be randomly assigned to receive tenofovir gel through either FP services (intervention arm) or through the CAPRISA research clinics (control arm). As part of the study intervention, a quality improvement approach will be used to assist the FP services to expand their current services to include tenofovir gel provision.
Discussion
This protocol aims to address an important implementation question on whether FP services are able to effectively incorporate tenofovir gel provision for this at-risk group of women in South Africa. Provision of tenofovir gel to the women from the CAPRISA 004 trial meets the ethical obligation for post-trial access, and helps identify a potential avenue for future scale-up of microbicides within the public health system of South Africa.
Trial registration
This trial was registered with the South Africa Department of Health (reference: DOH-27-0812-4129) and ClinicalTrials.gov (reference: NCT01691768) on 05 July 2012.
doi:10.1186/1745-6215-15-496
PMCID: PMC4300828  PMID: 25527071
South Africa; HIV prevention; Microbicide; Tenofovir gel; Health systems strengthening; Implementation
3.  TRIM5α and TRIM22 Are Differentially Regulated According to HIV-1 Infection Phase and Compartment 
Journal of Virology  2014;88(8):4291-4303.
ABSTRACT
The antiviral role of TRIM E3 ligases in vivo is not fully understood. To test the hypothesis that TRIM5α and TRIM22 have differential transcriptional regulation and distinct anti-HIV roles according to infection phase and compartment, we measured TRIM5α, TRIM22, and type I interferon (IFN-I)-inducible myxovirus resistance protein A (MxA) levels in peripheral blood mononuclear cells (PBMCs) during primary and chronic HIV-1 infection, with chronic infection samples being matched PBMCs and central nervous system (CNS)-derived cells. Associations with biomarkers of disease progression were explored. The impact of IFN-I, select proinflammatory cytokines, and HIV on TRIM E3 ligase-specific expression was investigated. PBMCs from individuals with primary and chronic HIV-1 infection had significantly higher levels of MxA and TRIM22 than did PBMCs from HIV-1-negative individuals (P < 0.05 for all comparisons). PBMCs from chronic infection had lower levels of TRIM5α than did PBMCs from primary infection or HIV-1-uninfected PBMCs (P = 0.0001 for both). In matched CNS-derived samples and PBMCs, higher levels of MxA (P = 0.001) and TRIM5α (P = 0.0001) in the CNS were noted. There was a negative correlation between TRIM22 levels in PBMCs and plasma viral load (r = −0.40; P = 0.04). In vitro, IFN-I and, rarely, proinflammatory cytokines induced TRIM5α and TRIM22 in a cell type-dependent manner, and the knockdown of either protein in CD4+ lymphocytes resulted in increased HIV-1 infection. These data suggest that there are infection-phase-specific and anatomically compartmentalized differences in TRIM5α and TRIM22 regulation involving primarily IFN-I and specific cell types and indicate subtle differences in the antiviral roles and transcriptional regulation of TRIM E3 ligases in vivo.
IMPORTANCE Type I interferon-inducible TRIM E3 ligases are a family of intracellular proteins with potent antiviral activities mediated through diverse mechanisms. However, little is known about the contribution of these proteins to antiviral immunity in vivo and how their expression is regulated. We show here that TRIM5α and TRIM22, two prominent members of the family, have different expression patterns in vivo and that the expression pattern depends on HIV-1 infection status and phase. Furthermore, expression differs in peripheral blood versus central nervous system anatomical sites of infection. Only TRIM22 expression correlated negatively with HIV-1 viral load, but gene silencing of both proteins enhances HIV-1 infection of target cells. We report subtle differences in TRIM5α and TRIM22 gene induction by IFN-I and proinflammatory cytokines in CD4+ lymphocytes, monocytes, and neuronal cells. This study enhances our understanding of antiviral immunity by intrinsic antiviral factors and how their expression is determined.
doi:10.1128/JVI.03603-13
PMCID: PMC3993776  PMID: 24478420
4.  Recombination-mediated escape from primary CD8+ T cells in acute HIV-1 infection 
Retrovirology  2014;11(1):69.
Background
A major immune evasion mechanism of HIV-1 is the accumulation of non-synonymous mutations in and around T cell epitopes, resulting in loss of T cell recognition and virus escape.
Results
Here we analyze primary CD8+ T cell responses and virus escape in a HLA B*81 expressing subject who was infected with two T/F viruses from a single donor. In addition to classic escape through non-synonymous mutation/s, we also observed rapid selection of multiple recombinant viruses that conferred escape from T cells specific for two epitopes in Nef.
Conclusions
Our study shows that recombination between multiple T/F viruses provide greater options for acute escape from CD8+ T cell responses than seen in cases of single T/F virus infection. This process may contribute to the rapid disease progression in patients infected by multiple T/F viruses.
Electronic supplementary material
The online version of this article (doi:10.1186/s12977-014-0069-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12977-014-0069-9
PMCID: PMC4180588  PMID: 25212771
HIV-1; T cell; Multiple infection; Recombination; Immunodominance; Acute infection
5.  Limited HIV-1 Superinfection in Seroconverters from the CAPRISA 004 Microbicide Trial 
Journal of Clinical Microbiology  2014;52(3):844-848.
HIV-1 superinfection (SI) occurs when an infected individual acquires a distinct new viral strain. The rate of superinfection may be reflective of the underlying HIV risk in a population. The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 clinical trial demonstrated that women who used a tenofovir-containing microbicide gel had lower rates of HIV infection than women using a placebo gel. Women who contracted HIV-1 during the trial were screened for the occurrence of superinfection by next-generation sequencing of the viral gag and env genes. There were two cases (one in each trial arm) of subtype C superinfection identified from the 76 women with primary infection screened at two time points (rate of superinfection, 1.5/100 person-years). Both women experienced a >0.5-log increase in viral load during the window when superinfection occurred. The rate of superinfection was significantly lower than the overall primary HIV incidence in the microbicide trial (incidence rate ratio [IRR], 0.20; P = 0.003). The women who seroconverted during the trial reported a significant increase in sexual contact with their stable partner 4 months after seroconversion (P < 0.001), which may have lowered the risk of superinfection in this population. The lower frequency of SI compared to the primary incidence is in contrast to a report from a general heterosexual African population but agrees with a study of high-risk women in Kenya. A better understanding of the rate of HIV superinfection could have important implications for ongoing HIV vaccine research.
doi:10.1128/JCM.03143-13
PMCID: PMC3957790  PMID: 24371237
6.  Differential Impact of Magnitude, Polyfunctional Capacity, and Specificity of HIV-Specific CD8+ T Cell Responses on HIV Set Point 
Journal of Virology  2014;88(3):1819-1824.
Defining the characteristics of HIV-specific CD8+ T cell responses that lead to viral control is crucial for vaccine development. We evaluated the differential impact of magnitude, polyfunctional capacity, and specificity of the CD8+ response at approximately 6 months postinfection on the viral set point at 12 months in a cohort of HIV-infected individuals. High frequencies of Gag and Nef responses endowed with four functions were the best predictors of a low viral set point.
doi:10.1128/JVI.02968-13
PMCID: PMC3911608  PMID: 24227857
7.  Neither microbial translocation nor TLR responsiveness are likely explanations for pre-existing immune activation in women who subsequently acquired HIV in CAPRISA004 
Journal of acquired immune deficiency syndromes (1999)  2013;63(3):10.1097/QAI.0b013e31828e604b.
Innate immune activation was a strong predictor of HIV acquisition in women at risk for HIV in CAPRISA004. Identifying the cause/s of activation could enable targeted prevention interventions. In this study, plasma concentrations of lipopolysaccharide, soluble CD14 and intestinal fatty-acid binding protein did not differ between subjects who did or did not subsequently acquire HIV, nor were these levels correlated with plasma cytokines or natural killer cell activation. There was no difference between HIV-acquirers and non-acquirers in the chemokine and cytokine responses of peripheral blood mononuclear cells stimulated with TLR2, 4 or 7/8 agonists. Further studies are required.
doi:10.1097/QAI.0b013e31828e604b
PMCID: PMC3683111  PMID: 23481666
HIV; microbial translocation; LPS; sCD14; I-FABP; TLR2; TLR4; TLR7/8; immune activation
8.  When to start antiretroviral therapy during tuberculosis treatment 
Purpose of review
Effective treatment exists for TB and for HIV but treating both diseases simultaneously presents several challenges. This review assessed the evidence for timing of antiretroviral therapy (ART) initiation in patents co-infected with TB.
Recent findings
Published evidence clearly demonstrates that TB HIV integration is essential for improved survival, but the question of when to start ART during TB treatment is more complex. Five randomised controlled trials assessed this question; four trials showed no difference in incidence rates of AIDS or death between TB patients initiating ART within 2 months compared to later during TB therapy, while one trial showed a significant survival gain with ART initiation within 2 weeks of TB therapy start. All five studies found improved AIDS-free survival with earlier ART initiation in TB patients with low CD4+ T-cell counts, except among patients with TB meningitis. The survival benefit was however, accompanied by increased immune reconstitution inflammatory syndrome events.
Summary
The trial data support the World Health Organisation recommendations on when to start ART in TB-HIV co-infected patients including earlier ART initiation in severely immune-compromised patients. However, several challenges remain in integrating TB and HIV treatment in public health care services. Additional research on timing of ART is needed for patients with drug-resistant and extra-pulmonary TB, notably TB meningitis.
doi:10.1097/QCO.0b013e32835ba8f9
PMCID: PMC3616247  PMID: 23188213
HIV; tuberculosis; antiretroviral therapy; immune reconstitution inflammatory syndrome (IRIS)
9.  The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis 
Purpose
Drug interactions are of concern when treating patients co-infected with human immunodeficiency virus (HIV) and tuberculosis. Concomitant use of efavirenz (EFV) with the enzyme inducer rifampicin might be expected to increase EFV clearance. We investigated the influence of concomitant tuberculosis treatment on the plasma clearance of EFV.
Methods
Fifty-eight patients were randomized to receive their EFV-containing antiretroviral therapy either during or after tuberculosis treatment. Steady-state EFV plasma concentrations (n=209 samples) were measured, 83 in the presence of rifampicin. Data were analyzed using a non-linear mixed effects model, and the model was evaluated using non-parametric bootstrap and visual predictive checks.
Results
The patients had a median age of 32 (range 19–55) years and 43.1% were women. There was a bimodal distribution of apparent clearance, with slow EFV metabolizers accounting for 23.6% of the population and having a metabolic capacity 36.4% of that of the faster metabolizers. Apparent EFV clearance after oral administration in fast metabolizers was 12.9 L/h/70 kg whilst off tuberculosis treatment and 9.1 L/h/70 kg when on tuberculosis treatment. In slow metabolizers, the clearance estimates were 3.3 and 4.7 L/h/70 kg in the presence and absence of TB treatment, respectively. Overall there was a 29.5% reduction in EFV clearance during tuberculosis treatment.
Conclusion
Unexpectedly, concomitant rifampicin-containing tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure. While the reasons for this interaction require further investigation, cytochrome P450 2B6 polymorphisms in the population studied may provide some explanation.
doi:10.1007/s00228-011-1166-5
PMCID: PMC3888951  PMID: 22108776
Pharmacokinetics; Tuberculosis; HIV; Efavirenz; Rifampicin
10.  Antiretroviral prophylaxis: a defining moment for HIV prevention 
Lancet  2011;378(9809):e23-e25.
doi:10.1016/S0140-6736(11)61136-7
PMCID: PMC3253379  PMID: 21771566
11.  Mucosal Escherichia coli Bactericidal Activity and Immune Mediators Are Associated With HIV-1 Seroconversion in Women Participating in the HPTN 035 Trial 
The Journal of Infectious Diseases  2012;206(12):1931-1935.
The mucosal environment may impact the risk for human immunodeficiency virus type 1 (HIV-1) acquisition. Immune mediators were measured in vaginal fluid collected from HPTN 035 participants who acquired HIV-1 and from those who remained HIV-1 negative (controls). Mediator concentrations were similar in samples obtained before as compared to after HIV-1 acquisition in the 8 seroconverters. Compared with controls, seroconverters were more likely to have detectable levels of HβD-2 (odds ratio [OR], 2.39; P = .005) and greater Escherichia coli bactericidal activity (OR, 1.22; P = .01) prior to seroconversion. E. coli bactericidal activity remained significant in a multivariable analysis (P = .02) and may be a biomarker for HIV-1 acquisition.
doi:10.1093/infdis/jis555
PMCID: PMC3502373  PMID: 22966121
12.  Sustainability of task-shifting for antiretroviral treatment 
Lancet  2012;380(9857):1907-1908.
doi:10.1016/S0140-6736(12)62110-2
PMCID: PMC3616248  PMID: 23200500
13.  Multiple Pathways of Escape from HIV Broadly Cross-Neutralizing V2-Dependent Antibodies 
Journal of Virology  2013;87(9):4882-4894.
Broadly cross-neutralizing (BCN) antibodies are likely to be critical for an effective HIV vaccine. However, the ontogeny of such antibodies and their relationship with autologous viral evolution is unclear. Here, we characterized viral evolution in CAP256, a subtype C-infected individual who developed potent BCN antibodies targeting positions R166 and K169 in the V2 region. CAP256 was superinfected at 3 months postinfection with a virus that was highly sensitive to BCN V2-dependent monoclonal antibodies. The autologous neutralizing response in CAP256 was directed at V1V2, reaching extremely high titers (>1:40,000) against the superinfecting virus at 42 weeks, just 11 weeks prior to the development of the BCN response targeting the same region. Recombination between the primary and superinfecting viruses, especially in V2 and gp41, resulted in two distinct lineages by 4 years postinfection. Although neutralization of some CAP256 clones by plasma from as much as 2 years earlier suggested incomplete viral escape, nonetheless titers against later clones were reduced at least 40-fold to less than 1:1,000. Escape mutations were identified in each lineage, either at R166 or at K169, suggesting that strain-specific and BCN antibodies targeted overlapping epitopes. Furthermore, the early dependence of CAP256 neutralizing antibodies on the N160 glycan decreased with the onset of neutralization breadth, indicating a change in specificity. These data suggest rapid maturation, within 11 weeks, of CAP256 strain-specific antibodies to acquire breadth, with implications for the vaccine elicitation of BCN V2-dependent antibodies. Overall these studies demonstrate that ongoing viral escape is possible, even from BCN antibodies.
doi:10.1128/JVI.03424-12
PMCID: PMC3624332  PMID: 23408621
14.  Viral Escape from HIV-1 Neutralizing Antibodies Drives Increased Plasma Neutralization Breadth through Sequential Recognition of Multiple Epitopes and Immunotypes 
PLoS Pathogens  2013;9(10):e1003738.
Identifying the targets of broadly neutralizing antibodies to HIV-1 and understanding how these antibodies develop remain important goals in the quest to rationally develop an HIV-1 vaccine. We previously identified a participant in the CAPRISA Acute Infection Cohort (CAP257) whose plasma neutralized 84% of heterologous viruses. In this study we showed that breadth in CAP257 was largely due to the sequential, transient appearance of three distinct broadly neutralizing antibody specificities spanning the first 4.5 years of infection. The first specificity targeted an epitope in the V2 region of gp120 that was also recognized by strain-specific antibodies 7 weeks earlier. Specificity for the autologous virus was determined largely by a rare N167 antigenic variant of V2, with viral escape to the more common D167 immunotype coinciding with the development of the first wave of broadly neutralizing antibodies. Escape from these broadly neutralizing V2 antibodies through deletion of the glycan at N160 was associated with exposure of an epitope in the CD4 binding site that became the target for a second wave of broadly neutralizing antibodies. Neutralization by these CD4 binding site antibodies was almost entirely dependent on the glycan at position N276. Early viral escape mutations in the CD4 binding site drove an increase in wave two neutralization breadth, as this second wave of heterologous neutralization matured to recognize multiple immunotypes within this site. The third wave targeted a quaternary epitope that did not overlap any of the four known sites of vulnerability on the HIV-1 envelope and remains undefined. Altogether this study showed that the human immune system is capable of generating multiple broadly neutralizing antibodies in response to a constantly evolving viral population that exposes new targets as a consequence of escape from earlier neutralizing antibodies.
Author Summary
Four sites of vulnerability for broadly neutralizing antibodies to HIV-1 have been identified thus far. How these broadly reactive antibodies arise, and the host-pathogen interactions that drive the affinity maturation necessary for neutralization breadth are poorly understood. This study details the sequential development of three distinct broadly neutralizing antibody responses within a single HIV-1 infected individual over 4.5 years of infection. We show how escape from the first wave of antibodies targeting V2 exposed a second site that was the stimulus for a new wave of glycan dependent broadly neutralizing antibodies against the CD4 binding site. These data highlight how antibody evolution in response to viral escape mutations served to broaden the host immune response to these two epitopes. Finally, we document a third wave of neutralization that targets an undefined epitope that did not appear to overlap with the four known sites of vulnerability on the HIV-1 envelope. These data support the design of templates for sequential immunization strategies aimed at increasing neutralization breadth through the recognition of multiple epitopes and their immunotypes.
doi:10.1371/journal.ppat.1003738
PMCID: PMC3814426  PMID: 24204277
15.  Innate Immune Activation Enhances HIV Acquisition in Women, Diminishing the Effectiveness of Tenofovir Microbicide Gel 
The Journal of Infectious Diseases  2012;206(7):993-1001.
The antiretroviral agent, tenofovir, formulated as a vaginal microbicide gel, reduces human immunodeficiency virus (HIV) acquisition by 39% in women. This study assessed the role of preexisting immune activation in HIV acquisition in women from the CAPRISA 004 trial, to identify potential strategies to increase the effectiveness of tenofovir gel. Systemic cytokine and cellular immune mediators (platelets and natural killer [NK] cells) were assessed in women at high risk for HIV assigned to either tenofovir or placebo gel in the CAPRISA 004 trial. Notwithstanding tenofovir gel use, women who acquired HIV had significantly higher systemic innate immune activation prior to infection than women who remained uninfected. Activation of both soluble (cytokine) and cellular (NK cells) immune mediators were associated with HIV acquisition, individually or in combination. Hence, an innate immune activation suppressant could be added to tenofovir gel as a potential combination gel strategy in developing the next generation of higher efficacy antiretroviral microbicides.
doi:10.1093/infdis/jis465
PMCID: PMC3501691  PMID: 22829639
16.  Ratio of Monocytes to Lymphocytes in Peripheral Blood Identifies Adults at Risk of Incident Tuberculosis Among HIV-Infected Adults Initiating Antiretroviral Therapy 
The Journal of Infectious Diseases  2013;209(4):500-509.
Background. Eight decades ago, the ratio of monocytes to lymphocytes (hereafter, the “ML ratio”) was noted to affect outcomes of mycobacterial infection in rabbits. Recent transcriptomic studies support a role for relative proportions of myeloid and lymphoid transcripts in tuberculosis outcomes. The ML ratio in peripheral blood is known to be governed by hematopoietic stem cells with distinct biases.
Methods. The predictive value of the baseline ML ratio was modeled in 2 prospective cohorts of HIV-infected adults starting cART in South Africa (primary cohort, 1862 participants; replication cohort, 345 participants). Incident tuberculosis was diagnosed with clinical, radiographic, and microbiologic methods per contemporary guidelines. Kaplan-Meier survival analyses and Cox proportional hazards modeling were conducted.
Results. The incidence rate of tuberculosis differed significantly by baseline ML ratio: 32.61 (95% confidence interval [CI], 15.38–61.54), 16.36 (95% CI, 12.39–21.23), and 51.80 (95% CI, 23.10–101.71) per 1000 patient-years for ML ratios of less than the 5th percentile, between the 5th and 95th percentiles, and greater than the 95th percentile, respectively (P = .007). Neither monocyte counts nor lymphocyte counts alone were associated with tuberculosis. After adjustment for sex, World Health Organization human immunodeficiency virus disease stage, CD4+ T-cell counts, and previous history of tuberculosis, hazards of disease were significantly higher for patients with ML ratios of less than the 5th percentile or greater than the 95th percentile (adjusted hazard ratio, 2.47; 95% CI, 1.39–4.40; P = .002).
Conclusions. The ML ratio may be a useful, readily available tool to stratify the risk of tuberculosis and suggests involvement of hematopoietic stem cell bias in tuberculosis pathogenesis.
doi:10.1093/infdis/jit494
PMCID: PMC3903371  PMID: 24041796
tuberculosis; HIV; combination antiretroviral therapy; monocytes; lymphocytes; ML ratio
17.  Overview of Microbicides for the prevention of human immunodeficiency virus 
Human immunodeficiency virus (HIV) prevention tools that women can use and control are urgently needed. Microbicides are chemical products applied to the vagina or rectum to prevent the sexual transmission of HIV. Four classes of candidate microbicides have been tested to date: those that (1) enhance the natural defences in the vagina to inactivate HIV; (2) inactivate HIV in the vagina; (3) prevent HIV from attaching to, and fusing with, the host cells; and (4) prevent HIV from replicating in genital tract host cells. Despite numerous disappointing efficacy trial results over the past 20 years, substantial progress is now being made in microbicide development after the release of the CAPRISA 004 trial, which provided proof-of-concept that topical antiretroviral microbicides can prevent sexual transmission of HIV and herpes simplex type-2 infection. Microbicides, which fill an important gap for women-controlled prevention methods, have the potential to alter the course of the HIV pandemic.
doi:10.1016/j.bpobgyn.2012.01.010
PMCID: PMC3383397  PMID: 22386823
HIV; women; microbicide prevention
18.  Symptomatic Vaginal Discharge Is a Poor Predictor of Sexually Transmitted Infections and Genital Tract Inflammation in High-Risk Women in South Africa 
Background. Diagnosis and treatment of sexually transmitted infections (STIs) is a public health priority, particularly in regions where the incidence of human immunodeficiency virus (HIV) infection is high. In most developing countries, STIs are managed syndromically. We assessed the adequacy of syndromic diagnosis of STIs, compared with laboratory diagnosis of STIs, and evaluated the association between STI diagnosis and the risk of HIV acquisition in a cohort of high-risk women.
Methods. HIV-uninfected high-risk women (n = 242) were followed for 24 months. Symptoms of STIs were recorded, and laboratory diagnosis of common STI pathogens was conducted every 6 months. Forty-two cytokines were measured by Luminex in cervicovaginal lavage specimens at enrollment. Human immunodeficiency virus type 1 (HIV-1) infection was evaluated monthly.
Results. Only 12.3% of women (25 of 204) who had a laboratory-diagnosed, discharge-causing STI had clinically evident discharge. Vaginal discharge was thus a poor predictor of laboratory-diagnosed STIs (sensitivity, 12.3%; specificity, 93.8%). Cervicovaginal cytokine concentrations did not differ between women with asymptomatic STIs and those with symptomatic STIs and were elevated in women with asymptomatic STIs, compared with women with no STIs or bacterial vaginosis. Although laboratory-diagnosed STIs were associated with increased risk of HIV infection (hazard ratio, 3.3 [95% confidence interval, 1.5–7.2)], clinical symptoms were not.
Conclusions. Syndromic STI diagnosis dependent on vaginal discharge was poorly predictive of laboratory-diagnosed STI. Laboratory-diagnosed STIs were associated with increased susceptibility to HIV acquisition, while vaginal discharge was not.
doi:10.1093/infdis/jis298
PMCID: PMC3490689  PMID: 22517910
20.  Genital Tract Inflammation During Early HIV-1 Infection Predicts Higher Plasma Viral Load Set Point in Women 
The Journal of Infectious Diseases  2012;205(2):194-203.
Background. The biggest challenge in human immunodeficiency virus type 1 (HIV-1) prevention in Africa is the high HIV-1 burden in young women. In macaques, proinflammatory cytokine production in the genital tract is necessary for target cell recruitment and establishment of simian immunodeficiency virus (SIV) infection following vaginal inoculation. The purpose of this study was to assess if genital inflammation during early HIV-1 infection predisposes women to rapid disease progression.
Methods. Inflammatory cytokine concentrations were measured in cervicovaginal lavage (CVL) from 49 women 6, 17, 30, and 55 weeks after HIV-1 infection and from 22 of these women before infection. Associations between genital inflammation and viral load set point and blood CD4 cell counts 12 months after infection were investigated.
Results. Elevated genital cytokine concentrations 6 and 17 weeks after HIV-1 infection were associated with higher viral load set points and, to a lesser extent, with CD4 depletion. CVL cytokine concentrations during early infection did not differ relative to preinfection but were elevated in women who had vaginal discharge, detectable HIV-1 RNA in their genital tracts, and lower blood CD4 counts.
Conclusion. Genital inflammation during early HIV-1 infection was associated with higher viral load set point and CD4 depletion, which are markers of rapid disease progression. Strategies aimed at reducing genital inflammation during early HIV-1 infection may slow disease progression.
doi:10.1093/infdis/jir715
PMCID: PMC3244362  PMID: 22190580
21.  The Development of CD4 Binding Site Antibodies during HIV-1 Infection 
Journal of Virology  2012;86(14):7588-7595.
Broadly neutralizing antibodies to the CD4 binding site (CD4bs) of gp120 are generated by some HIV-1-infected individuals, but little is known about the prevalence and evolution of this antibody response during the course of HIV-1 infection. We analyzed the sera of 113 HIV-1 seroconverters from three cohorts for binding to a panel of gp120 core proteins and their corresponding CD4bs knockout mutants. Among sera collected between 99 and 258 weeks post-HIV-1 infection, 88% contained antibodies to the CD4bs and 47% contained antibodies to resurfaced stabilized core (RSC) probes that react preferentially with broadly neutralizing CD4bs antibodies (BNCD4), such as monoclonal antibodies (MAbs) VRC01 and VRC-CH31. Analysis of longitudinal serum samples from a subset of 18 subjects revealed that CD4bs antibodies to gp120 arose within the first 4 to 16 weeks of infection, while the development of RSC-reactive antibodies was more varied, occurring between 10 and 152 weeks post-HIV-1 infection. Despite the presence of these antibodies, serum neutralization mediated by RSC-reactive antibodies was detected in sera from only a few donors infected for more than 3 years. Thus, CD4bs antibodies that bind a VRC01-like epitope are often induced during HIV-1 infection, but the level and potency required to mediate serum neutralization may take years to develop. An improved understanding of the immunological factors associated with the development and maturation of neutralizing CD4bs antibodies during HIV-1 infection may provide insights into the requirements for eliciting this response by vaccination.
doi:10.1128/JVI.00734-12
PMCID: PMC3416294  PMID: 22573869
22.  Integration of Antiretroviral Therapy with Tuberculosis Treatment 
The New England journal of medicine  2011;365(16):1492-1501.
Background
We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, optimal time to initiate ART during tuberculosis treatment remains contentious.
Methods
To address this, we conducted a 3-arm, open-label randomized controlled trial in South Africa in acid-fast bacilli smear positive patients (n=642) with HIV and CD4+ counts <500 cells/mm3. Findings on the early therapy group (ART initiated within 4 weeks of tuberculosis treatment initiation, n=214) and late therapy group (ART initiated within the first 4 weeks of the continuation phase of tuberculosis treatment, n=215) are presented here.
Results
Median CD4+ count and viral load at baseline was 150 cells/mm3 and 161000 copies/ml, being similar in both groups. Incidence rate of AIDS or death was 6.9 (18/259.4) and 7.8 (19/244.2) per 100 person-years in the early and late therapy groups respectively (Incidence Rate Ratio (IRR)=0.89; 95%Confidence Interval (95%CI): 0.44,1.79; P=0.73). However, in patients with CD4+ counts <50 cells/mm3, the incidence rates of AIDS or death were 8.5 (early) and 26.3 (late) per 100 person-years (IRR=0.32; 95%CI: 0.07,1.13; P=0.06). Immune reconstitution inflammatory syndrome (IRIS) incidence rates were 20.2 (early) and 7.7 (late) per 100 person-years (IRR=2.62; 95%CI: 1.48,4.82; P<0.001). Adverse events requiring antiretroviral drug switches occurred in 10 (early) and 1 (late) patients (P=0.006).
Conclusions
The benefits of AIDS-free survival balanced against the risks of IRIS and ART-related adverse events, support early ART initiation in patients with CD4+ counts <50 cells/mm3 and deferred ART initiation to the continuation phase of tuberculosis treatment when CD4+ counts are higher.
doi:10.1056/NEJMoa1014181
PMCID: PMC3233684  PMID: 22010915
23.  Epidemiological Impact of Tenofovir Gel on the HIV Epidemic in South Africa 
Background
Tenofovir gel, an antiretroviral-based vaginal microbicide, reduced HIV acquisition by 39% in women in a recent randomised controlled clinical trial in South Africa.
Methods
To inform policy we used a dynamical model of HIV transmission, calibrated to the epidemic in South Africa, to determine the population-level impact of this microbicide on HIV incidence, prevalence and deaths and to evaluate its cost-effectiveness.
Results
If women use Tenofovir-gel in 80% or more of sexual encounters (high coverage), it could avert 2.33 (0.12 to 4.63) million new infections and save 1.30 (0.07 to 2.42) million lives and if used in 25% of sexual encounters (low coverage), it could avert 0.50 (0.04 to 0.77) million new infections and save 0.29 (0.02 to 0.44) million deaths, over the next 20 years. At US$0.50 per application, the cost per infection averted at low coverage is US$2,392 (US$562 to US$4,222) and the cost per disability-adjusted life year saved is US$104 (US$27 to US$181); at high coverage the costs are about 30% less.
Conclusion
Over twenty years the use of Tenofovir gel in South Africa could avert up to 2 million new infections and 1 million AIDS deaths. Even with low rates of gel use it is highly cost-effective and compares favourably with other control methods. This female controlled prevention method could have a significant impact on the epidemic of HIV in South Africa. Programmes should aim to achieve gel use in more than 25% of sexual encounters to significantly alter the course of the epidemic.
doi:10.1097/QAI.0b013e3182253c19
PMCID: PMC3175282  PMID: 21654503
HIV prevention; microbicide gel; Tenofovir; South Africa; cost effectiveness
24.  Stabilizing HIV prevalence masks high HIV incidence rates amongst rural and urban women in KwaZulu-Natal, South Africa 
Background In mature generalized human immunodeficiency virus (HIV) epidemics, as survival from accessing antiretroviral treatment (ART) increases, HIV prevalence data may be suboptimal and difficult to interpret without HIV incidence rates.
Objective To determine the HIV incidence rate among rural and urban women in KwaZulu-Natal, South Africa.
Methods We conducted a prospective cohort study from March 2004 to May 2007. Volunteers were recruited from a rural family-planning clinic and an urban clinic for sexually transmitted infections. Consenting, HIV-uninfected women aged 14–30 years were enrolled. Demographic, clinical, sexual and behavioural data were collected using standardized questionnaires with HIV risk reduction counselling and HIV testing. Pelvic examinations were completed at quarterly visits.
Results The HIV prevalence at screening was 35.7% [95% confidence interval (CI) 32.7–38.8] amongst rural women and 59.3% (95% CI 56.5–62.0) amongst urban women. A total of 594/2240 (26.5%) enrolled women contributed to 602 person-years (PYs) of follow-up. The median age was 22 years [inter-quartile range 18–23 years]. HIV incidence rate was 6.5/100 PY (95% CI 4.4–9.2) amongst rural women and 6.4/100 PY (95% CI 2.6–13.2) amongst urban women. HIV incidence rate of 17.2/100 PY (95% CI 2.1–62.2) was highest amongst urban women <20 years of age and 10.2/100 PY (95% CI 4.1–20.9) amongst rural women ≥25 years of age.
Conclusion HIV incidence rates are devastatingly high in young women in rural and urban KwaZulu-Natal, despite reports of stabilized HIV prevalence observed in current surveillance data. The diffuse nature of the HIV epidemic underscores the urgent need to enhance HIV prevention and treatment modalities.
doi:10.1093/ije/dyq176
PMCID: PMC3156366  PMID: 21047913
HIV incidence; HIV prevalence; young women; South Africa
25.  Mannose-rich glycosylation patterns on HIV-1 subtype C gp120 and sensitivity to the lectins, Griffithsin, Cyanovirin-N and Scytovirin 
Virology  2010;402(1):187-196.
Griffithsin (GRFT), Cyanovirin-N (CV-N) and Scytovirin (SVN) are lectins that inhibit HIV-1 infection by binding to multiple mannose-rich glycans on the HIV-1 envelope glycoproteins (Env). Here we show that these lectins neutralize subtype C primary virus isolates in addition to Env-pseudotyped viruses obtained from plasma and cervical vaginal lavages. Among 15 subtype C pseudoviruses, the median IC50 values were 0.4, 1.8 and 20.1 nM for GRFT, CV-N and SVN, respectively, similar to what was found for subtype B and A. Analysis of Env sequences suggested that concomitant lack of glycans at positions 234 and 295 resulted in natural resistance to these compounds, which was confirmed by site-directed mutagenesis. Furthermore, the binding sites for these lectins overlapped that of the 2G12 monoclonal antibody epitope, which is generally absent on subtype C Env. This data support further research on these lectins as potential microbicides in the context of HIV-1 subtype C infection.
doi:10.1016/j.virol.2010.03.021
PMCID: PMC3401642  PMID: 20392471
Griffithsin; Cyanovirin-N; Scytovirin; lectins; HIV-1 subtype C; microbicides; 2G12 monoclonal antibody

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