Browsing by Author "Naranbhai, Vivek."

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Antibody maturation in women who acquire HIV infection while using antiretroviral pre-exposure prophylaxis.
(Oxford University Press., 2015) Laeyendecker, Oliver.; Redd, Andrew D.; Nason, Martha.; Longosz, Andrew F.; Abdool Karim, Quarraisha.; Naranbhai, Vivek.; Garrett, Nigel Joel.; Eshleman, Susan H.; Abdool Karim, Salim Safurdeen.; Quinn, Thomas C.
Abstract available in pdf.
The association between the ratio of monocytes: lymphocytes and risk of tuberculosis among HIV-infected postpartum women.
(Lippincott Williams & Wilkins., 2014) Naranbhai, Vivek.; Moodley, Dhayendre.; Chipato, Tsungai.; Stranix-Chibanda, Lynda.; Nakabiito, Clemensia.; Kamateeka, Moreen.; Musoke, Philippa.; Manji, Karim.; George, Kathleen.; Emel, Lynda M.; Richardson, Paul.; Andrew, Philip.; Fowler, Mary Glenn.; Fletcher, Helen.; McShane, Helen.; Coovadia, Hoosen Mahomed.; Hill, Adrian V. S.
Abstract available in pdf.
The association between the ratio of monocytes: lymphocytes at age 3 months and risk of tuberculosis (TB) in the first two years of life.
(BioMed Central., 2014) Naranbhai, Vivek.; Kim, Soyeon.; Fletcher, Helen.; Cotton, Mark F.; Violari, Avy.; Mitchell, Charles.; Nachman, Sharon.; McSherry, George.; McShane, Helen.; Hill, Adrian V. S.; Madhi, Shabir A.
Background: Recent transcriptomic studies revived a hypothesis suggested by historical studies in rabbits that the ratio of peripheral blood monocytes to lymphocytes (ML) is associated with risk of tuberculosis (TB) disease. Recent data confirmed the hypothesis in cattle and in adults infected with HIV. Methods: We tested this hypothesis in 1,336 infants (540 HIV-infected, 796 HIV-exposed, uninfected (HEU)) prospectively followed in a randomized controlled trial of isoniazid prophylaxis in Southern Africa, the IMPAACT P1041 study. We modeled the relationship between ML ratio at enrollment (91 to 120 days after birth) and TB disease or death in HIV-infected children and latent Mycobacterium tuberculosis (MTB) infection, TB disease or death in HEU children within 96 weeks (with 12 week window) of randomization. Infants were followed-up prospectively and routinely assessed for MTB exposure and outcomes. Cox proportional hazards models allowing for non-linear associations were used; in all cases linear models were the most parsimonious. Results: Increasing ML ratio at baseline was significantly associated with TB disease/death within two years (adjusted hazard ratio (HR) 1.17 per unit increase in ML ratio; 95% confidence interval (CI) 1.01 to 1.34; P = 0.03). Neither monocyte count nor lymphocyte counts alone were associated with TB disease. The association was not statistically dissimilar between HIV infected and HEU children. Baseline ML ratio was associated with composite endpoints of TB disease and death and/or TB infection. It was strongest when restricted to probable and definite TB disease (HR 1.50; 95% CI 1.19 to 1.89; P = 0.006). Therefore, per 0.1 unit increase in the ML ratio at three to four months of age, the hazard of probable or definite TB disease before two years was increased by roughly 4% (95% CI 1.7% to 6.6%). Conclusion: Elevated ML ratio at three- to four-months old is associated with increased hazards of TB disease before two years among children in Southern Africa. While significant, the modest effect size suggests that the ML ratio plays a modest role in predicting TB disease-free survival; its utility may, therefore, be limited to combination with existing tools to stratify TB risk, or to inform underlying pathophysiologic determinants of TB disease.
CAPRISA 004 tenofovir microbicide trial: no impact of tenofovir gel on the HIV transmission bottleneck.
(Oxford University Press., 2011) Valley-Omar, Ziyaad.; Sibeko, Sengeziwe.; Anderson, Jeffrey A.; Goodier, Sarah A.; Werner, Lise.; Arney, Leslie.; Naranbhai, Vivek.; Treurnicht, Florette K.; Abrahams, Melissa-Rose.; Bandawe, Gama P.; Swanstrom, Ronald.; Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Williamson, Carolyn.
Alterations of the genital mucosal barrier may influence the number of viruses transmitted from a human immunodeficiency virus–infected source host to the newly infected individual. We used heteroduplex tracking assay and single-genome sequencing to investigate the effect of a tenofovir-based microbicide gel on the transmission bottleneck in women who seroconverted during the CAPRISA 004 microbicide trial. Seventy-seven percent (17 of 22; 95% confidence interval [CI], 56%–90%) of women in the tenofovir gel arm were infected with a single virus compared with 92% (13 of 14; 95% CI, 67%–>99%) in the placebo arm (P = .37). Tenofovir gel had no discernable impact on the transmission bottleneck.
Changes in natural killer cell activation and function during primary HIV-1 infection.
(Plos., 2012) Naranbhai, Vivek.; Altfeld, Marcus.; Abdool Karim, Salim Safurdeen.; Ndung'u, Peter Thumbi.; Abdool Karim, Quarraisha.; Carr, William Henry.
Background. Recent reports suggest that Natural Killer (NK) cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection. Methodology/Principal Findings. Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, α4β7). Non-parametric statistical tests were used. Both NK cells and T-cells were significantly activated following HIV acquisition (p = 0.03 and p<0.0001, respectively), but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r = 0.68;p<0.0001; post-infection, during primary infection r = 0.074;p = 0.09). Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r = 0.32'p = 0.04 and r = 0.35;p = 0.02, respectively). The frequency of Killer Immunoglobulin-like Receptor-expressing (KIRpos) NK cells increased following HIV acquisition (p = 0.006), and KIRpos NK cells were less activated than KIRneg NK cells amongst individuals sampled while seronegative or serodiscordant (p = 0.001;p<0.0001 respectively). During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p = 0.006 and p = 0.002, respectively). However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated during primary infection, particularly at early time-points (p<0.0001). Conclusions/Significance. Analyses of immune cells before and after HIV infection revealed an increase in both NK-cell activation and KIR expression, but reduced cytotoxicity during acute infection. The increase in frequency of NK cells able to traffic to lymph nodes following HIV infection suggests that these cells may play a role in events in secondary lymphoid tissue.
Clinical and mycological predictors of cryptococcosis-associated immune reconstitution inflammatory syndrome.
(Wolters Kluwer Health., 2013) Chang, Christina C.; Dorasamy, Afton A.; Gosnell, Bernadett I.; Elliott, Julian H.; Spelman, Tim.; Omarjee, Saleha.; Naranbhai, Vivek.; Ndung'u, Peter Thumbi.; Moosa, Mahomed Yunus Suleman.; Lewin, Sharon R.; French, Martyn A.; Coovadia, Yacoob Mahomed.
Abstract available in PDF file.
Comparative Proteomics of Activated THP-1 Cells Infected with Mycobacterium tuberculosis Identifies Putative Clearance Biomarkers for Tuberculosis Treatment.
(Kaewseekhao, B., Naranbhai, V., Roytrakul, S., Namwat, W., Paemanee, A., Lulitanond, V., Chaiprasert, A. and Faksri, K. 2015. Comparative Proteomics of Activated THP-1 Cells Infected with Mycobacterium tuberculosis Identifies Putative Clearance Biomarkers for Tuberculosis Treatment. PloS one 10(7), e0134168., 2015) Kaewseekhao, Benjawan.; Naranbhai, Vivek.; Roytrakul, Sittiruk.; Namwat, Wises.; Paemanee, Atchara.; Lulitanond, Viraphong.; Chaiprasert, Angkana.; Faksri, Kiatichai.
Abstract available in pdf.
Compartmentalisation of innate immune responses in the central nervous system during cryptococcal meningitis/HIV co-infection.
(Wolters Kluwer Health., 2014) Naranbhai, Vivek.; Chang, Christina C.; Durgiah, Raveshni.; Omarjee, Saleha.; Lim, Andrew.; Moosa, Mahomed Yunus Suleman.; Elliott, Julian H.; Ndung'u, Peter Thumbi.; Lewin, Sharon R.; French, Martyn A.; Carr, William Henry.
Abstract available in PDF file.
Development of methods for cross-sectional HIV incidence estimation in a large, community randomized trial.
(PLOS ONE., 2013) Laeyendecker, Oliver.; Kulich, Michal.; Donnell, Deborah.; Koma´rek, Arnosˇt.; Omelka, Marek.; Mullis, Caroline E.; Szekeres, Greg.; Piwowar-Manning, Estelle.; Fiamma, Agnes.; Gray, Ronald H.; Lutalo, Tom.; Morrison, Charles S.; Salata, Robert A.; Chipato, Tsungai.; Celum, Connie Locke.; Kahle, Erin M.; Taha, Taha E.; Kumwenda, Newton I.; Abdool Karim, Quarraisha.; Naranbhai, Vivek.; Lingappa, Jairam R.; Sweat, Michael D.; Coates, Thomas.; Eshleman, Susan H.
Background: Accurate methods of HIV incidence determination are critically needed to monitor the epidemic and determine the population level impact of prevention trials. One such trial, Project Accept, a Phase III, community-randomized trial, evaluated the impact of enhanced, community-based voluntary counseling and testing on population-level HIV incidence. The primary endpoint of the trial was based on a single, cross-sectional, post-intervention HIV incidence assessment. Methods and Findings: Test performance of HIV incidence determination was evaluated for 403 multi-assay algorithms [MAAs] that included the BED capture immunoassay [BED-CEIA] alone, an avidity assay alone, and combinations of these assays at different cutoff values with and without CD4 and viral load testing on samples from seven African cohorts (5,325 samples from 3,436 individuals with known duration of HIV infection [1 month to >10 years]). The mean window period (average time individuals appear positive for a given algorithm) and performance in estimating an incidence estimate (in terms of bias and variance) of these MAAs were evaluated in three simulated epidemic scenarios (stable, emerging and waning). The power of different test methods to detect a 35% reduction in incidence in the matched communities of Project Accept was also assessed. A MAA was identified that included BED-CEIA, the avidity assay, CD4 cell count, and viral load that had a window period of 259 days, accurately estimated HIV incidence in all three epidemic settings and provided sufficient power to detect an intervention effect in Project Accept. Conclusions: In a Southern African setting, HIV incidence estimates and intervention effects can be accurately estimated from cross-sectional surveys using a MAA. The improved accuracy in cross-sectional incidence testing that a MAA provides is a powerful tool for HIV surveillance and program evaluation.
Genital inflammation and the risk of HIV acquisition in women.
(Oxford University Press., 2015) Masson, Lindi.; Passmore, Jo-Ann Shelley.; Liebenberg, Lenine Julie.; Werner, Lise.; Baxter, Cheryl.; Arnold, Kelly B.; Williamson, Carolyn.; Little, Francesca.; Mansoor, Leila Essop.; Naranbhai, Vivek.; Lauffenburger, Douglas A.; Ronacher, Katharina.; Walzl, Gerhard.; Garrett, Nigel Joel.; Williams, Brent L.; Couto-Rodriguez, Mara.; Hornig, Mady.; Lipkin, Walter Ian.; Grobler, Anna Christina.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
High burden of human papillomavirus (HPV) infection among young women in KwaZulu-Natal, South Africa.
(Public Library of Science., 2016) Ebrahim, Sumayyah.; Mndende, Xolani K.; Kharsany, Ayesha Bibi Mahomed.; Mbulawa, Zizipho Z.; Naranbhai, Vivek.; Werner, Lise.; Samsunder, Natasha.; Abdool Karim, Quarraisha.; Williamson, Anna-Lise.; Fröhlich, Janet Ann.
Abstract available in PDF file.
HIV disease progression in seroconvertors from the CAPRISA 004 tenofovir gel pre-exposure prophylaxis trial.
(Lippincott Williams & Wilkins., 2015) Garrett, Nigel Joel.; Werner, Lise.; Naicker, Nivashnee.; Naranbhai, Vivek.; Sibeko, Sengeziwe.; Samsunder, Natasha.; Gray, Clive M.; Williamson, Carolyn.; Morris, Lynn.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
HIV prevention and treatment research in sub-Saharan Africa: where are the adolescents?
(Lippincott Williams & Wilkins., 2005) Naranbhai, Vivek.; Abdool Karim, Quarraisha.
No abstract available.
Impact of blood processing variations on natural killer cell frequency, activation, chemokine receptor expression and function.
(Elsevier for Association of Medical Laboratory Immunologists., 2010) Naranbhai, Vivek.; Bartman, Pat.; Ndlovu, Dudu.; Ramkalawon, Pamela.; Ndung'u, Peter Thumbi.; Wilson, Douglas Paul Kinghurst.; Altfeld, Marcus.; Carr, William Henry.
Understanding the role of natural killer (NK) cells in human disease pathogenesis is crucial and necessitates study of patient samples directly ex vivo. Manipulation of whole blood by density gradient centrifugation or delays in sample processing due to shipping, however, may lead to artifactual changes in immune response measures. Here, we assessed the impact of density gradient centrifugation and delayed processing of both whole blood and peripheral blood mononuclear cells (PBMC) at multiple timepoints (2–24 h) on flow cytometric measures of NK cell frequency, activation status, chemokine receptor expression, and effector functions. We found that density gradient centrifugation activated the NK cells and modified the chemokine receptor expression. Delays in processing beyond 8 h activated NK cells in PBMC but not in whole blood. Likewise, processing delays decreased chemokine receptor (CCR4 and CCR7) expression in both PBMC and whole blood. Finally, delays in processing PBMC were associated with a decreased ability of NK cells to degranulate (as measured by CD107a expression) or secrete cytokines (IFN-γ and TNF-α). In summary, our findings suggest that density gradient centrifugation and delayed processing of PBMC can alter measures of clinically relevant NK cell characteristics including effector functions; and therefore should be taken into account in designing clinical research studies.
Innate immune activation enhances HIV acquisition in women, diminishing the effectiveness of tenofovir microbicide gel.
(Oxford University Press., 2011) Naranbhai, Vivek.; Abdool Karim, Salim Safurdeen.; Altfeld, Marcus.; Samsunder, Natasha.; Durgiah, Raveshni.; Sibeko, Sengeziwe.; Abdool Karim, Quarraisha.; Carr, William Henry.
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.
Interventions to modify sexual risk behaviours for preventing HIV in homeless youth.
(John Wiley & Sons, Ltd., 2011) Naranbhai, Vivek.; Abdool Karim, Quarraisha.; Meyer-Weitz, Anna.
Background - Homeless youth are at high risk for HIV infection as a consequence of risky sexual behavior. Interventions in homeless youth are challenging. Assessment of the effectiveness of interventions to modify sexual risk behaviours for preventing HIV in homeless youth is needed. Objectives - To evaluate and summarize the effectiveness of interventions for modifying sexual risk behaviours and preventing transmission of HIV among homeless youth. Search methods - We searched electronic databases (CENTRAL, Medline, EMBASE, AIDSearch, Gateway, PsycInfo, LILACS), reference lists of eligible articles, international health agency publication lists, and clinical trial registries. The search was updated January 2010. We contacted authors of published reports and other key role players. Selection criteria - Randomized studies of interventions to modify sexual risk behavior (biological, self-report sexual-risk behavior or health seeking behavior) in homeless youth (12–24 years). Data collection and analysis - Data from eligible studies were extracted by two reviewers. We assessed risk of bias per the Cochrane Collaborations tool. None of the eligible studies reported any primary biological outcomes for this review and the reporting of self-report sexual risk behavior outcomes was highly variable across studies precluding calculation of summary measures of effect; we present the outcomes descriptively for each study. We contacted authors for missing or ambiguous data. Results - We identified three eligible studies after screening a total of 255 unique records. All three were performed in the United States of America and recruited substance-abusing male and female adolescents (total N=615) through homeless shelters into randomised controlled trials of independent and non-overlapping behavioural interventions. The three trials differed in theoretical background, delivery method, dosage (number of sessions,) content and outcome assessments. Overall, the variability in delivery and outcomes precluded estimation of summary of effect measures. We assessed the risk of bias to be high for each of the studies. Whilst some effect of the interventions on outcome measures were reported, heterogeneity and lack of robustness in these studies necessitate caution in interpreting the effectiveness of these interventions. Authors’ conclusions - The body of evidence does not permit conclusions on the impact of interventions to modify sexual risk behaviour in homeless youth. More research is required. While the psychosocial and contextual factors that fuel sexual risk behaviours among homeless youth challenge stringent methodologies of RCT’s, novel ways for program delivery and trial retention are in need of development. Future trials should endeavour to comply with rigorous methodology in design, delivery, outcome measurement and reporting.
Killer-cell Immunoglobulin-like Receptor (KIR) gene profiles modify HIV disease course, not HIV acquisition in South African women.
(BioMed Central., 2016) Naranbhai, Vivek.; de Assis Rosa, Debra.; Werner, Lise.; Moodley, Ramona.; Hong, Heather.; Kharsany, Ayesha Bibi Mahomed.; Mlisana, Koleka Patience.; Sibeko, Sengeziwe.; Garrett, Nigel Joel.; Chopera, Denis Rutendo.; Carr, William Henry.; Abdool Karim, Quarraisha.; Hill, Adrian V. S.; Abdool Karim, Salim Safurdeen.; Altfeld, Marcus.; Gray, Clive M.; Ndung'u, Peter Thumbi.
Abstract available in PDF file.
Killer-cell immunoglobulin-like receptor genotyping and HLA killer-cell immunoglobulin-like receptor-ligand identification by real-time polymerase chain reaction.
(John Wiley & Sons., 2011) Hong, H. A.; Loubser, A. S.; de Assis Rosa, Debra.; Naranbhai, Vivek.; Carr, William Henry.; Paximadis, Maria.; Lewis, David A.; Tiemessen, Caroline Tanya.; Gray, Clive M.
The effector function of natural killer (NK) cells is modulated by surface expression of a range of killer-cell immunoglobulin-like receptors (KIRs) that interact with human leukocyte antigen (HLA) class I ligands. We describe the use of real-time polymerase chain reaction (PCR) assays that allow easy and quick detection of 16 KIR genes and the presence/absence of KIR-ligands based on allelic discrimination at codon 80 in the HLA-A/B Bw4 and HLA-C C1/C2 genes. These methods overcome the tedious and expensive nature of conventional KIR genotyping and HLA class I typing using sequence-specific primer (SSP) PCR, sequence-specific oligonucleotide (SSO) hybridization or sequence-based typing (SBT). Using these two cost-effective assays, we measured the frequencies of KIRs, KIR-ligands and KIR/KIR-ligand pairs in a cohort of Black women recruited in South Africa.
Natural killer cell function in women at high risk for HIV acquisition: insights from a microbicide trial.
(Lippincott Williams & Wilkins., 2012) Naranbhai, Vivek.; Altfeld, Marcus.; Abdool Karim, Quarraisha.; Ndung'u, Peter Thumbi.; Abdool Karim, Salim Safurdeen.; Carr, William Henry.
Objective: To assess the role of natural killer (NK) cells in HIV acquisition. Design: We conducted a nested case–control substudy to the Center for the AIDS Programme of Research in South Africa (CAPRISA004) tenofovir gel trial. Methods: Thirty women who acquired HIV infection (cases) and 30 women with high-risk sexual activity who remained HIV-negative (controls) were selected. Proliferation, degranulation and interferon-y (IFNy) secretion were measured by multiparametric flow cytometry after culture of recombinant human interleukin-2 (rhIL-2)-activated peripheral blood mononuclear cells with 721.221 cells or in-vitro HIV-infected, autologous CD4+ T-cell blasts. Relationships between pre-acquisition NK cell responses and HIV acquisition were modeled with logistic regression models. Results: NK cells from cases had lower IFNy responses to human leukocyte antigen-deficient 721.221 cells than controls (median %IFNyposNK cells: 13.7 vs. 21.6%, P=0.03). rhIL-2-activated NK cells from cases had responses to autologous HIV-infected target cells distinct from controls: cases had fewer proliferating and more frequent degranulating NK cells. NK cells from cases had significantly lower IFNy responses to in-vitro HIV-infected autologous T cells than controls even after adjusting for responses to uninfected blasts (median %IFNyposNK-cells: 0.53 vs. 2.09%, P=0.007). Responses to in-vitro HIV-infected autologous T cells were significantly lower in herpes simplex virus 2 (HSV-2)-infected women (P=0.003). IFNy NK cell responses to autologous HIV-infected cells were associated with lower risk of HIV acquisition (odds ratio adjusted for age, gel arm, HSV-2 and immune activation: 0.582, 95% confidence interval 0.347–0.977, P=0.04). Conclusion: At the time of exposure to HIV, women with impaired NK cell IFNy responses were more likely to acquire HIV infection. NK cells, as early responders to viral exposure, were associated with lower risk of HIV acquisition, independent of the intercalated effect of HSV-2 infection suppressing NK cell responses.
No evidence for selection of HIV-1 with enhanced gag-protease or nef function among breakthrough infections in the CAPRISA 004 tenofovir microbicide trial.
(2013) Chopera, Denis Rutendo.; Mann, Jaclyn Kelly.; Mwimanzi, Philip.; Omarjee, Saleha.; Kuang, Xiaomei T.; Ndabambi, Nonkululeko.; Goodier, Sarah A.; Martin, Eric.; Naranbhai, Vivek.; Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Brumme, Zabrina L.; Ndung'u, Peter Thumbi.; Williamson, Carolyn.; Brockman, Mark A.
Background: Use of antiretroviral-based microbicides for HIV-1 prophylaxis could introduce a transmission barrier that inadvertently facilitates the selection of fitter viral variants among incident infections. To investigate this, we assessed the in vitro function of gag-protease and nef sequences from participants who acquired HIV-1 during the CAPRISA 004 1% tenofovir microbicide gel trial. Methods and Results: We isolated the earliest available gag-protease and nef gene sequences from 83 individuals and examined their in vitro function using recombinant viral replication capacity assays and surface protein down regulation assays, respectively. No major phylogenetic clustering and no significant differences in gag-protease or nef function were observed in participants who received tenofovir gel versus placebo gel prophylaxis. Conclusion: Results indicate that the partial protective effects of 1% tenofovir gel use in the CAPRISA 004 trial were not offset by selection of transmitted/early HIV-1 variants with enhanced Gag-Protease or Nef fitness.