Browsing by Author "Werner, Lise."

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Adherence in the treatment of patients with extensively drug-resistant tuberculosis and HIV in South Africa: a prospective cohort study.
(Lippincott Williams & Wilkins., 2014) O'Donnell, Max Roe.; Wolf, Allison.; Werner, Lise.; Horsburgh, Charles Robert.; Padayatchi, Nesri.
Abstract available in pdf.
APOBEC3G expression is dysregulated in primary HIV-1 infection and polymorphic variants influence CD4R T-cell counts and plasma viral load.
(Lippincott Williams & Wilkins., 2008) Reddy, Kavidha.; Winkler, Cheryl Ann.; Werner, Lise.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Ndung'u, Peter Thumbi.
Objectives: In the absence of HIV-1 virion infectivity factor (Vif), cellular cytosine deaminases such as apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) inhibit the virus by inducing hypermutations on viral DNA, among other mechanisms of action. We investigated the association of APOBEC3G mRNA levels and genetic variants on HIV-1 susceptibility, and early disease pathogenesis using viral load and CD4+ T-cell counts as outcomes. Methods: Study participants were 250 South African women at high risk for HIV-1 subtype C infection.We used real-time PCR to measure the expression of APOBEC3G in HIV-negative and HIV-positive primary infection samples. APOBEC3G variants were identified by DNA re-sequencing and TaqMan genotyping. Results: We found no correlation between APOBEC3G expression levels and plasma viral loads (r=0.053, P=0.596) or CD4+ T-cell counts (r=0.030, P=0.762) in 32 seroconverters. APOBEC3G expression levels were higher in HIV-negative individuals as compared with HIV-positive individuals (P<0.0001), including matched pre and postinfection samples from the same individuals (n=13, P<0.0001). Twenty-four single nucleotide polymorphisms, including eight novel, were identified within APOBEC3G by re-sequencing and genotyping. The H186R mutation, a codon-changing variant in exon 4, and a 3' extragenic mutation (rs35228531) were associated with high viral loads (P=0.0097 and P<0.0001) and decreased CD4+ T-cell levels (P=0.0081 and P<0.0001), respectively. Conclusion: These data suggest that APOBEC3G transcription is rapidly downregulated upon HIV-1 infection. During primary infection, APOBEC3G expression levels in peripheral blood mononuclear cells do not correlate with viral loads or CD4+ T-cell counts. Genetic variation of APOBEC3G may significantly affect early HIV-1 pathogenesis, although the mechanism remains unclear and warrants further investigation.
Association of polymorphisms in the LEDGF/p75 gene (PSIP1) with susceptibility to HIV-1 infection and disease progression.
(Lippincott Williams & Wilkins., 2011) Madlala, Paradise Zamokuhle.; Gijsbers, Rik.; Christ, Frauke.; Hombrouck, Anneleen.; Werner, Lise.; Mlisana, Koleka Patience.; An, Ping.; Abdool Karim, Salim Safurdeen.; Winkler, Cheryl Ann.; Debyser, Zeger.; Ndung'u, Peter Thumbi.
Objective: LEDGF/p75, encoded by the PSIP1 gene, interacts with HIV-1 integrase and targets HIV-1 integration into active genes. We investigated the influence of polymorphisms in PSIP1 on HIV-1 acquisition and disease progression in black South Africans. Methods: Integrase binding domain of LEDGF/p75 was sequenced in 126 participants. Four haplotype tagging SNPs rs2277191, rs1033056, rs12339417 and rs10283923 referred to as SNP1, SNP2, SNP3 and SNP4, respectively, and one exonic SNP rs61744944 (SNP5, Q472L) were genotyped in 195 HIV-1 seronegative, 52 primary and 403 chronically infected individuals using TaqMan assays. LEDGF/p75 expression was quantified by real-time RT-PCR. The impact of Q472L mutation on the interaction with HIV_1 IN was measured by AlphaScreen. Results: rs2277191 (SNP1) A was more frequent among seropositives (P=0.06, Fisher’s exact test). Among individuals followed longitudinally SNP1A trended towards association with higher likelihood of HIV-1 acquisition [relative hazard (RH)=2.21, P=0.08; Cox model] and it was also associated with rapid disease progression (RH=5.98, P=0.04; Cox model) in the recently infected (primary infection) cohort. rs12339417 (SNP3)C was associated with slower decline of CD4+ T cells (P=0.02) and lower messenger RNA (mRNA) levels of LEDGF/p75 (P<0.01). Seroconverters had higher preinfection mRNA levels of LEDGF/p75 (P<0.01) and these levels decreased after HIV-1 infection (P=0.02). Conclusions: Genetic variants of PSIP1 may affect HIV-1 outcomes. Further studies are needed to confirm the effect of genetic variation of PSIP1 on HIV-1 pathogenesis in different cohorts.
Association of polymorphisms in the regulatory region of the cyclophilin A gene (PPIA) with gene expression and HIV/AIDS disease progression.
(Wolters Kluwer Health., 2016) Madlala, Paradise Zamokuhle.; Singh, Ravesh.; An, Ping.; Werner, Lise.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Winkler, Cheryl Ann.; Ndung'u, Peter Thumbi.
Abstract available in PDF file.
Association of TRIM22 with the Type 1 Interferon Response and Viral Control during Primary HIV-1 Infection.
(American Society for Microbiology., 2010) Singh, Ravesh.; Gaiha, Gaurav.; Werner, Lise.; Mlisana, Koleka Patience.; Luban, Jeremy.; Walker, Bruce D.; Abdool Karim, Salim Safurdeen.; Ndung'u, Peter Thumbi.; Brass, Abraham.; McKim, Kevin.
Type 1 interferons (IFNs) induce the expression of the tripartite interaction motif (TRIM) family of E3 ligases, but the contribution of these antiviral factors to HIV pathogenesis is not completely understood. We hypothesized that the increased expression of select type 1 IFN and TRIM isoforms is associated with a significantly lower likelihood of HIV-1 acquisition and viral control during primary HIV-1 infection. We measured IFN-a, IFN-b, myxovirus resistance protein A (MxA), human TRIM5a (huTRIM5a), and TRIM22 mRNA levels in peripheral blood mononuclear cells (PBMCs) of high-risk, HIV-1-uninfected participants and HIV-1-positive study participants. Samples were available for 32 uninfected subjects and 28 infected persons, all within 1 year of infection. HIV-1-positive participants had higher levels of IFN-b(P=0.0005), MxA (P=0.007), and TRIM22 (P=0.01) and lower levels of huTRIM5a (P< 0.001) than did HIV-1-negative participants. TRIM22 but not huTRIM5a correlated positively with type 1 IFN (IFN-a, IFN-b, and MxA) (all P<0.0001). In a multivariate model, increased MxA expression showed a significant positive association with viral load (P=0.0418). Furthermore, TRIM22 but not huTRIM5a, IFN-a, IFN-b, or MxA showed a negative correlation with plasma viral load (P=0.0307) and a positive correlation with CD4 T-cell counts (P=0.0281). In vitro studies revealed that HIV infection induced TRIM22 expression in PBMCs obtained from HIV-negative donors. Stable TRIM22 knockdown resulted in increased HIV-1 particle release and replication in Jurkat reporter cells. Collectively, these data suggest concordance between type 1 IFN and TRIM22 but not huTRIM5a expression in PBMCs and that TRIM22 likely acts as an antiviral effector in vivo.
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.
Challenges of diagnosing acute HIV-1 subtype C infection in African women: performance of a clinical algorithm and the need for point-of-care nucleic-acid based testing.
(Plos., 2012) Mlisana, Koleka Patience.; Sobieszczyk, Magdalena E.; Werner, Lise.; Feinstein, Addi.; van Loggerenberg, Francois.; Naicker, Nivashnee.; Williamson, Carolyn.; Garrett, Nigel Joel.
Background. Prompt diagnosis of acute HIV infection (AHI) benefits the individual and provides opportunities for public health intervention. The aim of this study was to describe most common signs and symptoms of AHI, correlate these with early disease progression and develop a clinical algorithm to identify acute HIV cases in resource limited setting. Methods. 245 South African women at high-risk of HIV-1 were assessed for AHI and received monthly HIV-1 antibody and RNA testing. Signs and symptoms at first HIV-positive visit were compared to HIV-negative visits. Logistic regression identified clinical predictors of AHI. A model-based score was assigned to each predictor to create a risk score for every woman. Results. Twenty-eight women seroconverted after a total of 390 person-years of follow-up with an HIV incidence of 7.2/100 person-years (95%CI 4.5–9.8). Fifty-seven percent reported ≥1 sign or symptom at the AHI visit. Factors predictive of AHI included age <25 years (OR = 3.2; 1.4–7.1), rash (OR = 6.1; 2.4–15.4), sore throat (OR = 2.7; 1.0–7.6), weight loss (OR = 4.4; 1.5–13.4), genital ulcers (OR = 8.0; 1.6–39.5) and vaginal discharge (OR = 5.4; 1.6–18.4). A risk score of 2 correctly predicted AHI in 50.0% of cases. The number of signs and symptoms correlated with higher HIV-1 RNA at diagnosis (r = 0.63; p<0.001). Conclusions. Accurate recognition of signs and symptoms of AHI is critical for early diagnosis of HIV infection. Our algorithm may assist in risk-stratifying individuals for AHI, especially in resource-limited settings where there is no routine testing for AHI. Independent validation of the algorithm on another cohort is needed to assess its utility further. Point-of-care antigen or viral load technology is required, however, to detect asymptomatic, antibody negative cases enabling early interventions and prevention of transmission.
Characterization of anti-HIV-1 neutralizing and binding antibodies in chronic HIV-1 subtype C infection.
(Elsevier., 2012) Archary, Derseree.; Rong, Rong.; Gordon, Michelle Lucille.; Boliar, Saikat.; Madiga, Maphuti C.; Gray, Elin Solomonovna.; Dugast, Anne-Sophie.; Hermanus, Tandile.; Goulder, Philip Jeremy Renshaw.; Coovadia, Hoosen Mahomed.; Werner, Lise.; Morris, Lynn.; Alter, Galit.; Derdeyn, Cynthia A.; Ndung'u, Peter Thumbi.
Neutralizing (nAbs) and high affinity binding antibodies may be critical for an efficacious HIV-1 vaccine. We characterized virus-specific nAbs and binding antibody responses over 21 months in eight HIV-1 subtype C chronically infected individuals with heterogeneous rates of disease progression. Autologous nAb titers of study exit plasma against study entry viruses were significantly higher than contemporaneous responses at study entry (p=0.002) and exit (p=0.01). NAb breadth and potencies against subtype C viruses were significantly higher than for subtype A (p=0.03 and p=0.01) or B viruses (p=0.03; p=0.05) respectively. Gp41-IgG binding affinity was higher than gp120-IgG (p=0.0002). IgG–FcγR1 affinity was significantly higher than FcγRIIIa (p<0.005) at study entry and FcγRIIb (p<0.05) or FcγRIIIa (p<0.005) at study exit. Evolving IgG binding suggests alteration of immune function mediated by binding antibodies. Evolution of nAbs was a potential marker of HIV-1 disease progression.
Clofazimine in the treatment of extensively drug-resistant tuberculosis with HIV coinfection in South Africa: a retrospective cohort study.
(Oxford University Press., 2014) Padayatchi, Nesri.; Gopal, Murali.; Naidoo, Rowena.; Werner, Lise.; Naidoo, Kimesh.; Master, Iqbal.; O'Donnell, Max Roe.
Abstract available in pdf.
Differences in HIV-1 neutralization breadth in two geographically distinct cohorts in Africa.
(Oxford University Press., 2015) Bandawe, Gama P.; Moore, Penelope L.; Werner, Lise.; Gray, Elin Solomonovna.; Sheward, Daniel J.; Madiga, Maphuti C.; Nofemela, Andile.; Thebus, Ruwayhida.; Marais, Jinny C.; Maboko, Leonard.; Abdool Karim, Salim Safurdeen.; Hoelscher, Michael.; Morris, Lynn.; Williamson, Carolyn.
Abstract available in pdf.
Distinct genital tract HIV-specific antibody profiles associated with Tenofovir gel.
(Nature., 2016) Archary, Derseree.; Seaton, Kelly E.; Passmore, Jo-Ann Shelley.; Werner, Lise.; Deal, Aaron W.; Dunphy, Laura J.; Arnold, Kelly B.; Yates, Nicole L.; Lauffenburger, Douglas A.; Bergin, Philip.; Liebenberg, Lenine Julie.; Samsunder, Natasha.; Mureithi, Marianne W.; Altfeld, Marcus.; Garrett, Nigel Joel.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Morris, Lynn.; Tomaras, Georgia D.
Abstract available in PDF file.
Drug concentrations after topical and oral antiretroviral pre-exposure prophylaxis: implications for HIV prevention in women.
(Elsevier., 2011) Abdool Karim, Salim Safurdeen.; Kashuba, Angela D. M.; Werner, Lise.; Abdool Karim, Quarraisha.
No abstract available.
Duffy-Null–Associated Low Neutrophil Counts Influence HIV-1 Susceptibility in High-Risk South African Black Women.
(Oxford University Press., 2010) Ramsuran, Veron.; Kulkarni, Hemant.; He, Weijing.; Mlisana, Koleka Patience.; Wright, Edwina J.; Werner, Lise.; Castiblanco, John.; Dhanda, Rahul.; Le, Tuan.; Dolan, Matthew J.; Guan, Weihua.; Weiss, Robin A.; Clark, Robert A.; Abdool Karim, Salim Safurdeen.; Ahuja, Sunil K.; Ndung'u, Peter Thumbi.
Background. The Duffy-null trait and ethnic netropenia are both highly prevalent in Africa. The influence of pre-seroconversion levels of peripheral blood cell counts (PBCs) on the risk of acquiring human immunodeficiency virus (HIV)–1 infection among Africans is unknown. Methods. The triangular relationship among pre-seroconversion PBC counts, host genotypes, and risk of HIV acquisition was determined in a prospective cohort of black South African high-risk female sex workers. Twenty seven women had seroconversion during follow-up, and 115 remained HIV negative for 2 years, despite engaging in high-risk activity. Results. Pre-seroconversion neutrophil counts in women who subsequently had seroconversion were significantly lower, whereas platelet counts were higher, compared with those who remained HIV negative. Comprising 27% of the cohort, subjects with pre-seroconversion neutrophil counts of <2500 cells/mm3 had a ~3-fold greater risk of acquiring HIV infection. In a genome-wide association analyses, an African-specific polymorphism (rs2814778) in the promoter of Duffy Antigen Receptor for Chemokines (DARC -46T>C) was significantly associated with neutrophil counts (P = 7.9 x10-11). DARC -46C/C results in loss of DARC expression on erthyrocytes (Duffy-null) and resistance to Plasmodium vivax malaria, and in our cohort, only subjects with this genotype had pre-seroconversion neutrophil counts of <2500 cells/mm3. The risk of acquiring HIV infection was ~3-fold greater in those with the trait of Duffy-null–associated low neutrophil counts, compared with all other study participants. Conclusions. Pre-seroconversion neutrophil and platelet counts influence risk of HIV infection. The trait of Duffy-null–associated low neutrophil counts influences HIV susceptibility. Because of the high prevalence of this trait among persons of African ancestry, it may contribute to the dynamics of the HIV epidemic in Africa.
Effects of introducing Xpert MTB/RIF test on multi-drug resistant tuberculosis diagnosis in KwaZulu-Natal South Africa.
(BioMed Central., 2014) Dlamini-Mvelase, Nomonde R.; Werner, Lise.; Phili, Rogerio.; Cele, Lindiwe P.; Mlisana, Koleka Patience.
Abstract available in pdf.
Fluidity of HIV-1-Specific T-Cell Responses during Acute and Early Subtype C HIV-1 Infection and Associations with Early Disease Progression.
(American Society for Microbiology, 2010) Mlotshwa, Mandla.; Riou, Catherine.; Chopera, Denis Rutendo.; de Assis Rosa, Debra.; Ntale, Roman.; Treurnicht, Florette K.; Woodman, Zenda.; Werner, Lise.; van Loggerenberg, Francois.; Mlisana, Koleka Patience.; Williamson, Carolyn.; Gray, Clive M.; Abdool Karim, Salim Safurdeen.
Deciphering immune events during early stages of human immunodeficiency virus type 1 (HIV-1) infection is critical for understanding the course of disease. We characterized the hierarchy of HIV-1-specific T-cell gamma interferon (IFN-y) enzyme-linked immunospot (ELISPOT) assay responses during acute subtype C infection in 53 individuals and associated temporal patterns of responses with disease progression in the first 12 months. There was a diverse pattern of T-cell recognition across the proteome, with the recognition of Nef being immunodominant as early as 3 weeks postinfection. Over the first 6 months, we found that there was a 23% chance of an increased response to Nef for every week postinfection (P = 0.0024), followed by a nonsignificant increase to Pol (4.6%) and Gag (3.2%). Responses to Env and regulatory proteins appeared to remain stable. Three temporal patterns of HIV-specific T-cell responses could be distinguished: persistent, lost, or new. The proportion of persistent T-cell responses was significantly lower (P = 0.0037) in individuals defined as rapid progressors than in those progressing slowly and who controlled viremia. Almost 90% of lost T-cell responses were coincidental with autologous viral epitope escape. Regression analysis between the time to fixed viral escape and lost T-cell responses (r = 0.61; P = 0.019) showed a mean delay of 14 weeks after viral escape. Collectively, T-cell epitope recognition is not a static event, and temporal patterns of IFN-y-based responses exist. This is due partly to viral sequence variation but also to the recognition of invariant viral epitopes that leads to waves of persistent T-cell immunity, which appears to associate with slower disease progression in the first year of infection.
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.
Genital tenofovir concentrations correlate with protection against HIV infection in the CAPRISA 004 trial: importance of adherence for microbicide effectiveness.
(Wolters Kluwer., 2015) Kashuba, Angela D. M.; Gengiah, Tanuja Narayansamy.; Werner, Lise.; Yang, Kuo-Hsiung.; White, Nicole R.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
Genital—systemic chemokine gradients and the risk of HIV acquisition in women.
(Wolters Kluwer Health., 2017) Liebenberg, Lenine Julie.; Masson, Lindi.; Arnold, Kelly B.; McKinnon, Lyle R.; Werner, Lise.; Proctor, Elizabeth.; Archary, Derseree.; Mansoor, Leila Essop.; Lauffenburger, Douglas A.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Passmore, Jo-Ann Shelley.
Abstract available in pdf.
Health-related quality of life dynamics of HIV-positive South African women up to ART initiation : evidence from the CAPRISA 002 acute infection cohort study.
(Springer., 2014) Tomita, Andrew.; Garrett, Nigel Joel.; Werner, Lise.; Burns, Jonathan Kenneth.; Mpanza, Lindiwe.; Mlisana, Koleka Patience.; van Loggerenberg, Francois.; Abdool Karim, Salim Safurdeen.
Few studies have investigated the long-term dynamics in health-related quality of life (HRQoL) among HIV-positive persons from acute infection. From 2004, 160 women were enrolled into the CAPRISA 002 Acute Infection study at two sites in the province of KwaZulu-Natal and underwent 3–6 monthly HRQoL assessments using the functional assessment of HIV infection (FAHI) instrument. Overall and 5 sub-scale FAHI scores [physical well-being (PWB), emotional well-being (EWB), functional and global well-being (FGWB), social well-being (SWB) and cognitive functioning (CF)] were calculated up to antiretroviral therapy (ART) initiation and scores at enrollment were compared to the acute, early and established infection phases. Mixed-effects regression models adjusting for behavioral and clinical factors were applied to assess HRQoL trends and the proportion of women meeting minimally important differences was calculated. Our analyses revealed that overall/sub-scale scores improved over time, except from PWB and CF. A higher educational status, contraceptive use and a higher BMI were the strongest predictors of higher overall/sub-scale FAHI scores. CD4 count and HIV viral load were strongly associated with PWB and CF, but not overall FAHI and other sub-scales. Women newly diagnosed with acute HIV infection face profound HRQoL challenges. While early ART delivery may be important for PWB and CF, factors such as education, contraception provision and good nutritional status should be promoted to maximize HRQoL in HIV positive individuals.
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.