Browsing by Author "Mlisana, Koleka Patience."

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Adaptive changes in HIV-1 subtype C proteins during early infection are driven by changes in HLA-associated immune pressure.
(Elsevier., 2009) Treurnicht, Florette K.; Seoighe, Cathal.; Martin, Darren Patrick.; Wood, N.; Abrahams, Melissa-Rose.; de Assis Rosa, Debra.; Bredell, Helba.; Woodman, Zenda.; Hide, Winston.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Gray, Clive M.; Williamson, Carolyn.
It is unresolved whether recently transmitted human immunodeficiency viruses (HIV) have genetic features that specifically favour their transmissibility. To identify potential “transmission signatures”, we compared 20 full-length HIV-1 subtype C genomes from primary infections, with 66 sampled from ethnically and geographically matched individuals with chronic infections. Controlling for recombination and phylogenetic relatedness, we identified 39 sites at which amino acid frequency spectra differed significantly between groups. These sites were predominantly located within Env, Pol and Gag (14/39, 9/39 and 6/39 respectively) and were significantly clustered (33/39) within known immunoreactive peptides. Within 6 months of infection, we detected reversion-to-consensus mutations at 14 sites and potential CTL escape mutations at seven. Here we provide evidence that frequent reversion mutations probably allows the virus to recover replicative fitness which, together with immune escape driven by the HLA alleles of the new hosts, differentiate sequences from chronic infections from those sampled shortly after transmission.
Anaemia in acute HIV-1 Subtype C infection.
(Plos., 2007) Mlisana, Koleka Patience.; Auld, Sara C.; Grobler, Anna Christina.; van Loggerenberg, Francois.; Williamson, Carolyn.; Iriogbe, Itua.; Sobieszczyk, Magdalena E.; Abdool Karim, Salim Safurdeen.
Background: The high prevalence of anaemia and the increased morbidity and mortality associated with anaemia during AIDS has been well described yet there has been little information about anaemia and changes in haemoglobin levels during acute and early HIV-1 infection. Methods: HIV-negative women (n = 245) were enrolled into an observational cohort as part of the Centre for the AIDS Programme of Research in South Africa (CAPRISA) Acute Infection Study. Acute infection was diagnosed following a positive HIV RNA PCR in the absence of antibodies, or detection of HIV-1 antibodies within 3 months of a previously negative antibody test. Haemotologic parameters were assessed before infection and at regular intervals in the first twelve months of HIV infection. Results: Fifty-seven participants with acute HIV infection were identified at a median of 14.5 days post-infection (range 10– 81) and were enrolled in the CAPRISA Acute Infection cohort at a median of 41 days post-infection (range 15–104). Mean haemoglobin prior to HIV-1 infection was 12.7 g/dL, with a mean decline of 0.46 g/dL following infection. The prevalence of anaemia increased from 25.0% prior to HIV-1 infection to 52.6% at 3 months post-infection, 61.1% at 6 months postinfection, and 51.4% at 12 months post-infection. Conclusions: Haematologic derangements and anaemia with a trend towards iron deficiency are common with acute HIV-1 subtype C infection in this small cohort. The negative impact of anaemia concurrent with established HIV infection upon morbidity and mortality has been well documented but the prognostic potential and long-term effects of anaemia during acute HIV-1 infection remain unknown.
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 HIV-Specific and Total CD8+ T Memory Phenotypes in Subtype C HIV-1 Infection with Viral Set Point.
(The American Association of Immunologists, Inc., 2009) Burgers, Wendy A.; Riou, Catherine.; Mlotshwa, Mandla.; Maenetje, Pholo.; de Assis Rosa, Debra.; Brenchley, Jason.; Mlisana, Koleka Patience.; Douek, Daniel C.; Koup, Richard A.; Roederer, Mario.; De Bruyn, Guy.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Gray, Clive M.
Understanding early immunological events during HIV-1 infection that may set the course of disease progression is important for identifying correlates of viral control. This study explores the association of differentiation profiles of HIV-specific and total memory CD8+ T cells with viral set point. A cohort of 47 HIV-1-infected individuals, with differing viral set points at 12 mo, were recruited during acute infection. We identified that the magnitude of IFN-γ+ T cell responses at 6 mo postinfection did not associate with viral set point at 12 mo. A subset of 16 individuals was further studied to characterize CD8+ T cells for expression patterns of markers for memory differentiation, survival (CD127), senescence (CD57), and negative regulation (programmed death-1). We show that viral control and the predicted tempo of HIV disease progression in the first year of infection was associated with a synchronous differentiation of HIV-specific and total CD8+ memory subpopulations. At 6–9 mo postinfection, those with low viral set points had a significantly higher proportion of early differentiated HIV-specific and total memory CD8+ cells of a central memory (CD45RO+CD27+CCR7+) and intermediate memory (CD45RO−CD27+CCR7−) phenotype. Those with high viral set points possessed significantly larger frequencies of effector memory (CD45RO+CD27−CCR7−) cells. The proportions of memory subsets significantly correlated with CD38+CD8+ T cells. Thus, it is likely that a high Ag burden resulting in generalized immune activation may drive differentiation of HIV-specific and total memory CD8+ T cells.
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.
Beyond syndromic management: opportunities for diagnosis-based treatment of sexually transmitted infections in low- and middle-income countries.
(Public Library of Science., 2018) Garrett, Nigel Joel.; Osman, Farzana.; Maharaj, Bhavna.; Naicker, Nivashnee.; Gibbs, Andrew.; Norman, Emily.; Samsunder, Natasha.; Ngobese, Hope.; Mitchev, Nireshni.; Singh, Ravesh.; Abdool Karim, Salim Safurdeen.; Kharsany, Ayesha Bibi Mahomed.; Mlisana, Koleka Patience.; Rompalo, Anne.; Mindel, Adrian.
Abstract available in pdf.
Broad neutralization of human immunodeficiency virus type 1 mediated by plasma antibodies against the gp41 membrane proximal external region.
(American Society for Microbiology., 2009) Gray, Elin Solomonovna.; Madiga, Maphuti C.; Moore, Penelope L.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Binley, James M.; Shaw, George M.; Mascola, John R.; Morris, Lynn.
We identified three cross-neutralizing plasma samples with high-titer anti-membrane proximal external region (MPER) peptide binding antibodies from among 156 chronically human immunodeficiency virus type 1-infected individuals. In order to establish if these antibodies were directly responsible for the observed neutralization breadth, we used MPER-coated magnetic beads to deplete plasmas of these specific antibodies. Depletion of anti-MPER antibodies from BB34, CAP206, and SAC21 resulted in 77%, 68%, and 46% decreases, respectively, in the number of viruses neutralized. Antibodies eluted from the beads showed neutralization profiles similar to those of the original plasmas, with potencies comparable to those of the known anti-MPER monoclonal antibodies (MAbs), 4E10, 2F5, and Z13e1. The anti-MPER neutralizing antibodies in BB34 were present in the immunoglobulin G3 subclass-enriched fraction. Alanine scanning of the MPER showed that the antibodies from these three plasmas had specificities distinct from those of the known MAbs, requiring one to three crucial residues at positions 670, 673, and 674. These data demonstrate the existence of MPER-specific cross-neutralizing antibodies in plasma, although the ability to elicit such potent antiviral antibodies during natural infection appears to be rare. Nevertheless, the identification of three novel antibody specificities within the MPER supports its further study as a promising target for vaccine design.
The C3-V4 region is a major target of autologous neutralizing antibodies in human immunodeficiency virus type 1 subtype C Infection.
(American Society for Microbiology., 2008) Moore, Penelope L.; Gray, Elin Solomonovna.; Choge, Isaac Ang'Ang'A.; Ranchobe, Nthabeleng.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Morris, Lynn.
The early autologous neutralizing antibody response in human immunodeficiency virus type 1 (HIV-1) subtype C infections is often characterized by high titers, but the response is type specific with little to no cross-neutralizing activity. The specificities of these early neutralizing antibodies are not known; however, the type specificity suggests that they may target the variable regions of the envelope. Here, we show that cross-reactive anti-V3 antibodies developed within 3 to 12 weeks in six individuals but did not mediate autologous neutralization. Using a series of chimeric viruses, we found that antibodies directed at the V1V2, V4, and V5 regions contributed to autologous neutralization in some individuals, with V1V2 playing a more substantial role. However, these antibodies did not account for the total neutralizing capacity of these sera against the early autologous virus. Antibodies directed against the C3-V4 region were involved in autologous neutralization in all four sera studied. In two sera, transfer of the C3-V4 region rendered the chimera as sensitive to antibody neutralization as the parental virus. Although the C3 region, which contains the highly variable α2-helix was not a direct target in most cases, it contributed to the formation of neutralization epitopes as substitution of this region resulted in neutralization resistance. These data suggest that the C3 and V4 regions combine to form important structural motifs and that epitopes in this region are major targets of the early autologous neutralizing response in HIV-1 subtype C infection.
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.
Co-enrollment in multiple HIV prevention trials - experiences from the CAPRISA 004 Tenofovir gel trial.
(Elsevier., 2011) Abdool Karim, Quarraisha.; Kharsany, Ayesha Bibi Mahomed.; Naidoo, Kasavan.; Yende Zuma, Nonhlanhla.; Gengiah, Tanuja Narayansamy.; Omar, Zaheen.; Arulappan, Natasha.; Mlisana, Koleka Patience.; Luthuli, Londiwe R.; Abdool Karim, Salim Safurdeen.
Background—In settings where multiple HIV prevention trials are conducted in close proximity, trial participants may attempt to enroll in more than one trial simultaneously. Co-enrollment impacts on participant’s safety and validity of trial results. We describe our experience, remedial action taken, inter-organizational collaboration and lessons learnt following the identification of co-enrolled participants. Experiences—Between February and April 2008, we identified 185 of the 398 enrolled participants as ineligible. In violation of the study protocol exclusion criteria, there was simultaneous enrollment in another HIV prevention trial (ineligible co-enrolled, n=135), and enrollment of women who had participated in a microbicide trial within the past 12 months (ineligible not co-enrolled, n=50). Following a complete audit of all enrolled participants, ineligible participants were discontinued via study exit visits from trial follow-up. Custom-designed education program on co-enrollment impacting on participants’ safety and validity of the trial results were implemented. Shared electronic database between research units were established to enable verification of each volunteer’s trial participation and to prevent future co-enrollments. Lessons Learnt—Interviews with ineligible enrolled women revealed that high-quality care; financial incentives; altruistic motives; preference for sex with gel; wanting to increase their likelihood of receiving active gel; perceived low risk of discovery and peer pressure as the reasons for their enrolment in the CAPRISA 004 trial. Conclusion—Instituting education programs based on the reasons reported by women for seeking enrolment in more than one trial and using a shared central database system to identify co-enrollments have effectively prevented further co-enrollments.
Conserved positive selection signals in HIV-1 gp41 across multiple subtypes and difference in selection signals detectable in gp41 sequences sampled during acute and chronic HIV-1 subtype C infection.
(BioMed Central., 2008) Martin, Darren Patrick.; Treurnicht, Florette K.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Gama, Bandawe P.
Background. The high diversity of HIV variants driving the global AIDS epidemic has caused many to doubt whether an effective vaccine against the virus is possible. However, by identifying the selective forces that are driving the ongoing diversification of HIV and characterising their genetic consequences, it may be possible to design vaccines that pre-empt some of the virus’ more common evasion tactics. One component of such vaccines might be the envelope protein, gp41. Besides being targeted by both the humoral and cellular arms of the immune system this protein mediates fusion between viral and target cell membranes and is likely to be a primary determinant of HIV transmissibility. Results. Using recombination aware analysis tools we compared site specific signals of selection in gp41 sequences from different HIV-1 M subtypes and circulating recombinant forms and identified twelve sites evolving under positive selection across multiple major HIV-1 lineages. To identify evidence of selection operating during transmission our analysis included two matched datasets sampled from patients with acute or chronic subtype C infections. We identified six gp41 sites apparently evolving under different selection pressures during acute and chronic HIV-1 infections. These sites mostly fell within functional gp41 domains, with one site located within the epitope recognised by the broadly neutralizing antibody, 4E10. Conclusions. Whereas these six sites are potentially determinants of fitness and are therefore good candidate targets for subtype-C specific vaccines, the twelve sites evolving under diversifying selection across multiple subtypes might make good candidate targets for broadly protective vaccines.
Continued Follow-Up of Phambili Phase 2b Randomized HIV-1 Vaccine Trial Participants Supports Increased HIV-1 Acquisition among Vaccinated Men.
(Public Library of Science., 2015) Moodie, Zoe.; Metch, Barbara.; Bekker, Linda-Gail.; Churchyard, Gavin J.; Nchabeleng, Maphoshane.; Mlisana, Koleka Patience.; Laher, Faatima.; Roux, Surita.; Mngadi, Kathryn Therese.; Innes, Craig.; Mathebula, Matsontso.; Allen, Mary.; Bentley, Carter.; Gilbert, Peter B.; Robertson, Michael.; Kublin, James.; Corey, Lawrence.; Gray, Glenda Elizabeth.
Abstract available in pdf.
Decreased incidence of dual infections in South African subtype C-infected women compared to a cohort ten years earlier.
(Mary Ann Liebert., 2011) Woodman, Zenda.; Mlisana, Koleka Patience.; Treurnicht, Florette K.; Abrahams, Melissa-Rose.; Thebus, Ruwayhida.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.
Previously, we determined the incidence of dual infections in a South African cohort and its association with higher viral setpoint. Ten years later, we compare the incidence and impact of dual infections at transmission on viral setpoint in a geographically similar cohort (n=46) making use of both the heteroduplex mobility assay (HMA) and the more recent single genome amplification (SGA) approach. HIV incidence was lower in this cohort (7% compared to 18%), and we find a similar reduction in the number of dual infections (9% compared to 19%). Unlike the previous study, there was no association between either dual infection (n=4) or multivariant transmission (n=7) and disease progression. This study emphasized the importance of monitoring changes in the HIV epidemic as it may have important ramifications on our understanding of the natural history of disease.
Diagnostic accuracy of the Xpert CT/NG and OSOM Trichomonas Rapid assays for point-of-care STI testing among young women in South Africa: a cross-sectional study.
(BMJ Publishing Group., 2019) Osman, Farzana.; Naidoo, Jessica.; Dorward, Jienchi.; Singh, Ravesh.; Ngobese, Hope.; Rompalo, Anne.; Mindel, Adrian.; Garrett, Nigel Joel.; Mlisana, Koleka Patience.
Abstract available in PDF.
Differential impact of magnitude, polyfunctional capacity, and specificity of HIV-specific CD8+ T cell responses on HIV set point.
(American Society for Microbiology., 2014) Riou, Catherine.; Burgers, Wendy A.; Mlisana, Koleka Patience.; Roederer, Mario.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Gray, Clive M.; Koup, Richard A.
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.
Does participation in an HIV vaccine efficacy trial affect risk behaviour in South Africa?
(Elsevier., 2012) Gray, Glenda Elizabeth.; Metch, Barbara.; Churchyard, Gavin J.; Mlisana, Koleka Patience.; Nchabeleng, Maphoshane.; Allen, Mary.; Moodie, Zoe.; Kublin, James.; Bekker, Linda-Gail.
Background: Increased sexual risk behaviour in participants enrolled in HIV prevention trials has been a concern. The HVTN 503/Phambili study, a phase 2B study of the Merck Ad-5 multiclade HIV vaccine in South Africa, suspended enrollment and vaccinations following the results of the Step study. Participants were notified of their treatment allocation and continue to be followed. We investigated changes in risk behaviour over time and assessed the impact of study unblinding. Methods: 801 participants were enrolled. Risk behaviours were assessed with an interviewer administered questionnaire at 6-month intervals. We assessed change from enrolment to the first 6-month assessment pre-unblinding and between enrolment and at least 6 months post-unblinding on all participants with comparable data. A one-time unblinding risk perception questionnaire was administered post-unblinding. Results: A decrease in participants reporting unprotected sex was observed in both measured time periods for men and women, with no differences by treatment arm. At 6 months (pre-unblinding), 29.6% of men and 35.8% of women reported changing from unprotected to protected sex (p < 0.0001 for each). Men (22%) were more likely than women (14%) to report behaviour change after unblinding (p = 0.009). Post-enrolment, 142 (45%) of 313 previously uncircumcised men underwent medical circumcision. 663 participants completed the unblinding questionnaire. More vaccine (24.6%) as compared to placebo recipients (12.0%) agreed that they were more likely to get HIV than most people (p < 0.0001), and attributed this to receiving the vaccine. Conclusion: We did not find evidence of risk compensation during this clinical trial. Some risk behaviour reductions including male circumcision were noted irrespective of treatment allocation.
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.
Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women.
(American Association for the Advancement of Science., 2010) Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Fröhlich, Janet Ann.; Grobler, Anna Christina.; Baxter, Cheryl.; Mansoor, Leila Essop.; Kharsany, Ayesha Bibi Mahomed.; Sibeko, Sengeziwe.; Mlisana, Koleka Patience.; Omar, Zaheen.; Gengiah, Tanuja Narayansamy.; Maarschalk, Silvia.; Arulappan, Natasha.; Mlotshwa, Mukelisiwe.; Morris, Lynn.; Taylor, Douglas.
The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.