Browsing by Author "Morris, Lynn"
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- ItemOpen AccessEstablishing a cohort at high risk of HIV infection in South Africa: challenges and experiences of the CAPRISA 002 acute infection study(Public Library of Science, 2008) van Loggerenberg, Francois; Mlisana, Koleka; Williamson, Carolyn; Auld, Sara C; Morris, Lynn; Gray, Clive M; Karim, Quarraisha Abdool; Grobler, Anneke; Barnabas, Nomampondo; Iriogbe, ItuaObjectives To describe the baseline demographic data, clinical characteristics and HIV-incidence rates of a cohort at high risk for HIV infection in South Africa as well as the challenges experienced in establishing and maintaining the cohort. Methodology/Principle FINDINGS: Between August 2004 and May 2005 a cohort of HIV-uninfected women was established for the CAPRISA 002 Acute Infection Study, a natural history study of HIV-1 subtype C infection. Volunteers were identified through peer-outreach. The cohort was followed monthly to determine HIV infection rates and clinical presentation of early HIV infection. Risk reduction counselling and male and female condoms were provided. After screening 775 individuals, a cohort of 245 uninfected high-risk women was established. HIV-prevalence at screening was 59.6% (95% CI: 55.9% to 62.8%) posing a challenge in accruing HIV-uninfected women. The majority of women (78.8%) were self-identified as sex-workers with a median of 2 clients per day. Most women (95%) reported more than one casual sexual partner in the previous 3 months (excluding clients) and 58.8% reported condom use in their last sexual encounter. Based on laboratory testing, 62.0% had a sexually transmitted infection at baseline. During 390 person-years of follow-up, 28 infections occurred yielding seroincidence rate of 7.2 (95% CI: 4.5 to 9.8) per 100 person-years. Despite the high mobility of this sex worker cohort retention rate after 2 years was 86.1%. High co-morbidity created challenges for ancillary care provision, both in terms of human and financial resources. Conclusions/Significance Challenges experienced were high baseline HIV-prevalence, lower than anticipated HIV-incidence and difficulties retaining participants. Despite challenges, we have successfully accrued this cohort of HIV-uninfected women with favourable retention, enabling us to study the natural history of HIV-1 during acute HIV-infection. Our experiences provide lessons for others establishing similar cohorts, which will be key for advancing the vaccine and prevention research agenda in resource-constrained settings.
- ItemOpen AccessFeatures of recently transmitted HIV-1 clade C viruses that impact antibody recognition: implications for active and passive immunization(Public Library of Science, 2016) Rademeyer, Cecilia; Korber, Bette; Seaman, Michael S; Giorgi, Elena E; Thebus, Ruwayhida; Robles, Alexander; Sheward, Daniel J; Wagh, Kshitij; Garrity, Jetta; Carey, Brittany R; Gao, Hongmei; Greene, Kelli M; Tang, Haili; Bandawe, Gama P; Marais, Jinny C; Diphoko, Thabo E; Hraber, Peter; Tumba, Nancy; Moore, Penny L; Gray, Glenda E; Kublin, James; McElrath, M Juliana; Vermeulen, Marion; Middelkoop, Keren; Bekker, Linda-Gail; Hoelscher, Michael; Maboko, Leonard; Makhema, Joseph; Robb, Merlin L; Karim, Salim Abdool; Karim, Quarraisha Abdool; Kim, Jerome H; Hahn, Beatrice H; Gao, Feng; Swanstrom, Ronald; Morris, Lynn; Montefiori, David C; Williamson, CarolynAuthor Summary: Vaccine and passive immunization prophylactic trials that rely on antibody-mediated protection are planned for HIV-1 clade C epidemic regions of southern Africa, which have amongst the highest HIV-1 incidences globally. This includes a phase 2b trial of passively administered monoclonal antibody, VRC01; as well as a phase 3 trial using the clade C modified version of the partially efficacious RV144 vaccine. The extraordinary diversity of HIV-1 poses a major obstacle to these interventions, and our study aimed to determine the implications of viral diversity on antibody recognition. Investigations using our panel of very early viruses augment current knowledge of vulnerable targets on transmitted viruses for vaccine design and passive immunization studies. Evidence of antigenic drift with viruses becoming more resistant over time suggests that these prevention modalities will need to be updated over time and that combinations of antibodies will be necessary to achieve coverage in passive immunization studies. We further show that it may be more difficult to obtain protection in the genetically diverse clade C epidemic compared to RV144 where the epidemic is less diverse, although it should be noted that the correlates of infection risk are yet to be defined in the clade C setting.
- ItemOpen AccessHIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-gp120 aptamer(Public Library of Science, 2014) de Campos, Walter R Lopes; Chirwa, Nthato; London, Grace; Rotherham, Lia S; Morris, Lynn; Mayosi, Bongani M; Khati, MakobetsaHIV-associated cardiomyopathy (HIVCM) is of clinical concern in developing countries because of a high HIV-1 prevalence, especially subtype C, and limited access to highly active antiretroviral therapy (HAART). For these reasons, we investigated the direct and indirect effects of HIV-1 subtype C infection of cultured human cardiomyocytes and the mechanisms leading to cardiomyocytes damage; as well as a way to mitigate the damage. We evaluated a novel approach to mitigate HIVCM using a previously reported gp120 binding and HIV-1 neutralizing aptamer called UCLA1. We established a cell-based model of HIVCM by infecting human cardiomyocytes with cell-free HIV-1 or co-culturing human cardiomyocytes with HIV-infected monocyte derived macrophages (MDM). We discovered that HIV-1 subtype C unproductively (i.e. its life cycle is arrested after reverse transcription) infects cardiomyocytes. Furthermore, we found that HIV-1 initiates apoptosis of cardiomyocytes through caspase-9 activation, preferentially via the intrinsic or mitochondrial initiated pathway. CXCR4 receptor-using viruses were stronger inducers of apoptosis than CCR5 utilizing variants. Importantly, we discovered that HIV-1 induced apoptosis of cardiomyocytes was mitigated by UCLA1. However, UCLA1 had no protective effective on cardiomyocytes when apoptosis was triggered by HIV-infected MDM. When HIV-1 was treated with UCLA1 prior to infection of MDM, it failed to induce apoptosis of cardiomyocytes. These data suggest that HIV-1 causes a mitochondrial initiated apoptotic cascade, which signal through caspase-9, whereas HIV-1 infected MDM causes apoptosis predominantly via the death-receptor pathway, mediated by caspase-8. Furthermore the data suggest that UCLA1 protects cardiomyocytes from caspase-mediated apoptosis, directly by binding to HIV-1 and indirectly by preventing infection of MDM.
- ItemOpen AccessOptimal combinations of broadly neutralizing antibodies for prevention and treatment of HIV-1 Clade C infection(Public Library of Science, 2016) Wagh, Kshitij; Bhattacharya, Tanmoy; Williamson, Carolyn; Robles, Alex; Bayne, Madeleine; Garrity, Jetta; Rist, Michael; Rademeyer, Cecilia; Yoon, Hyejin; Lapedes, Alan; Gao, Hongmei; Greene, Kelli; Louder, Mark K; Kong, Rui; Karim, Salim Abdool; Burton, Dennis R; Barouch, Dan H; Nussenzweig, Michel C; Mascola, John R; Morris, Lynn; Montefiori, David C; Korber, Bette; Seaman, Michael SAuthor Summary In recent years, a new generation of monoclonal antibodies has been isolated from HIV-1 infected individuals that exhibit broad and potent neutralizing activity when tested against diverse strains of virus. There is a high level of interest in the field in determining if these antibodies can be used to prevent or treat HIV-1 infection. Because HIV-1 is adept at escaping from immune recognition, it is generally thought that combinations of multiple antibodies targeting different sites will be required for efficacy, much the same as seen for conventional antiretroviral drugs. How many and which antibodies to include in such combinations is not known. In this study, a new mathematical model was developed and used to accurately predict various measures of neutralizing activity for all possible combinations having a total of 2, 3, or 4 of the most promising antibodies. Through a systematic and comprehensive comparison, we identified optimal combinations of antibodies that best complement one another for enhanced anti-viral activity, and therefore may be most effective for the prevention or treatment of HIV-1 infection. These results provide important parameters that inform the selection of antibodies to develop for clinical use.
- ItemOpen AccessPrevalence of HIV-1 drug resistance amongst newly diagnosed HIV-infected infants age 4–8 weeks, enrolled in three nationally representative PMTCT effectiveness surveys, South Africa: 2010, 2011–12 and 2012–13(2019-09-16) Hunt, Gillian M; Ledwaba, Johanna; Salimo, Anna; Kalimashe, Monalisa; Dinh, Thu-Ha; Jackson, Debra; Sherman, Gayle; Puren, Adrian; Ngandu, Nobubelo K; Lombard, Carl; Morris, Lynn; Goga, AmeenaAbstract Background South Africa (SA) has expanded efforts to reduce mother-to-child transmission of HIV (MTCT) to less than 2% at six weeks after birth and to less than 5% at 18 months postpartum by 2016. Despite improved antiretroviral regimens and coverage between 2001 and 2016, there is little data on infant HIV drug resistance. This paper tracks the prevalence of HIV drug resistance patterns amongst HIV infected infants from three nationally representative studies that assessed the effectiveness of national programs to prevent MTCT (PMTCT). The first study was conducted in 2010 (under the dual therapy PMTCT policy), the second from 2011 to 12 (PMTCT Option A policy) and the third from 2012 to 13 (PMTCT Option A policy). From 2010 to 2013, infant non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure increased from single dose to daily throughout breastfeeding; maternal nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI exposure increased with initiation of NNRTI-and NRTI- containing triple antiretroviral therapy (ART) earlier in gestation and at higher CD4 cell counts. Methods Three nationally representative surveys were conducted in 2010, 2011–12 and 2012–13. During the surveys, mothers with known, unknown, or no exposure to antiretrovirals for PMTCT and their infants were included, and MTCT was measured. For this paper, infant dried blood spots (iDBS) from HIV PCR positive infants aged 4–8 weeks, with consent for additional iDBS testing, were analysed for HIV drug resistance at the National Institute of Communicable Diseases (NICD), SA, using an in-house assay validated by the Centers for Disease Control and Prevention (CDC). Total viral nucleic acid was extracted from 2 spots and amplified by nested PCR to generate a ~ 1 kb amplicon that was sequenced using Sanger sequencing technologies. Sequence assembly and editing was performed using RECall v3. Results Overall, HIV-1 drug resistance was detected in 51% (95% Confidence interval (CI) [45–58%]) of HIV PCR positive infants, 37% (95% CI [28–47%]) in 2010, 64% (95% CI [53–74%]) in 2011 and 63% (95% CI [47–77%]) in 2012 (p < 0.0001), particularly to the NNRTI drug class. Pooled analyses across all three surveys demonstrated that infants whose mothers received ART showed the highest prevalence of resistance (74%); 26% (21/82) of HIV PCR positive infants with no or undocumented antiretroviral drug (ARV) exposure harboured NNRTI resistance. Conclusions These data demonstrate increasing NNRTI resistance amongst newly-diagnosed infants in a high HIV prevalence setting where maternal ART coverage increased across the years, starting earlier in gestation and at higher CD4 cell counts. This is worrying as lifelong maternal ART coverage for HIV positive pregnant and lactating women is increasing. Also of concern is that resistant virus was detected in HIV positive infants whose mothers were not exposed to ARVs, raising questions about circulating resistant virus. Numbers in this group were too small to assess trends over the three years.
- ItemOpen AccessSequential Immunization with gp140 boosts immune responses primed by modified vaccinia Ankara or DNA in HIV-uninfected South African participants(Public Library of Science, 2016) Churchyard, Gavin; Mlisana, Koleka; Karuna, Shelly; Williamson, Anna-Lise; Williamson, Carolyn; Morris, Lynn; Tomaras, Georgia D; De Rosa, Stephen C; Gilbert, Peter B; Gu, Niya; Yu, Chenchen; Mkhize, Nonhlanhla N; Hermanus, Tandile; Allen, Mary; Pensiero, Michael; Barnett, Susan W; Gray, Glenda; Bekker, Linda-Gail; Montefiori, David C; Kublin, James; Corey, LawrenceBACKGROUND: The safety and immunogenicity of SAAVI DNA-C2 (4 mg IM), SAAVI MVA-C (2.9 x 10 9 pfu IM) and Novartis V2-deleted subtype C gp140 (100 mcg) with MF59 adjuvant in various vaccination regimens was evaluated in HIV-uninfected adults in South Africa. METHODS: Participants at three South African sites were randomized (1:1:1:1) to one of four vaccine regimens: MVA prime, sequential gp140 protein boost (M/M/P/P); concurrent MVA/gp140 (MP/MP); DNA prime, sequential MVA boost (D/D/M/M); DNA prime, concurrent MVA/gp140 boost (D/D/MP/MP) or placebo. Peak HIV specific humoral and cellular responses were measured. RESULTS: 184 participants were enrolled: 52% were female, all were Black/African, median age was 23 years (range, 18-42 years) and 79% completed all vaccinations. 159 participants reported at least one adverse event, 92.5% were mild or moderate. Five, unrelated, serious adverse events were reported. The M/M/P/P and D/D/MP/MP regimens induced the strongest peak neutralizing and binding antibody responses and the greatest CD4+ T-cell responses to Env. All peak neutralizing and binding antibody responses decayed with time. The MVA, but not DNA, prime contributed to the humoral and cellular immune responses. The D/D/M/M regimen was poorly immunogenic overall but did induce modest CD4+ T-cell responses to Gag and Pol. CD8+ T-cell responses to any antigen were low for all regimens. CONCLUSIONS: The SAAVI DNA-C2, SAAVI MVA-C and Novartis gp140 with MF59 adjuvant in various combinations were safe and induced neutralizing and binding antibodies and cellular immune responses. Sequential immunization with gp140 boosted immune responses primed by MVA or DNA. The best overall immune responses were seen with the M/M/P/P regimen. Trial Registration ClinicalTrials.gov NCT01418235
- ItemOpen AccessStudies on multiply exposed but persistently HIV-1 seronegative sex workers from KwaZulu/Natal, South Africa(2002) Malaza, Abraham Lucky; Williamson, Carolyn; Morris, LynnThe overall aim of this study was to determine whether host genetic factors are associated with resistance to HIV-1 infection in a group of highly exposed persistently seronegative sex workers from KwaZulu/Natal, South Africa. A cohort of 17 African highly exposed but persistently seronegative (HEPS) commercial sex workers (CSW) were identified who had been in sex work for more than four years (range between 4-26 years). The women had been followed monthly for at least four years as part of HIV-1 prevention programmes (Ramjee, et al., 1998). The overall aim of this study was to identify the frequency of polymorphisms and mutations in chemokine genes, chemokine receptors and chemokine receptor promoter region which ma y be associated with HIV-1 resistance and prolonged disease progression. Secondly, to determine if the chemokine receptors on CD4 T-cells are sufficiently expressed and functional to enable infection. This information will shed light on correlates of immunity as influenced by these polymorphisms and this knowledge will help in the bigger objective of determining factors influencing disease progression as well as the development of an effective HIV-1 vaccine in South Africa.
- ItemOpen AccessUnderstanding the interplay between HIV-1 diversity, humoral immune responses and viral fitness(2014) Bandawe, Gama Petulo; Williamson, Carolyn; Morris, LynnHIV-1 antibody dependent cell cytotoxicity (ADCC) and neutralizing antibody (nAb) responses are both thought to be important responses to elicit through vaccination. This thesis characterises neutralizing response in two cohorts in Africa, and in a detailed study of one individual, elucidates the interplay between ADCC and nAb responses in early infection, and the impact of humoral escape on viral fitness. It remains an open question whether different geographically distinct population groups vary in their neutralization responses to HIV-1. We compared neutralizing antibody responses in two African cohorts and found 35% of the Tanzanians in the HIV Superinfection Study (HISIS) cohort had neutralization breath (neutralized >50% of panel viruses) at two years post infection compared to only 9% in the Centres for AIDS Program of Research in South Africa (CAPRISA) cohort. Cumulative viral loads between 3 and 12 months post infection were strongly associated with neutralization breadth (p<0.001), and were higher in the Tanzanian cohort (p=0.046). No association was found between breadth and dual infection, subtype or features of the envelope. One elite neutralizer was identified in the HISIS cohort with responses targeting the CD4 binding site. While neutralizing antibodies are considered central for protection from infection, ADCC activity correlated with reduced risk of HIV-1 acquisition in the RV144 trial. There is limited understanding of the overlapping ADCC and neutralizing antibody functions in early infection. We investigated the kinetics and targets of both responses in one individual from CAPRISA. ADCC responses were detected 4 weeks post infection, with nAbs responses emerging at 7 weeks post infection. We identified five neutralization escape patterns in the V4 region of the envelope by 11 weeks post-infection. Four of these also conferred ADCC escape; however the fifth neutralization escape variant resulted in increased sensitivity to ADCC. This variant was eliminated in vivo by 29 weeks post infection. Finally, we studied the effect of neutralizing and ADCC antibody escape mutations on the virus' ability to mediate fusion, infectivity and replicative fitness. Envelopes bearing immune escape adaptations had lower cell-cell fusion ability compared to the T/F virus. The mutations also resulted in reduced infectivity of infectious molecular clone virus stocks. However, only the largest deletion in the V4 caused reduced growth in peripheral blood mononuclear cells (PBMC). In conclusion, the study finds that neutralizing antibody responses are influenced by community viral loads. The study defined the first ADCC epitope reported in the V4 region, and describes overlapping targets for ADCC and neutralizing antibodies. Where neutralization escape resulted in increased ADCC sensitivity, this was a dead end escape pathway. Finally we find that early V4 escape from both ADCC and nAb responses had a fitness impact on the virus. We thus demonstrate a mechanism through which ADCC and neutralizing antibodies can synergistically influence viral evolution and potentially produce a protective immune response.
- ItemOpen AccessViral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes(Public Library of Science, 2013) Wibmer, Constantinos Kurt; Bhiman, Jinal N; Gray, Elin S; Tumba, Nancy; Karim, Salim S Abdool; Williamson, Carolyn; Morris, Lynn; Moore, Penny LIdentifying 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.