25 results on '"Chopera D"'
Search Results
2. Killer-cell Immunoglobulin-like Receptor (KIR) gene profiles modify HIV disease course, not HIV acquisition in South African women
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Naranbhai, V., de Assis Rosa, D., Werner, L., Moodley, R., Hong, H., Kharsany, A., Mlisana, K., Sibeko, S., Garrett, N., Chopera, D., Carr, W. H., Abdool Karim, Q., Hill, A. V. S., Abdool Karim, S. S., Altfeld, M., Gray, C. M., Ndung’u, T., Division of Immunology, and Faculty of Health Sciences
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Disease progression ,HIV ,HIV Infections ,chemical and pharmacologic phenomena ,HLA-C Antigens ,Viral Load ,KIR ,HLA ,Cohort Studies ,Killer Cells, Natural ,South Africa ,Infectious Diseases ,Acquisition ,Haplotypes ,Receptors, KIR ,Viral control ,Humans ,Female ,Prospective Studies ,Alleles ,Research Article - Abstract
Background Killer-cell Immunoglobulin-like Receptors(KIR) interact with Human Leukocyte Antigen(HLA) to modify natural killer- and T-cell function. KIR are implicated in HIV acquisition by small studies that have not been widely replicated. A role for KIR in HIV disease progression is more widely replicated and supported by functional studies. Methods To assess the role of KIR and KIR ligands in HIV acquisition and disease course, we studied at-risk women in South Africa between 2004–2010. Logistic regression was used for nested case–control analysis of 154 women who acquired vs. 155 who did not acquire HIV, despite high exposure. Linear mixed-effects models were used for cohort analysis of 139 women followed prospectively for a median of 54 months (IQR 31–69) until 2014. Results Neither KIR repertoires nor HLA alleles were associated with HIV acquisition. However, KIR haplotype BB was associated with lower viral loads (−0.44log10 copies/ml;SE = 0.18;p = 0.03) and higher CD4+ T-cell counts(+80 cells/μl;SE = 42;p = 0.04). This was largely explained by the protective effect of KIR2DL2/KIR2DS2 on the B haplotype and reciprocal detrimental effect of KIR2DL3 on the A haplotype. Conclusions Although neither KIR nor HLA appear to have a role in HIV acquisition, our data are consistent with involvement of KIR2DL2 in HIV control. Additional studies to replicate these findings are indicated. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-1361-1) contains supplementary material, which is available to authorized users.
- Published
- 2016
3. Killer-cell Immunoglobulin-like Receptor (KIR) gene profiles modify HIV disease course, not HIV acquisition in South African women
- Author
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Naranbhai, V., primary, de Assis Rosa, D., additional, Werner, L., additional, Moodley, R., additional, Hong, H., additional, Kharsany, A., additional, Mlisana, K., additional, Sibeko, S., additional, Garrett, N., additional, Chopera, D., additional, Carr, W. H., additional, Abdool Karim, Q., additional, Hill, A. V. S., additional, Abdool Karim, S. S., additional, Altfeld, M., additional, Gray, C. M., additional, and Ndung’u, T., additional
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- 2015
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4. Limited evidence for alterations in Gag-mediated HIV replication capacity over the course of the North American epidemic (1979-present)
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Cotton, L., Chopera, D., Penney, K., Carlson, J., Martin, E., Le, A., Kuang, T., Walker, B., Fuchs, J., Buchbinder, S., Wagner, T., John, M., Mallal, S., Koblin, B., Mayer, K., Poon, A., Brockman, M., Brumme, Z., Cotton, L., Chopera, D., Penney, K., Carlson, J., Martin, E., Le, A., Kuang, T., Walker, B., Fuchs, J., Buchbinder, S., Wagner, T., John, M., Mallal, S., Koblin, B., Mayer, K., Poon, A., Brockman, M., and Brumme, Z.
- Abstract
The extent to which HIV replication capacity (RC) has changed over the epidemic’s course, and the influence of HLA-associated immune pressure as its driving force remains unknown. We performed a comparative study of immune escape and RC in historic (1979-1989) and modern Gag subtype B sequences from North America.
- Published
- 2012
5. Temporal Association of HLA-B*81:01- and HLA-B*39:10-Mediated HIV-1 p24 Sequence Evolution with Disease Progression.
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Ntale, R. S., Chopera, D. R., Ngandu, N. K., de Rosa, D. Assis, Zembe, L., Gamieldien, H., Mlotshwa, M., Werner, L., Woodman, Z., Mlisana, K., Karim, S. Abdool, Gray, C. M., and Williamson, C.
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HLA histocompatibility antigens , *HIV infections , *DISEASE progression , *GENE frequency , *CYTOTOXIC T cells , *GENETIC mutation - Abstract
HLA-B*81:01 and HLA-B*39:10 alleles have been associated with viremic control in HIV-1 subtype C infection. Both alleles re-strict the TL9 epitope in p24 Gag, and cytotoxic-T-lymphocyte (CTL)-mediated escape mutations in this epitope have been asso-ciated with an in vitro fitness cost to the virus. We investigated the timing and impact of mutations in the TL9 epitope on disease progression in five B*81:01- and two B*39:10-positive subtype C-infected individuals. Whereas both B*39:10 participants sam-pled at 2 months postinfection had viruses with mutations in the TL9 epitope, in three of the five (3/5) B*81:01 participants, TL9 escape mutations were only detected 10 months after infection, taking an additional 10 to 15 months to reach fixation. In the two remaining B*81:01 individuals, one carried a TL9 escape variant at 2 weeks postinfection, whereas no escape mutations were de-tected in the virus from the other participant for up to 33 months postinfection, despite CTL targeting of the epitope. In all par-ticipants, escape mutations in TL9 were linked to coevolving residues in the region of Gag known to be associated with host tro-pism. Late escape in TL9, together with coevolution of putative compensatory mutations, coincided with a spontaneous increase in viral loads in two individuals who were otherwise controlling the infection. These results provide in vivo evidence of the detri-mental impact of B*81:01 -mediated viral evolution, in a single Gag p24 epitope, on the control of viremia. [ABSTRACT FROM AUTHOR]
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- 2012
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6. Beneficial HLA-mediated viral polymorphisms on the transmitted virus additively influence disease progression in HIV-1, subtype C infection
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Ntale RS, Chopera DR, Ngandu NK, Abrahams M, Debra A, Mlotswa M, Werner L, Woodman Z, Mlisana K, Karim S, Gray CM, and Williamson C
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2012
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7. Beneficial HLA-mediated viral polymorphisms on the transmitted virus additively influence disease progression in HIV-1, subtype C infection
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Ntale, R S, Chopera, D R, Ngandu, N K, Abrahams, M, Debra, A, Mlotswa, M, Werner, L, Woodman, Z, Mlisana, K, Karim, S, Gray, CM, Williamson, C, CAPRISA 002 AI Study Team, Institute of Infectious Disease and Molecular Medicine, and Faculty of Health Sciences
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lcsh:Immunologic diseases. Allergy ,Mutation ,biology ,business.industry ,viruses ,Clone (cell biology) ,Human leukocyte antigen ,medicine.disease_cause ,Bioinformatics ,Virology ,Peripheral blood mononuclear cell ,Beneficial HLA-mediated viral polymorphisms ,Virus ,Infectious Diseases ,Cohort ,biology.protein ,Oral Presentation ,Medicine ,Allele ,Antibody ,business ,lcsh:RC581-607 - Abstract
Methods Gag was sequenced from 56 participants with acute HIV infection from the CAPRISA 002 cohort. For the newly identified mutation, replication fitness of viruses in PBMCs was compared in a subtype C infectious molecular clone. Disease progression was compared in participants infected with viruses carrying polymorphisms associated with beneficial HLAB*57/58:01 and B7 supertype (B*39:10/81:01) allelic selective pressure in HLA mismatched participants.
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8. Developing a diversity, equity and inclusion compass to guide scientific capacity strengthening efforts in Africa.
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Kasprowicz VO, Waddilove KD, Chopera D, Khumalo S, Harilall S, Wong EB, Karita E, Sanders EJ, Kilembe W, Gaseitsiwe S, and Ndung'u T
- Abstract
Diversity, equity and inclusion (DEI) in science is vital to improve the scientific process and ensure societal uptake and application of scientific results. DEI challenges include a full spectrum of issues from the lack of, and promotion of, women in science, to the numerous barriers in place that limit representation of African scientists in global scientific efforts. DEI principles in African science remain relatively underdeveloped, with limited engagement and discussion among all stakeholders to ensure that initiatives are relevant to local environments. The Sub-Saharan African Network for TB/HIV research Excellence (SANTHE) is a network of African-led research in HIV, tuberculosis (TB), associated co-morbidities, and emerging pathogens, now based in eight African countries. Our aim, as a scientific capacity strengthening network, was to collaboratively produce a set of DEI guidelines and to represent them visually as a DEI compass. We implemented a consortium-wide survey, focus group discussions and a workshop where we were able to identify the key DEI challenges as viewed by scientists and support staff within the SANTHE network. Three thematic areas were identified: 1. Conquering Biases, 2. Respecting the Needs of a Diverse Workforce (including mental health challenges, physical disability, career stability issues, demands of parenthood, and female-specific challenges), and 3. Promotion of African Science. From this we constructed a compass that included proposed steps to start addressing these issues. The use of the compass metaphor allows 're-adjustment/re-positioning' making this a dynamic output. The compass can become a tool to establish an institution's DEI priorities and then to progress towards them., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kasprowicz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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9. How to improve research capacity strengthening efforts: learning from the monitoring and evaluation of four research consortia in Africa.
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Kasprowicz VO, Jeffery C, Mbuvi D, Bukirwa V, Ouattara K, Kirimi F, Heitz-Tokpa K, Gorrethy M, Chopera D, Nakanjako D, Bonfoh B, Elliott A, Kinyanjui S, Bates I, and Ndung'u T
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- Humans, Africa, Data Accuracy, Capacity Building, Investments
- Abstract
Recent efforts to shift the control and leadership of health research on African issues to Africa have led to increased investments for scientific research capacity strengthening (RCS) on the continent and a greater demand for accountability, value for money and demonstration of return on investment. There is limited literature on monitoring and evaluation (M&E) of RCS systems and there is a clear need to further explore whether the M&E frameworks and approaches that are currently used are fit for purpose. The M&E approaches taken by four African RCS consortia funded under the Developing Excellence in Leadership, Training and Science in Africa (DELTAS) I initiative were assessed using several methods, including a framework comparison of the M&E approaches, semi-structured interviews and facilitated discussion sessions. The findings revealed a wide range in the number of indicators used in the M&E plans of individual consortium, which were uniformly quantitative and at the output and outcome levels. Consortia revealed that additional information could have been captured to better evaluate the success of activities and measure the ripple effects of their efforts. While it is beneficial for RCS consortia to develop and implement their own M&E plans, this could be strengthened by routine engagement with funders/programme managers to further align efforts. It is also important for M&E plans to consider qualitative data capture for assessment of RCS efforts. Efforts could be further enhanced by supporting platforms for cross-consortia sharing, particularly when trying to assess more complex effects. Consortia should make sure that processes for developmental evaluation, and capturing and using the associated learning, are in place. Sharing the learning associated with M&E of RCS efforts is vital to improve future efforts. Investing and improving this aspect of RCS will help ensure tracking of progress and impact of future efforts, and ensure accountability and the return on investment. The findings are also likely applicable well beyond health research., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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10. crAssphage genomes identified in fecal samples of an adult and infants with evidence of positive genomic selective pressure within tail protein genes.
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Brown BP, Chopera D, Havyarimana E, Wendoh J, Jaumdally S, Nyangahu DD, Gray CM, Martin DP, Varsani A, and Jaspan HB
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- Adult, Bacteriophages classification, Bacteriophages genetics, Caudovirales classification, Caudovirales genetics, Female, Gastrointestinal Microbiome, Genomics, Humans, Infant, Infant, Newborn, Male, Phylogeny, Young Adult, Bacteriophages isolation & purification, Caudovirales isolation & purification, Feces virology, Genome, Viral, Viral Tail Proteins genetics
- Abstract
crAssphages are a broad group of diverse bacteriophages in the order Caudovirales that have been found to be highly abundant in the human gastrointestinal tract. Despite their high prevalence, we have an incomplete understanding of how crAssphages shape and respond to ecological and evolutionary dynamics in the gut. Here, we report genomes of crAssphages from feces of one South African woman and three infants. Across the complete genome sequences of the South African crAssphages described here, we identify particularly elevated positive selection in RNA polymerase and phage tail protein encoding genes, contrasted against purifying selection, genome-wide. We further validate these findings against a crAssphage genome from previous studies. Together, our results suggest hotspots of selection within crAssphage RNA polymerase and phage tail protein encoding genes are potentially mediated by interactions between crAssphages and their bacterial partners., (Copyright © 2020 Elsevier B.V. All rights reserved.)
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- 2021
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11. African-led health research and capacity building- is it working?
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Kasprowicz VO, Chopera D, Waddilove KD, Brockman MA, Gilmour J, Hunter E, Kilembe W, Karita E, Gaseitsiwe S, Sanders EJ, and Ndung'u T
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- Adult, Africa South of the Sahara, Female, Humans, Male, Middle Aged, Research Design, Biomedical Research organization & administration, Biomedical Research statistics & numerical data, Capacity Building, Health Information Exchange, Intersectoral Collaboration, Research Personnel education
- Abstract
Background: Africa bears a disproportionately high burden of globally significant disease but has lagged in knowledge production to address its health challenges. In this contribution, we discuss the challenges and approaches to health research capacity strengthening in sub-Saharan Africa and propose that the recent shift to an African-led approach is the most optimal., Methods and Findings: We introduce several capacity building approaches and recent achievements, explore why African-led research on the continent is a potentially paradigm-shifting and innovative approach, and discuss the advantages and challenges thereof. We reflect on the approaches used by the African Academy of Sciences (AAS)-funded Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) consortium as an example of an effective African-led science and capacity building programme. We recommend the following as crucial components of future efforts: 1. Directly empowering African-based researchers, 2. Offering quality training and career development opportunities to large numbers of junior African scientists and support staff, and 3. Effective information exchange and collaboration. Furthermore, we argue that long-term investment from international donors and increasing funding commitments from African governments and philanthropies will be needed to realise a critical mass of local capacity and to create and sustain world-class research hubs that will be conducive to address Africa's intractable health challenges., Conclusions: Our experiences so far suggest that African-led research has the potential to overcome the vicious cycle of brain-drain and may ultimately lead to improvement of health and science-led economic transformation of Africa into a prosperous continent.
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- 2020
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12. Combining Viral Genetics and Statistical Modeling to Improve HIV-1 Time-of-infection Estimation towards Enhanced Vaccine Efficacy Assessment.
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Rossenkhan R, Rolland M, Labuschagne JPL, Ferreira RC, Magaret CA, Carpp LN, Matsen Iv FA, Huang Y, Rudnicki EE, Zhang Y, Ndabambi N, Logan M, Holzman T, Abrahams MR, Anthony C, Tovanabutra S, Warth C, Botha G, Matten D, Nitayaphan S, Kibuuka H, Sawe FK, Chopera D, Eller LA, Travers S, Robb ML, Williamson C, Gilbert PB, and Edlefsen PT
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- Evolution, Molecular, Genetic Variation, HIV Infections virology, Humans, Mutation, Phylogeny, Sequence Analysis, Time Factors, Viral Load, AIDS Vaccines, HIV Infections prevention & control, HIV-1 genetics, Models, Statistical
- Abstract
Knowledge of the time of HIV-1 infection and the multiplicity of viruses that establish HIV-1 infection is crucial for the in-depth analysis of clinical prevention efficacy trial outcomes. Better estimation methods would improve the ability to characterize immunological and genetic sequence correlates of efficacy within preventive efficacy trials of HIV-1 vaccines and monoclonal antibodies. We developed new methods for infection timing and multiplicity estimation using maximum likelihood estimators that shift and scale (calibrate) estimates by fitting true infection times and founder virus multiplicities to a linear regression model with independent variables defined by data on HIV-1 sequences, viral load, diagnostics, and sequence alignment statistics. Using Poisson models of measured mutation counts and phylogenetic trees, we analyzed longitudinal HIV-1 sequence data together with diagnostic and viral load data from the RV217 and CAPRISA 002 acute HIV-1 infection cohort studies. We used leave-one-out cross validation to evaluate the prediction error of these calibrated estimators versus that of existing estimators and found that both infection time and founder multiplicity can be estimated with improved accuracy and precision by calibration. Calibration considerably improved all estimators of time since HIV-1 infection, in terms of reducing bias to near zero and reducing root mean squared error (RMSE) to 5-10 days for sequences collected 1-2 months after infection. The calibration of multiplicity assessments yielded strong improvements with accurate predictions (ROC-AUC above 0.85) in all cases. These results have not yet been validated on external data, and the best-fitting models are likely to be less robust than simpler models to variation in sequencing conditions. For all evaluated models, these results demonstrate the value of calibration for improved estimation of founder multiplicity and of time since HIV-1 infection.
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- 2019
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13. Dual HLA B*42 and B*81-reactive T cell receptors recognize more diverse HIV-1 Gag escape variants.
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Ogunshola F, Anmole G, Miller RL, Goering E, Nkosi T, Muema D, Mann J, Ismail N, Chopera D, Ndung'u T, Brockman MA, and Ndhlovu ZM
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- Adult, Amino Acid Sequence, CD8-Positive T-Lymphocytes immunology, Clone Cells, Female, Humans, Male, Reproducibility of Results, Viral Load, Young Adult, gag Gene Products, Human Immunodeficiency Virus chemistry, HIV-1 metabolism, HLA-B Antigens immunology, Mutation genetics, Receptors, Antigen, T-Cell metabolism, gag Gene Products, Human Immunodeficiency Virus genetics
- Abstract
Some closely related human leukocyte antigen (HLA) alleles are associated with variable clinical outcomes following HIV-1 infection despite presenting the same viral epitopes. Mechanisms underlying these differences remain unclear but may be due to intrinsic characteristics of the HLA alleles or responding T cell repertoires. Here we examine CD8
+ T cell responses against the immunodominant HIV-1 Gag epitope TL9 (TPQDLNTML180-188 ) in the context of the protective allele B*81:01 and the less protective allele B*42:01. We observe a population of dual-reactive T cells that recognize TL9 presented by both B*81:01 and B*42:01 in individuals lacking one allele. The presence of dual-reactive T cells is associated with lower plasma viremia, suggesting a clinical benefit. In B*42:01 expressing individuals, the dual-reactive phenotype defines public T cell receptor (TCR) clones that recognize a wider range of TL9 escape variants, consistent with enhanced control of viral infection through containment of HIV-1 sequence adaptation.- Published
- 2018
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14. Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression.
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Kiguoya MW, Mann JK, Chopera D, Gounder K, Lee GQ, Hunt PW, Martin JN, Ball TB, Kimani J, Brumme ZL, Brockman MA, and Ndung'u T
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- Africa, Eastern, Genetic Variation, HIV-1 classification, HIV-1 genetics, Humans, Virus Release, Disease Progression, Genotype, HIV Infections pathology, HIV Infections virology, HIV-1 physiology, Virus Replication, gag Gene Products, Human Immunodeficiency Virus genetics
- Abstract
There are marked differences in the spread and prevalence of HIV-1 subtypes worldwide, and differences in clinical progression have been reported. However, the biological reasons underlying these differences are unknown. Gag-protease is essential for HIV-1 replication, and Gag-protease-driven replication capacity has previously been correlated with disease progression. We show that Gag-protease replication capacity correlates significantly with that of whole isolates ( r = 0.51; P = 0.04), indicating that Gag-protease is a significant contributor to viral replication capacity. Furthermore, we investigated subtype-specific differences in Gag-protease-driven replication capacity using large well-characterized cohorts in Africa and the Americas. Patient-derived Gag-protease sequences were inserted into an HIV-1 NL4-3 backbone, and the replication capacities of the resulting recombinant viruses were measured in an HIV-1-inducible reporter T cell line by flow cytometry. Recombinant viruses expressing subtype C Gag-proteases exhibited substantially lower replication capacities than those expressing subtype B Gag-proteases ( P < 0.0001); this observation remained consistent when representative Gag-protease sequences were engineered into an HIV-1 subtype C backbone. We identified Gag residues 483 and 484, located within the Alix-binding motif involved in virus budding, as major contributors to subtype-specific replicative differences. In East African cohorts, we observed a hierarchy of Gag-protease-driven replication capacities, i.e., subtypes A/C < D < intersubtype recombinants ( P < 0.0029), which is consistent with reported intersubtype differences in disease progression. We thus hypothesize that the lower Gag-protease-driven replication capacity of subtypes A and C slows disease progression in individuals infected with these subtypes, which in turn leads to greater opportunity for transmission and thus increased prevalence of these subtypes. IMPORTANCE HIV-1 subtypes are unevenly distributed globally, and there are reported differences in their rates of disease progression and epidemic spread. The biological determinants underlying these differences have not been fully elucidated. Here, we show that HIV-1 Gag-protease-driven replication capacity correlates with the replication capacity of whole virus isolates. We further show that subtype B displays a significantly higher Gag-protease-mediated replication capacity than does subtype C, and we identify a major genetic determinant of these differences. Moreover, in two independent East African cohorts we demonstrate a reproducible hierarchy of Gag-protease-driven replicative capacity, whereby recombinants exhibit the greatest replication, followed by subtype D, followed by subtypes A and C. Our data identify Gag-protease as a major determinant of subtype differences in disease progression among HIV-1 subtypes; furthermore, we propose that the poorer viral replicative capacity of subtypes A and C may paradoxically contribute to their more efficient spread in sub-Saharan Africa., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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15. Fibroblast-Derived Extracellular Matrix Induces Chondrogenic Differentiation in Human Adipose-Derived Mesenchymal Stromal/Stem Cells in Vitro.
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Dzobo K, Turnley T, Wishart A, Rowe A, Kallmeyer K, van Vollenstee FA, Thomford NE, Dandara C, Chopera D, Pepper MS, and Parker MI
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- Adipose Tissue, White cytology, Cell Proliferation, Cell Shape, Cell Survival, Cells, Cultured, Cellular Senescence, Chondrogenesis, Fibroblasts metabolism, Gene Expression, Humans, Cell Differentiation, Extracellular Matrix physiology, Mesenchymal Stem Cells physiology
- Abstract
Mesenchymal stromal/stem cells (MSCs) represent an area being intensively researched for tissue engineering and regenerative medicine applications. MSCs may provide the opportunity to treat diseases and injuries that currently have limited therapeutic options, as well as enhance present strategies for tissue repair. The cellular environment has a significant role in cellular development and differentiation through cell-matrix interactions. The aim of this study was to investigate the behavior of adipose-derived MSCs (ad-MSCs) in the context of a cell-derived matrix so as to model the in vivo physiological microenvironment. The fibroblast-derived extracellular matrix (fd-ECM) did not affect ad-MSC morphology, but reduced ad-MSC proliferation. Ad-MSCs cultured on fd-ECM displayed decreased expression of integrins α2 and β1 and subsequently lost their multipotency over time, as shown by the decrease in CD44, Octamer-binding transcription factor 4 (OCT4), SOX2, and NANOG gene expression. The fd-ECM induced chondrogenic differentiation in ad-MSCs compared to control ad-MSCs. Loss of function studies, through the use of siRNA and a mutant Notch1 construct, revealed that ECM-mediated ad-MSCs chondrogenesis requires Notch1 and β-catenin signaling. The fd-ECM also showed anti-senescence effects on ad-MSCs. The fd-ECM is a promising approach for inducing chondrogenesis in ad-MSCs and chondrogenic differentiated ad-MSCs could be used in stem cell therapy procedures.
- Published
- 2016
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16. In Vitro Reversible and Time-Dependent CYP450 Inhibition Profiles of Medicinal Herbal Plant Extracts Newbouldia laevis and Cassia abbreviata: Implications for Herb-Drug Interactions.
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Thomford NE, Dzobo K, Chopera D, Wonkam A, Maroyi A, Blackhurst D, and Dandara C
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- Biological Availability, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme Inhibitors pharmacokinetics, Dose-Response Relationship, Drug, Enzyme Activation drug effects, Herb-Drug Interactions, Humans, Inhibitory Concentration 50, Kinetics, Mass Spectrometry, Molecular Structure, Plant Extracts pharmacokinetics, Tissue Distribution, Cassia chemistry, Cytochrome P-450 Enzyme Inhibitors chemistry, Cytochrome P-450 Enzyme Inhibitors pharmacology, Lamiales chemistry, Plant Extracts chemistry, Plant Extracts pharmacology
- Abstract
This study evaluated the effects of Newbouldia laevis and Cassia abbreviata extracts on CYP450 enzyme activity. Recombinant CYP450 enzyme and fluorogenic substrates were used for evaluating inhibition, allowing the assessment of herb-drug interactions (HDI). Phytochemical fingerprinting was performed using UPLC-MS. The herbal extracts were risk ranked for HDI based on the IC50 values determined for each CYP enzyme. Newbouldia laevis inhibited CYP1A2, CYP2C9, and CYP2C19 enzyme activities with Ki of 2.84 µg/mL, 1.55 µg/mL, and 1.23 µg/mL, respectively. N. laevis exhibited a TDI (4.17) effect on CYP1A2 but not CYP2C9 and CYP2C19 enzyme activities. Cassia abbreviata inhibited CYP1A2, CYP2C9, and CYP2C19 enzyme activities showing a Ki of 4.86 µg/mL, 5.98 µg/mL, and 1.58 µg/mL, respectively. TDI potency assessment for Cassia abbreviata showed it as a potential TDI candidate (1.64) for CYP1A2 and CYP2C19 (1.72). UPLC-MS analysis showed that Newbouldia laevis and Cassia abbreviata possess polyphenols that likely give them their therapeutic properties; some of them are likely to be responsible for the observed inhibition. The observations made in this study suggest the potential for these herbal compounds to interact, especially when co-administered with other medications metabolized by these CYP450 enzymes.
- Published
- 2016
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17. Inhibition of CYP2B6 by Medicinal Plant Extracts: Implication for Use of Efavirenz and Nevirapine-Based Highly Active Anti-Retroviral Therapy (HAART) in Resource-Limited Settings.
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Thomford NE, Awortwe C, Dzobo K, Adu F, Chopera D, Wonkam A, Skelton M, Blackhurst D, and Dandara C
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- Alkynes, Antiretroviral Therapy, Highly Active, Benzoxazines pharmacology, Cyclopropanes, Cytochrome P-450 CYP2B6 genetics, Cytochrome P-450 CYP2B6 metabolism, Cytochrome P-450 CYP2B6 Inhibitors chemistry, Cytochrome P-450 CYP2B6 Inhibitors pharmacology, Herb-Drug Interactions, Humans, Magnoliopsida chemistry, Nevirapine pharmacology, Plant Extracts chemistry, Plant Extracts pharmacology, Plants, Medicinal chemistry
- Abstract
Highly active antiretroviral therapy (HAART) has greatly improved health parameters of HIV infected individuals. However, there are several challenges associated with the chronic nature of HAART administration. For populations in health transition, dual use of medicinal plant extracts and conventional medicine poses a significant challenge. There is need to evaluate interactions between commonly used medicinal plant extracts and antiretroviral drugs used against HIV/AIDS. Efavirenz (EFV) and nevirapine (NVP) are the major components of HAART both metabolized by CYP2B6, an enzyme that can potentially be inhibited or induced by compounds found in medicinal plant extracts. The purpose of this study was to evaluate the effects of extracts of selected commonly used medicinal plants on CYP2B6 enzyme activity. Recombinant human CYP2B6 was used to evaluate inhibition, allowing the assessment of herb-drug interactions (HDI) of medicinal plants Hyptis suaveolens, Myrothamnus flabellifolius, Launaea taraxacifolia, Boerhavia diffusa and Newbouldia laevis. The potential of these medicinal extracts to cause HDI was ranked accordingly for reversible inhibition and also classified as potential time-dependent inhibitor (TDI) candidates. The most potent inhibitor for CYP2B6 was Hyptis suaveolens extract (IC50 = 19.09 ± 1.16 µg/mL), followed by Myrothamnus flabellifolius extract (IC50 = 23.66 ± 4.86 µg/mL), Launaea taraxacifolia extract (IC50 = 33.87 ± 1.54 µg/mL), and Boerhavia diffusa extract (IC50 = 34.93 ± 1.06 µg/mL). Newbouldia laevis extract, however, exhibited weak inhibitory effects (IC50 = 100 ± 8.71 µg/mL) on CYP2B6. Launaea taraxacifolia exhibited a TDI (3.17) effect on CYP2B6 and showed a high concentration of known CYP450 inhibitory phenolic compounds, chlorogenic acid and caffeic acid. The implication for these observations is that drugs that are metabolized by CYP2B6 when co-administered with these herbal medicines and when adequate amounts of the extracts reach the liver, there is a high likelihood of standard doses affecting drug plasma concentrations which could lead to toxicity.
- Published
- 2016
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18. Killer-cell Immunoglobulin-like Receptor (KIR) gene profiles modify HIV disease course, not HIV acquisition in South African women.
- Author
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Naranbhai V, de Assis Rosa D, Werner L, Moodley R, Hong H, Kharsany A, Mlisana K, Sibeko S, Garrett N, Chopera D, Carr WH, Abdool Karim Q, Hill AV, Abdool Karim SS, Altfeld M, Gray CM, and Ndung'u T
- Subjects
- Adult, Alleles, CD4-Positive T-Lymphocytes immunology, Cohort Studies, Disease Progression, Female, HIV Infections diagnosis, HLA-C Antigens, Haplotypes, Humans, Killer Cells, Natural immunology, Prospective Studies, South Africa, Viral Load, HIV Infections immunology, Receptors, KIR genetics
- Abstract
Background: Killer-cell Immunoglobulin-like Receptors (KIR) interact with Human Leukocyte Antigen (HLA) to modify natural killer- and T-cell function. KIR are implicated in HIV acquisition by small studies that have not been widely replicated. A role for KIR in HIV disease progression is more widely replicated and supported by functional studies., Methods: To assess the role of KIR and KIR ligands in HIV acquisition and disease course, we studied at-risk women in South Africa between 2004-2010. Logistic regression was used for nested case-control analysis of 154 women who acquired vs. 155 who did not acquire HIV, despite high exposure. Linear mixed-effects models were used for cohort analysis of 139 women followed prospectively for a median of 54 months (IQR 31-69) until 2014., Results: Neither KIR repertoires nor HLA alleles were associated with HIV acquisition. However, KIR haplotype BB was associated with lower viral loads (-0.44 log10 copies/ml; SE = 0.18; p = 0.03) and higher CD4+ T-cell counts (+80 cells/μl; SE = 42; p = 0.04). This was largely explained by the protective effect of KIR2DL2/KIR2DS2 on the B haplotype and reciprocal detrimental effect of KIR2DL3 on the A haplotype., Conclusions: Although neither KIR nor HLA appear to have a role in HIV acquisition, our data are consistent with involvement of KIR2DL2 in HIV control. Additional studies to replicate these findings are indicated.
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- 2016
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19. Pharmacogenomics Implications of Using Herbal Medicinal Plants on African Populations in Health Transition.
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Thomford NE, Dzobo K, Chopera D, Wonkam A, Skelton M, Blackhurst D, Chirikure S, and Dandara C
- Abstract
The most accessible points of call for most African populations with respect to primary health care are traditional health systems that include spiritual, religious, and herbal medicine. This review focusses only on the use of herbal medicines. Most African people accept herbal medicines as generally safe with no serious adverse effects. However, the overlap between conventional medicine and herbal medicine is a reality among countries in health systems transition. Patients often simultaneously seek treatment from both conventional and traditional health systems for the same condition. Commonly encountered conditions/diseases include malaria, HIV/AIDS, hypertension, tuberculosis, and bleeding disorders. It is therefore imperative to understand the modes of interaction between different drugs from conventional and traditional health care systems when used in treatment combinations. Both conventional and traditional drug entities are metabolized by the same enzyme systems in the human body, resulting in both pharmacokinetics and pharmacodynamics interactions, whose properties remain unknown/unquantified. Thus, it is important that profiles of interaction between different herbal and conventional medicines be evaluated. This review evaluates herbal and conventional drugs in a few African countries and their potential interaction at the pharmacogenomics level.
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- 2015
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20. Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point.
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Ndhlovu ZM, Kamya P, Mewalal N, Kløverpris HN, Nkosi T, Pretorius K, Laher F, Ogunshola F, Chopera D, Shekhar K, Ghebremichael M, Ismail N, Moodley A, Malik A, Leslie A, Goulder PJ, Buus S, Chakraborty A, Dong K, Ndung'u T, and Walker BD
- Subjects
- Adolescent, Apoptosis immunology, CD4 Lymphocyte Count, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes virology, Female, Flow Cytometry, HIV Infections blood, HIV Infections diagnosis, HIV Infections virology, HIV-1 genetics, HIV-1 immunology, HIV-1 physiology, Humans, Kinetics, Proto-Oncogene Proteins c-bcl-2 immunology, Proto-Oncogene Proteins c-bcl-2 metabolism, RNA, Viral genetics, RNA, Viral immunology, Time Factors, Viremia diagnosis, Viremia immunology, Young Adult, fas Receptor immunology, fas Receptor metabolism, CD8-Positive T-Lymphocytes immunology, HIV Infections immunology, Lymphocyte Activation immunology, Viral Load immunology
- Abstract
CD8(+) T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8(+) T cell response, with limited bystander activation of non-HIV memory CD8(+) T cells. HIV-specific CD8(+) T cells secreted little interferon-γ, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for T cell survival. The rapidity to peak CD8(+) T cell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8(+) T cell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
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21. Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses.
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Hancock G, Yang H, Yorke E, Wainwright E, Bourne V, Frisbee A, Payne TL, Berrong M, Ferrari G, Chopera D, Hanke T, Mothe B, Brander C, McElrath MJ, McMichael A, Goonetilleke N, Tomaras GD, Frahm N, and Dorrell L
- Subjects
- AIDS Vaccines immunology, Adult, CD8-Positive T-Lymphocytes classification, Epitopes, T-Lymphocyte immunology, Female, HIV Infections immunology, Humans, Immunodominant Epitopes immunology, Male, Middle Aged, Vaccination, Viral Load immunology, Young Adult, AIDS Vaccines therapeutic use, CD8-Positive T-Lymphocytes pathology, HIV Infections prevention & control, HIV Infections therapy, HIV-1 immunology, Immunity, Cellular
- Abstract
Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control.
- Published
- 2015
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22. Nef-mediated down-regulation of CD4 and HLA class I in HIV-1 subtype C infection: association with disease progression and influence of immune pressure.
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Mann JK, Chopera D, Omarjee S, Kuang XT, Le AQ, Anmole G, Danroth R, Mwimanzi P, Reddy T, Carlson J, Radebe M, Goulder PJR, Walker BD, Abdool Karim S, Novitsky V, Williamson C, Brockman MA, Brumme ZL, and Ndung'u T
- Subjects
- CD4-Positive T-Lymphocytes, Genes, MHC Class I genetics, HIV Infections genetics, HIV Infections immunology, HIV Infections metabolism, Humans, nef Gene Products, Human Immunodeficiency Virus genetics, Gene Expression Regulation immunology, Genes, MHC Class I physiology, HIV Infections virology, HIV-1 genetics, nef Gene Products, Human Immunodeficiency Virus metabolism
- Abstract
Nef plays a major role in HIV-1 pathogenicity. We studied HIV-1 subtype C infected individuals in acute/early (n = 120) or chronic (n = 207) infection to investigate the relationship between Nef-mediated CD4/HLA-I down-regulation activities and disease progression, and the influence of immune-driven sequence variation on these Nef functions. A single Nef sequence per individual was cloned into an expression plasmid, followed by transfection of a T cell line and measurement of CD4 and HLA-I expression. In early infection, a trend of higher CD4 down-regulation ability correlating with higher viral load set point was observed (r = 0.19, p = 0.05), and higher HLA-I down-regulation activity was significantly associated with faster rate of CD4 decline (p = 0.02). HLA-I down-regulation function correlated inversely with the number HLA-associated polymorphisms previously associated with reversion in the absence of the selecting HLA allele (r = -0.21, p = 0.0002). These data support consideration of certain Nef regions in HIV-1 vaccine strategies designed to attenuate the infection course., (Copyright © 2014 Elsevier Inc. All rights reserved.)
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- 2014
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23. A discussion of molecular biology methods for protein engineering.
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Zawaira A, Pooran A, Barichievy S, and Chopera D
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- Base Sequence, DNA Primers metabolism, Molecular Sequence Data, Mutagenesis genetics, Polymerase Chain Reaction, Molecular Biology methods, Protein Engineering methods
- Abstract
A number of molecular biology techniques are available to generate variants from a particular start gene for eventual protein expression. We discuss the basic principles of these methods in a repertoire that may be used to achieve the elemental steps in protein engineering. These include site-directed, deletion and insertion mutagenesis. We provide detailed case studies, drawn from our own experiences, packaged together with conceptual discussions and include an analysis of the techniques presented with regards to their uses in protein engineering.
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- 2012
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24. Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B 58:01-positive individuals.
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Chopera DR, Mlotshwa M, Woodman Z, Mlisana K, de Assis Rosa D, Martin DP, Abdool Karim S, Gray CM, and Williamson C
- Subjects
- Amino Acid Sequence, Base Sequence, CD4 Lymphocyte Count, DNA Primers, Disease Progression, Enzyme-Linked Immunosorbent Assay, HIV-1, HLA-B Antigens genetics, Humans, Molecular Epidemiology, Molecular Sequence Data, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Amino Acid, T-Lymphocytes, Cytotoxic immunology, Viral Load, HIV Infections immunology, HIV Infections virology, HLA-B Antigens immunology
- Abstract
Molecular epidemiology studies have identified HLA-B 58:01 as a protective HIV allele. However, not all B 58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B 58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could explain their different disease trajectories. Cytotoxic T-lymphocyte (CTL) responses during acute infection predominantly targeted the TW10 and KF9 epitopes in p24(Gag) and Nef, respectively. Failure to target the TW10 epitope in one B 58:01-positive individual was associated with low CD4(+) counts and rapid disease progression. Among those targeting TW10, escape mutations arose within 2 to 15 weeks of infection. Rapid escape was associated with preexisting compensatory mutations in the transmitted viruses, which were present at a high frequency (69%) in the study population. At 1 year postinfection, B 58:01-positive individuals who targeted and developed escape mutations in the TW10 epitope (n = 5) retained significantly higher CD4(+) counts (P = 0.04), but not lower viral loads, than non-B 58:01-positive individuals (n = 17). The high population-level frequency of these compensatory mutations may be limiting the protective effect of the B 58:01 allele.
- Published
- 2011
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25. Fluidity of HIV-1-specific T-cell responses during acute and early subtype C HIV-1 infection and associations with early disease progression.
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Mlotshwa M, Riou C, Chopera D, de Assis Rosa D, Ntale R, Treunicht F, Woodman Z, Werner L, van Loggerenberg F, Mlisana K, Abdool Karim S, Williamson C, and Gray CM
- Subjects
- Antibodies, Viral blood, Antibodies, Viral immunology, Cohort Studies, Disease Progression, Female, Follow-Up Studies, HIV Infections blood, HIV Infections virology, HIV-1 classification, Humans, Interferon-gamma blood, Interferon-gamma immunology, Male, T-Lymphocytes virology, HIV Infections immunology, HIV Infections pathology, HIV-1 immunology, T-Lymphocytes immunology
- Abstract
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-γ) 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-γ-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.
- Published
- 2010
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