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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Ability of HIV-1 Nef to downregulate CD4 and HLA class I differs among viral subtypes
Retrovirology, Volume 10, No. 1, Article 100, Year 2013
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Description
Background: The highly genetically diverse HIV-1 group M subtypes may differ in their biological properties. Nef is an important mediator of viral pathogenicity; however, to date, a comprehensive inter-subtype comparison of Nef in vitro function has not been undertaken. Here, we investigate two of Nef's most well-characterized activities, CD4 and HLA class I downregulation, for clones obtained from 360 chronic patients infected with HIV-1 subtypes A, B, C or D.Results: Single HIV-1 plasma RNA Nef clones were obtained from N=360 antiretroviral-naïve, chronically infected patients from Africa and North America: 96 (subtype A), 93 (B), 85 (C), and 86 (D). Nef clones were expressed by transfection in an immortalized CD4+ T-cell line. CD4 and HLA class I surface levels were assessed by flow cytometry. Nef expression was verified by Western blot. Subset analyses and multivariable linear regression were used to adjust for differences in age, sex and clinical parameters between cohorts. Consensus HIV-1 subtype B and C Nef sequences were synthesized and functionally assessed. Exploratory sequence analyses were performed to identify potential genotypic correlates of Nef function. Subtype B Nef clones displayed marginally greater CD4 downregulation activity (p = 0.03) and markedly greater HLA class I downregulation activity (p < 0.0001) than clones from other subtypes. Subtype C Nefs displayed the lowest in vitro functionality. Inter-subtype differences in HLA class I downregulation remained statistically significant after controlling for differences in age, sex, and clinical parameters (p < 0.0001). The synthesized consensus subtype B Nef showed higher activities compared to consensus C Nef, which was most pronounced in cells expressing lower protein levels. Nef clones exhibited substantial inter-subtype diversity: cohort consensus residues differed at 25% of codons, while a similar proportion of codons exhibited substantial inter-subtype differences in major variant frequency. These amino acids, along with others identified in intra-subtype analyses, represent candidates for mediating inter-subtype differences in Nef function.Conclusions: Results support a functional hierarchy of subtype B > A/D > C for Nef-mediated CD4 and HLA class I downregulation. The mechanisms underlying these differences and their relevance to HIV-1 pathogenicity merit further investigation. © 2013 Mann et al.; licensee BioMed Central Ltd.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3849644/bin/1742-4690-10-100-S1.xls
Authors & Co-Authors
Mann, Jaclyn Kelly
South Africa, Durban
University of Kwazulu-natal
Byakwaga, Helen
Uganda, Mbarara
Mbarara University of Science and Technology
United States, San Francisco
University of California, San Francisco
Kuang, Xiaomei T.
Canada, Burnaby
Simon Fraser University
Le, Anh Q.
Canada, Burnaby
Simon Fraser University
Brumme, Chanson J.
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Mwimanzi, Philip
Canada, Burnaby
Simon Fraser University
Omarjee, Saleha
South Africa, Durban
University of Kwazulu-natal
Martin, Eric
Canada, Burnaby
Simon Fraser University
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Lee, Guinevere Q.
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Baraki, Bemuluyigza
Canada, Burnaby
Simon Fraser University
Danroth, Ryan
Canada, Burnaby
Simon Fraser University
McCloskey, Rosemary M.
Canada, Burnaby
Simon Fraser University
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Muzoora, Conrad K.
Uganda, Mbarara
Mbarara University of Science and Technology
Bangsberg, David R.
United States, Boston
Massachusetts General Hospital
Hunt, Peter W.
United States, San Francisco
University of California, San Francisco
Goulder, Philip Jeremy Renshaw
United Kingdom, Oxford
University of Oxford
Walker, Bruce D.
United States, Boston
Massachusetts General Hospital
United States, Cambridge
Harvard University
United States, Chevy Chase
Howard Hughes Institute
Harrigan, P. Richard
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Martin, Jeffrey N.
United States, San Francisco
University of California, San Francisco
Ndung'u, Thumbi P.
South Africa, Durban
University of Kwazulu-natal
United States, Cambridge
Harvard University
Germany, Berlin
Max Planck Institute for Infection Biology
Brockman, Mark A.
Canada, Burnaby
Simon Fraser University
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Brumme, Zabrina L.
Canada, Burnaby
Simon Fraser University
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Statistics
Citations: 22
Authors: 22
Affiliations: 10
Identifiers
Doi:
10.1186/1742-4690-10-100
Research Areas
Infectious Diseases
Study Design
Cohort Study
Exploratory Study