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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
agricultural and biological sciences
Intersubtype Differences in the effect of a rare p24 Gag mutation on HIV-1 replicative fitness
Journal of Virology, Volume 86, No. 24, Year 2012
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Description
Certain immune-driven mutations in HIV-1, such as those arising in p24Gag, decrease viral replicative capacity. However, the intersubtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24Gag M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) (P=0.0005) and appears to be a rare escape variant selected by HLA-B58 supertype alleles (P<0.01). In contrast, in subtype C, it is a relatively common minor polymorphic variant (10 to 15%) whose appearance is not associated with a particular HLA allele. Using site-directed mutant viruses, we demonstrate that M250I reduces in vitro viral replicative capacity in both subtype B and subtype C sequences. However, whereas in subtype C downstream compensatory mutations at p24Gag codons 252 and 260 reduce the adverse effects of M250I, fitness costs in subtype B appear difficult to restore. Indeed, patient-derived subtype B sequences harboring M250I exhibited in vitro replicative defects, while those from subtype C did not. The structural implications of M250I were predicted by protein modeling to be greater in subtype B versus C, providing a potential explanation for its lower frequency and enhanced replicative defects in subtype B. In addition to accounting for genetic differences between HIV-1 subtypes, the design of cytotoxic-T-lymphocyte-based vaccines may need to account for differential effects of host-driven viral evolution on viral fitness. © 2012, American Society for Microbiology.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3503133/bin/supp_86_24_13423__index.html
https://efashare.b-cdn.net/share/pmc/articles/PMC3503133/bin/JVI.02171-12_zjv999096948so1.pdf
Authors & Co-Authors
Chopera, Denis R.
South Africa, Johannesburg
National Health Laboratory Service
Canada, Burnaby
Simon Fraser University
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Cotton, Laura A.
Canada, Burnaby
Simon Fraser University
Zawaira, Alexander
South Africa, Pretoria
The Council for Scientific and Industrial Research
Mann, Jaclyn Kelly
South Africa, Durban
The Nelson R. Mandela Medical School
Ngandu, Nobubelo Kwanele
South Africa, Johannesburg
National Health Laboratory Service
Ntale, Roman Saba
South Africa, Johannesburg
National Health Laboratory Service
Carlson, Jonathan M.
United States, Redmond
Microsoft Research
Mlisana, Koleka P.
South Africa, Congella
Centre for the Aids Programme of Research in South Africa
Woodman, Zenda L.
South Africa, Cape Town
University of Cape Town
Rosa, Debra De Assis
South Africa, Johannesburg
National Institute for Communicable Diseases
Martin, Eric
Canada, Burnaby
Simon Fraser University
Miura, Toshiyuki
Japan, Tokyo
The University of Tokyo
Pereyra, Florencia
United States, Cambridge
Massachusetts Institute of Technology
Walker, Bruce D.
United States, Cambridge
Massachusetts Institute of Technology
Gray, Clive M.
South Africa, Cape Town
University of Cape Town
Martin, Darren Patrick
South Africa, Johannesburg
National Health Laboratory Service
Ndung'u, Thumbi P.
South Africa, Durban
The Nelson R. Mandela Medical School
Brockman, Mark A.
Canada, Burnaby
Simon Fraser University
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Abdool Karim, Salim S.
South Africa, Congella
Centre for the Aids Programme of Research in South Africa
Brumme, Zabrina L.
Canada, Burnaby
Simon Fraser University
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Williamson, Carolyn
South Africa, Johannesburg
National Health Laboratory Service
Statistics
Citations: 21
Authors: 21
Affiliations: 11
Identifiers
Doi:
10.1128/JVI.02171-12
ISSN:
0022538X
e-ISSN:
10985514
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Infectious Diseases