Sponsor
This project was funded by research grants from the Canadian Institutes of Health Research (CIHR) (PJT-148621) and the National Institutes of Health (R01 MH054907 and P30 AI027763). G.U. was supported by a fellowship from the Canadian Queen Elizabeth II Diamond Jubilee Scholarship program (QES) (an initiative of Universities Canada in partnership with the Community Foundations of Canada, the Government of Canada, and Rideau Hall Foundation) and the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE; a DELTAS Africa Initiative [grant number DEL-15-006]). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)’s Alliance for Accelerating Excellence in Science in Africa (AESA) and is supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant number 107752/Z/15/Z) and the UK government. S.W.J. was supported by a CIHR Frederick Banting and Charles Best M.Sc. award. Z.L.B. was supported by a Scholar award from the Michael Smith Foundation for Health Research. M.A.B. was supported by the Canada Research Chairs program.
Published In
Journal of Virology
Document Type
Article
Publication Date
7-2020
Subjects
Viral proteins -- Metabolism, HIV infections -- Pathogenesis, HIV (Viruses), Retrovirus infections
Abstract
Downregulation of BST-2/tetherin and CD4 by HIV-1 viral protein U (Vpu) promotes viral egress and allows infected cells to evade host immunity. Little is known however about the natural variability in these Vpu functions among the genetically diverse viral subtypes that contribute to the HIV-1 pandemic. We collected Vpu isolates from 332 treatment-naive individuals living with chronic HIV-1 infection in Uganda, Rwanda, South Africa, and Canada. Together, these Vpu isolates represent four major HIV-1 group M subtypes (A [n = 63], B [n = 84], C [n = 94], and D [n = 59]) plus intersubtype recombinants and uncommon strains (n = 32). The ability of each Vpu clone to downregulate endogenous CD4 and tetherin was quantified using flow cytometry following transfection into an immortalized T-cell line and compared to that of a reference Vpu clone derived from HIV-1 subtype B NL4.3. Overall, the median CD4 downregulation function of natural Vpu isolates was similar to that of NL4.3 (1.01 [interquartile range {IQR}, 0.86 to 1.18]), while the median tetherin downregulation function was moderately lower than that of NL4.3 (0.90 [0.79 to 0.97]). Both Vpu functions varied significantly among HIV-1 subtypes (Kruskal-Wallis P < 0.0001). Specifically, subtype C clones exhibited the lowest CD4 and tetherin downregulation activities, while subtype D and B clones were most functional for both activities. We also identified Vpu polymorphisms associated with CD4 or tetherin downregulation function and validated six of these using site-directed mutagenesis. Our results highlight the marked extent to which Vpu function varies among global HIV-1 strains, raising the possibility that natural variation in this accessory protein may contribute to viral pathogenesis and/or spread.
Locate the Document
DOI
10.1128/JVI.00293-20
Persistent Identifier
https://archives.pdx.edu/ds/psu/33564
Citation Details
Umviligihozo, G., Cobarrubias, K. D., Chandrarathna, S., Jin, S. W., Reddy, N., Byakwaga, H., ... & Martin, J. N. (2020). Differential Vpu-mediated CD4 and tetherin downregulation function among major HIV-1 group M subtypes. Journal of Virology.
Description
Copyright © 2020 Umviligihozo et al.
This work is licensed under a Creative Commons Attribution 4.0 International License.