Preservation of tetherin and CD4 counter-activities in circulating Vpu alleles despite extensive sequence variation within HIV-1 infected individuals.
The HIV-1 Vpu protein is expressed from a bi-cistronic message late in the viral life cycle. It functions during viral assembly to maximise infectious virus release by targeting CD4 for proteosomal degradation and counteracting the antiviral protein tetherin (BST2/CD317). Single genome analysis of vpu repertoires throughout infection in 14 individuals infected with HIV-1 clade B revealed extensive amino acid diversity of the Vpu protein. For the most part, this variation in Vpu increases over the course of infection and is associated with predicted epitopes of the individual's MHC class I haplotype, suggesting CD8+ T cell pressure is the major driver of Vpu sequence diversity within the host. Despite this variability, the Vpu functions of targeting CD4 and counteracting both physical virus restriction and NF-κB activation by tetherin are rigorously maintained throughout HIV-1 infection. Only a minority of circulating alleles bear lesions in either of these activities at any given time, suggesting functional Vpu mutants are heavily selected against even at later stages of infection. Comparison of Vpu proteins defective for one or several functions reveals novel determinants of CD4 downregulation, counteraction of tetherin restriction, and inhibition of NF-κB signalling. These data affirm the importance of Vpu functions for in vivo persistence of HIV-1 within infected individuals, not simply for transmission, and highlight its potential as a target for antiviral therapy.
Department of Infectious Disease, King's College School of Medicine, Guy's Hospital, London, United Kingdom.
Suzanne
S
Pickering
MRC Centre for Medical Molecular Virology, University College London, London, United Kingdom.
Stephane
S
Hué
Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.
Eun-Young
EY
Kim
Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.
Susheel
S
Reddy
Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.
Steven M
SM
Wolinsky
Department of Infectious Disease, King's College School of Medicine, Guy's Hospital, London, United Kingdom.
Stuart J D
SJ
Neil
D000483:Alleles; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D014644:Genetic Variation / Q000276:immunology*; D057809:HEK293 Cells; D015658:HIV Infections / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
D015703:Antigens, CD; D015704:CD4 Antigens; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D016328:NF-kappa B; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins