title: Modest attenuation of HIV-1 Vpu alleles derived from elite controller plasma.
abstract: In the absence of antiretroviral therapy, infection with human immunodeficiency virus type 1 (HIV-1) can typically not be controlled by the infected host and results in the development of acquired immunodeficiency. In rare cases, however, patients spontaneously control HIV-1 replication. Mechanisms by which such elite controllers (ECs) achieve control of HIV-1 replication include particularly efficient immune responses as well as reduced fitness of the specific virus strains. To address whether polymorphisms in the accessory HIV-1 protein Vpu are associated with EC status we functionally analyzed a panel of plasma-derived vpu alleles from 15 EC and 16 chronic progressor (CP) patients. Antagonism of the HIV particle release restriction by the intrinsic immunity factor CD317/tetherin was well conserved among EC and CP Vpu alleles, underscoring the selective advantage of this Vpu function in HIV-1 infected individuals. In contrast, interference with CD317/tetherin induced NF-κB activation was little conserved in both groups. EC Vpus more frequently displayed reduced ability to downregulate cell surface levels of CD4 and MHC class I (MHC-I) molecules as well as of the NK cell ligand NTB-A. Polymorphisms potentially associated with high affinity interactions of the inhibitory killer immunoglobulin-like receptor (KIR) KIR2DL2 were significantly enriched among EC Vpus but did not account for these functional differences. Together these results suggest that in a subgroup of EC patients, some Vpu functions are modestly reduced, possibly as a result of host selection.
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, INF 324, Heidelberg, Germany; German Center for Infection Research, Heidelberg University, Heidelberg. Germany.
authors: Jingyan
authors: J
authors: Chen
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, INF 324, Heidelberg, Germany; German Center for Infection Research, Heidelberg University, Heidelberg. Germany.
authors: Nadine
authors: N
authors: Tibroni
authors: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors: Daniel
authors: D
authors: Sauter
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, INF 324, Heidelberg, Germany; German Center for Infection Research, Heidelberg University, Heidelberg. Germany.
authors: Johanna
authors: J
authors: Galaski
authors: Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
authors: Toshiyuki
authors: T
authors: Miura
authors: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, United States of America.
authors: Galit
authors: G
authors: Alter
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, INF 324, Heidelberg, Germany; German Center for Infection Research, Heidelberg University, Heidelberg. Germany.
authors: Birthe
authors: B
authors: Mueller
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, INF 324, Heidelberg, Germany; German Center for Infection Research, Heidelberg University, Heidelberg. Germany.
authors: Claudia
authors: C
authors: Haller
authors: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, United States of America; Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors: Bruce D
authors: BD
authors: Walker
authors: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
authors: Frank
authors: F
authors: Kirchhoff
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
authors: Zabrina L
authors: ZL
authors: Brumme
authors: Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, Japan; International Research Center for Medical Sciences (IRCMS), Kumamoto University, Japan.
authors: Takamasa
authors: T
authors: Ueno
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, INF 324, Heidelberg, Germany; German Center for Infection Research, Heidelberg University, Heidelberg. Germany.
authors: Oliver T
authors: OT
authors: Fackler
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D017124:Conserved Sequence; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D015658:HIV Infections / Q000097:blood* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D016013:Likelihood Functions; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010802:Phylogeny; D012367:RNA, Viral / Q000097:blood; D020539:Sequence Analysis, Protein; D015398:Signal Transduction; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry / Q000235:genetics*; D000086082:Viroporin Proteins
chemical_list: D015704:CD4 Antigens; D049452:Green Fluorescent Proteins; D015395:Histocompatibility Antigens Class I; D054298:Human Immunodeficiency Virus Proteins; D016328:NF-kappa B; D012367:RNA, Viral; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins