Modest attenuation of HIV-1 Vpu alleles derived from elite controller plasma

Jingyan Chen; Nadine Tibroni; Daniel Sauter; Johanna Galaski; Toshiyuki Miura; Galit Alter; Birthe Mueller; Claudia Haller; Bruce D Walker; Frank Kirchhoff; Zabrina L Brumme; Takamasa Ueno; Oliver T Fackler

doi:10.1371/journal.pone.0120434

Modest attenuation of HIV-1 Vpu alleles derived from elite controller plasma

PLoS One. 2015 Mar 20;10(3):e0120434. doi: 10.1371/journal.pone.0120434. eCollection 2015.

Authors

Affiliations

¹ Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, INF 324, Heidelberg, Germany; German Center for Infection Research, Heidelberg University, Heidelberg. Germany.
² Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
³ Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
⁴ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, United States of America.
⁵ 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.
⁶ Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
⁷ Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, Japan; International Research Center for Medical Sciences (IRCMS), Kumamoto University, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles*
Amino Acid Sequence
CD4 Antigens / metabolism
Cell Membrane / metabolism
Conserved Sequence
Disease Progression
Down-Regulation / genetics
Green Fluorescent Proteins / metabolism
HEK293 Cells
HIV Infections / blood*
HIV Infections / virology*
HIV-1 / genetics*
Histocompatibility Antigens Class I / metabolism
Human Immunodeficiency Virus Proteins / chemistry
Human Immunodeficiency Virus Proteins / genetics*
Humans
Likelihood Functions
Molecular Sequence Data
NF-kappa B / metabolism
Phylogeny
RNA, Viral / blood
Sequence Analysis, Protein
Signal Transduction
Viral Regulatory and Accessory Proteins / chemistry
Viral Regulatory and Accessory Proteins / genetics*

Substances

CD4 Antigens
Histocompatibility Antigens Class I
Human Immunodeficiency Virus Proteins
NF-kappa B
RNA, Viral
Viral Regulatory and Accessory Proteins
vpu protein, Human immunodeficiency virus 1
Green Fluorescent Proteins

Associated data

GENBANK/KM656058
GENBANK/KM656059
GENBANK/KM656060
GENBANK/KM656061
GENBANK/KM656062
GENBANK/KM656063
GENBANK/KM656064
GENBANK/KM656065
GENBANK/KM656066
GENBANK/KM656067
GENBANK/KM656068
GENBANK/KM656069
GENBANK/KM656070
GENBANK/KM656071
GENBANK/KM656072
GENBANK/KM656073

Grants and funding

This study was supported by the German Center for Infection Research (project 8.2 TTU HIV to OTF and MD student fellowship to JG), the Deutsche Forschungsgemeinschaft (grants to OTF, DS and FK) and grants-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan and the Ministry of Health, Labor, and Welfare of Japan (to TU). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.