Resistance of Major Histocompatibility Complex Class B (MHC-B) to Nef-Mediated Downregulation Relative to that of MHC-A Is Conserved among Primate Lentiviruses and Influences Antiviral T Cell Responses in HIV-1-Infected Individuals

被引：15

作者：

Mwimanzi, Francis ^{[1
]}

Toyoda, Mako ^{[1
]}

Mahiti, Macdonald ^{[1
,2
]}

Mann, Jaclyn K. ^{[3
]}

Martin, Jeffrey N. ^{[4
]}

Bangsberg, David ^{[5
]}

Brockman, Mark A. ^{[6
,7
]}

Goulder, Philip ^{[8
]}

Kirchhoff, Frank ^{[9
]}

Brumme, Zabrina L. ^{[6
,7
]}

Ndung'u, Thumbi ^{[3
,10
,11
,12
]}

Ueno, Takamasa ^{[1
,2
]}

机构：

[1] Kumamoto Univ, Ctr AIDS Res, Kumamoto, Japan

[2] Kumamoto Univ, Int Res Ctr Med Sci, Kumamoto, Japan

[3] Univ KwaZulu Natal, HIV Pathogenesis Programme, Durban, South Africa

[4] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[5] Portland State Univ, Oregon Hlth & Sci Univ, Sch Publ Hlth, Portland, OR 97207 USA

[6] Simon Fraser Univ, Burnaby, BC, Canada

[7] British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada

[8] Univ Oxford, Dept Paediat, Oxford, England

[9] Ulm Univ, Med Ctr, Inst Mol Virol, Ulm, Germany

[10] Africa Hlth Res Inst, Durban, South Africa

[11] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA USA

[12] Max Planck Inst Infect Biol, Berlin, Germany

来源：

JOURNAL OF VIROLOGY | 2018年 / 92卷 / 01期

基金：

新加坡国家研究基金会; 美国国家卫生研究院;

关键词：

HLA; Nef; human immunodeficiency virus; immune evasion; lentiviruses; SIMIAN IMMUNODEFICIENCY VIRUS; CLASS-I; HLA-B; RHESUS MACAQUE; DYNAMIC-RANGE; TYPE-1; NEF; HIV-1; ALLELES; MODULATION; INFECTION;

D O I：

10.1128/JVI.01409-17

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Patient-derived HIV-1 subtype B Nef clones downregulate HLA-A more efficiently than HLA-B. However, it remains unknown whether this property is common to Nef proteins across primate lentiviruses and how antiviral immune responses may be affected. We examined 263 Nef clones from diverse primate lentiviruses including different pandemic HIV-1 group M subtypes for their ability to downregulate major histocompatibility complex class A (MHC-A) and MHC-B from the cell surface. Though lentiviral Nef proteins differed markedly in their absolute MHC-A and MHC-B downregulation abilities, all lentiviral Nef lineages downregulated MHC-A, on average, 11 to 32% more efficiently than MHC-B. Nef genotype/phenotype analyses in a cohort of HIV-1 subtype C-infected patients (n = 168), together with site-directed mutagenesis, revealed Nef position 9 as a subtype-specific determinant of differential HLA-A versus HLA-B downregulation activity. Nef clones harboring nonconsensus variants at codon 9 downregulated HLA-B (though not HLA-A) significantly better than those harboring the consensus sequence at this site, resulting in reduced recognition of infected target cells by HIV-1-specific CD8(+) effector cells in vitro. Among persons expressing protective HLA class I alleles, carriage of Nef codon 9 variants was also associated with reduced ex vivo HIV-specific T cell responses. Our results demonstrate that Nef's inferior ability to downregulate MHC-B compared to that of MHC-A is conserved across primate lentiviruses and suggest that this property influences antiviral cellular immune responses. IMPORTANCE Primate lentiviruses encode the Nef protein that plays an essential role in establishing persistent infection in their respective host species. Nef interacts with the cytoplasmic region of MHC-A and MHC-B molecules and downregulates them from the infected cell surface to escape recognition by host cellular immunity. Using a panel of Nef alleles isolated from diverse primate lentiviruses including pandemic HIV-1 group M subtypes, we demonstrate that Nef proteins across all lentivi-

引用

页数：19