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Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa
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نویسنده
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hölzemer a. ,thobakgale c.f. ,jimenez cruz c.a. ,garcia-beltran w.f. ,carlson j.m. ,van teijlingen n.h. ,mann j.k. ,jaggernath m. ,kang s.-g. ,körner c. ,chung a.w. ,schafer j.l. ,evans d.t. ,alter g. ,walker b.d. ,goulder p.j. ,carrington m. ,hartmann p. ,pertel t. ,zhou r. ,ndung’u t. ,altfeld m.
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منبع
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plos medicine - 2015 - دوره : 12 - شماره : 11
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چکیده
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Background: viruses can evade immune surveillance,but the underlying mechanisms are insufficiently understood. here,we sought to understand the mechanisms by which natural killer (nk) cells recognize hiv-1-infected cells and how this virus can evade nk-cell-mediated immune pressure. methods and findings: two sequence mutations in p24 gag associated with the presence of specific kir/hla combined genotypes were identified in hiv-1 clade c viruses from a large cohort of infected,untreated individuals in south africa (n = 392),suggesting viral escape from kir+ nk cells through sequence variations within hla class i—presented epitopes. one sequence polymorphism at position 303 of p24 gag (tgag303v),selected for in infected individuals with both kir2dl3 and hla-c*03:04,enabled significantly better binding of the inhibitory kir2dl3 receptor to hla-c*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 ± 10.45 standard deviation [sd] and variant mean 44.67 ± 14.42 sd,p = 0.002). furthermore,activation of primary kir2dl3+ nk cells from healthy donors in response to hla-c*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 ± 0.07 standard error of the mean [sem] and variant mean 0.63 ± 0.07 sem,p = 0.012). structural modeling and surface plasmon resonance of kir/peptide/hla interactions in the context of the different viral sequence variants studied supported these results. future studies will be needed to assess processing and antigen presentation of the investigated hiv-1 epitope in natural infection,and the consequences for viral control. conclusions: these data provide novel insights into how viruses can evade nk cell immunity through the selection of mutations in hla-presented epitopes that enhance binding to inhibitory nk cell receptors. better understanding of the mechanisms by which hiv-1 evades nk-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of nk cells. © 2015 public library of science,all rights reserved.
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آدرس
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ragon institute of mgh,mit and harvard,cambridge,ma,united states,heinrich-pette-institut,leibniz institute for experimental virology,hamburg,germany,first department of internal medicine,university medical center hamburg—eppendorf,hamburg, Germany, ragon institute of mgh,mit and harvard,cambridge,ma,united states,hiv pathogenesis programme,doris duke medical research institute,kwazulu-natal research institute for tuberculosis and hiv,nelson r. mandela school of medicine,university of kwazulu-natal,durban, South Africa, computational biology center,ibm thomas j. watson research center,yorktown heights,ny, United States, ragon institute of mgh,mit and harvard,cambridge,ma, United States, microsoft research,los angeles,ca, United States, experimental immunology,academic medical center,amsterdam, Netherlands, hiv pathogenesis programme,doris duke medical research institute,kwazulu-natal research institute for tuberculosis and hiv,nelson r. mandela school of medicine,university of kwazulu-natal,durban, South Africa, hiv pathogenesis programme,doris duke medical research institute,kwazulu-natal research institute for tuberculosis and hiv,nelson r. mandela school of medicine,university of kwazulu-natal,durban, South Africa, computational biology center,ibm thomas j. watson research center,yorktown heights,ny, United States, ragon institute of mgh,mit and harvard,cambridge,ma,united states,heinrich-pette-institut,leibniz institute for experimental virology,hamburg, Germany, ragon institute of mgh,mit and harvard,cambridge,ma, United States, department of microbiology and immunobiology,harvard medical school,boston,ma,united states,division of microbiology,new england primate research center,southborough,ma, United States, department of microbiology and immunobiology,harvard medical school,boston,ma,united states,division of microbiology,new england primate research center,southborough,ma,united states,department of pathology and laboratory medicine,university of wisconsin,madison,madison,wi, United States, ragon institute of mgh,mit and harvard,cambridge,ma, United States, ragon institute of mgh,mit and harvard,cambridge,ma, United States, hiv pathogenesis programme,doris duke medical research institute,kwazulu-natal research institute for tuberculosis and hiv,nelson r. mandela school of medicine,university of kwazulu-natal,durban,south africa,department of paediatrics,university of oxford,oxford, United Kingdom, ragon institute of mgh,mit and harvard,cambridge,ma,united states,cancer and inflammation program,laboratory of experimental immunology,leidos biomedical research,frederick national laboratory for cancer research,frederick,md, United States, first department of internal medicine,division of infectious diseases,university of cologne,cologne,germany,institute for medical microbiology,immunology and hygiene,university of cologne,cologne, Germany, center for neurologic diseases,brigham and women’s hospital and harvard medical school,boston,ma, United States, computational biology center,ibm thomas j. watson research center,yorktown heights,ny, United States, ragon institute of mgh,mit and harvard,cambridge,ma,united states,hiv pathogenesis programme,doris duke medical research institute,kwazulu-natal research institute for tuberculosis and hiv,nelson r. mandela school of medicine,university of kwazulu-natal,durban,south africa,max planck institute for infection biology,berlin,germany,kwazulu-natal research institute for tuberculosis and hiv,nelson r. mandela school of medicine,university of kwazulu-natal,durban, South Africa, ragon institute of mgh,mit and harvard,cambridge,ma,united states,heinrich-pette-institut,leibniz institute for experimental virology,hamburg, Germany
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