Universität zu Köln

Hoelzemer, Angelique, Thobakgale, Christina F., Cruz, Camilo A. Jimenez, Garcia-Beltran, Wilfredo F., Carlson, Jonathan M., van Teijlingen, Nienke H., Mann, Jaclyn K., Jaggernath, Manjeetha, Kang, Seung-gu ORCID: 0000-0002-4010-0829, Koerner, Christian, Chung, Amy W., Schafer, Jamie L., Evans, David T., Alter, Galit, Walker, Bruce D., Goulder, Philip J., Carrington, Mary, Hartmann, Pia, Pertel, Thomas ORCID: 0000-0002-2286-6011, Zhou, Ruhong ORCID: 0000-0001-8624-5591, Ndung'u, Thumbi ORCID: 0000-0003-2962-3992 and Altfeld, Marcus ORCID: 0000-0001-5972-2997 (2015). 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. PLos Med., 12 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1549-1676

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Abstract

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 +/- .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

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hoelzemer, Angelique UNSPECIFIED UNSPECIFIED UNSPECIFIED Thobakgale, Christina F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cruz, Camilo A. Jimenez UNSPECIFIED UNSPECIFIED UNSPECIFIED Garcia-Beltran, Wilfredo F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Carlson, Jonathan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Teijlingen, Nienke H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mann, Jaclyn K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaggernath, Manjeetha UNSPECIFIED UNSPECIFIED UNSPECIFIED Kang, Seung-gu UNSPECIFIED orcid.org/0000-0002-4010-0829 UNSPECIFIED Koerner, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Chung, Amy W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schafer, Jamie L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Evans, David T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Alter, Galit UNSPECIFIED UNSPECIFIED UNSPECIFIED Walker, Bruce D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goulder, Philip J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Carrington, Mary UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Pia UNSPECIFIED UNSPECIFIED UNSPECIFIED Pertel, Thomas UNSPECIFIED orcid.org/0000-0002-2286-6011 UNSPECIFIED Zhou, Ruhong UNSPECIFIED orcid.org/0000-0001-8624-5591 UNSPECIFIED Ndung'u, Thumbi UNSPECIFIED orcid.org/0000-0003-2962-3992 UNSPECIFIED Altfeld, Marcus UNSPECIFIED orcid.org/0000-0001-5972-2997 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-387836
DOI:	10.1371/journal.pmed.1001900
Journal or Publication Title:	PLos Med.
Volume:	12
Number:	11
Date:	2015
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1549-1676
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language IMMUNOGLOBULIN-LIKE RECEPTOR; VIRUS TYPE-1 INFECTION; HLA CLASS-I; IMMUNE ESCAPE; NK CELLS; PHASE-1 TRIAL; FREE-ENERGY; KIR; RECOGNITION; PROTEINS Multiple languages Medicine, General & Internal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38783