KLRG1 Expression on Natural Killer Cells is Associated with HIV Persistence, and Its Targeting Promotes the Reduction of the Viral Reservoir

Overview

Journal Cell Rep Med

Publisher Cell Press

Specialties Biology
General Medicine

Date 2023 Sep 23

PMID 37741278

Authors

Antonio Astorga-Gamaza

David Perea

Nerea Sanchez-Gaona

Marta Calvet-Mirabent

Ana Gallego-Cortes

Judith Grau-Exposito

Ildefonso Sanchez-Cerrillo

Joan Rey

Josep Castellvi

Adrian Curran

Joaquin Burgos

Jordi Navarro

Paula Suanzes

Vicenc Falco

Meritxell Genesca

Enrique Martin-Gayo

Maria J Buzon

Affiliations

Soon will be listed here.

Abstract

Human immunodeficiency virus (HIV) infection induces immunological dysfunction, which limits the elimination of HIV-infected cells during treated infection. Identifying and targeting dysfunctional immune cells might help accelerate the purging of the persistent viral reservoir. Here, we show that chronic HIV infection increases natural killer (NK) cell populations expressing the negative immune regulator KLRG1, both in peripheral blood and lymph nodes. Antiretroviral treatment (ART) does not reestablish these functionally impaired NK populations, and the expression of KLRG1 correlates with active HIV transcription. Targeting KLRG1 with specific antibodies significantly restores the capacity of NK cells to kill HIV-infected cells, reactivates latent HIV present in CD4 T cells co-expressing KLRG1, and reduces the intact HIV genomes in samples from ART-treated individuals. Our data support the potential use of immunotherapy against the KLRG1 receptor to impact the viral reservoir during HIV persistence.

Citing Articles

NK cell depletion in bispecific antibody therapy is associated with lack of HIV control after ART interruption.

Sanchez-Gaona N, Perea D, Curran A, Burgos J, Navarro J, Suanzes P Commun Biol. 2025; 8(1):236.

PMID: 39953264 PMC: 11829058. DOI: 10.1038/s42003-025-07651-6.

The Single-Cell Landscape of Peripheral and Tumor-infiltrating Immune Cells in HPV- HNSCC.

Galvani R, Rojas A, Matuck B, Rupp B, Kumar N, Huynh K bioRxiv. 2025; .

PMID: 39868329 PMC: 11760799. DOI: 10.1101/2025.01.14.632928.

Machine learning approaches identify immunologic signatures of total and intact HIV DNA during long-term antiretroviral therapy.

Semenova L, Wang Y, Falcinelli S, Archin N, Cooper-Volkheimer A, Margolis D Elife. 2024; 13.

PMID: 39250423 PMC: 11383529. DOI: 10.7554/eLife.94899.

NK Cells in the Lymph Nodes and Their Role in Anti-Tumour Immunity.

Graham L, Khakoo S, Blunt M Biomedicines. 2024; 12(8).

PMID: 39200132 PMC: 11351147. DOI: 10.3390/biomedicines12081667.

The role of KLRG1: a novel biomarker and new therapeutic target.

Zhang Y, Chen S, Tang X, Peng Y, Jiang T, Zhang X Cell Commun Signal. 2024; 22(1):337.

PMID: 38898461 PMC: 11186184. DOI: 10.1186/s12964-024-01714-7.

References

Lanier L . Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008; 9(5):495-502. PMC: 2669298. DOI: 10.1038/ni1581. View

Eisele E, Siliciano R . Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity. 2012; 37(3):377-88. PMC: 3963158. DOI: 10.1016/j.immuni.2012.08.010. View

Tata A, Dodard G, Fugere C, Leget C, Ors M, Rossi B . Combination blockade of KLRG1 and PD-1 promotes immune control of local and disseminated cancers. Oncoimmunology. 2021; 10(1):1933808. PMC: 8208121. DOI: 10.1080/2162402X.2021.1933808. View

Wang J, Cheng Y, Shi L, Ying R, Wu X, Li G . KLRG1 negatively regulates natural killer cell functions through the Akt pathway in individuals with chronic hepatitis C virus infection. J Virol. 2013; 87(21):11626-36. PMC: 3807337. DOI: 10.1128/JVI.01515-13. View

Novelli L, Barbati C, Capuano C, Recalchi S, Ceccarelli F, Vomero M . KLRG1 is reduced on NK cells in SLE patients, inversely correlates with disease activity and is modulated by hydroxychloroquine . Lupus. 2023; 32(4):549-559. DOI: 10.1177/09612033231160979. View

Perelson A, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K . Decay characteristics of HIV-1-infected compartments during combination therapy. Nature. 1997; 387(6629):188-91. DOI: 10.1038/387188a0. View

Robbins S, Terrizzi S, Sydora B, Mikayama T, Brossay L . Differential regulation of killer cell lectin-like receptor G1 expression on T cells. J Immunol. 2003; 170(12):5876-85. DOI: 10.4049/jimmunol.170.12.5876. View

Blaser C, Kaufmann M, Pircher H . Virus-activated CD8 T cells and lymphokine-activated NK cells express the mast cell function-associated antigen, an inhibitory C-type lectin. J Immunol. 1998; 161(12):6451-4. View

Nabatanzi R, Cose S, Joloba M, Rowland Jones S, Nakanjako D . Effects of HIV infection and ART on phenotype and function of circulating monocytes, natural killer, and innate lymphoid cells. AIDS Res Ther. 2018; 15(1):7. PMC: 5853105. DOI: 10.1186/s12981-018-0194-y. View

10.

Serra-Peinado C, Grau-Exposito J, Luque-Ballesteros L, Astorga-Gamaza A, Navarro J, Gallego-Rodriguez J . Expression of CD20 after viral reactivation renders HIV-reservoir cells susceptible to Rituximab. Nat Commun. 2019; 10(1):3705. PMC: 6697690. DOI: 10.1038/s41467-019-11556-4. View

11.

Fenwick C, Joo V, Jacquier P, Noto A, Banga R, Perreau M . T-cell exhaustion in HIV infection. Immunol Rev. 2019; 292(1):149-163. PMC: 7003858. DOI: 10.1111/imr.12823. View

12.

Borys S, Bag A, Brossay L, Adeegbe D . The Yin and Yang of Targeting KLRG1 Tregs and Effector Cells. Front Immunol. 2022; 13:894508. PMC: 9098823. DOI: 10.3389/fimmu.2022.894508. View

13.

Streeck H, Kwon D, Pyo A, Flanders M, Chevalier M, Law K . Epithelial adhesion molecules can inhibit HIV-1-specific CD8⁺ T-cell functions. Blood. 2011; 117(19):5112-22. PMC: 3109536. DOI: 10.1182/blood-2010-12-321588. View

14.

Nie Y, Liu D, Yang W, Li Y, Zhang L, Cheng X . Increased expression of TIGIT and KLRG1 correlates with impaired CD56 NK cell immunity in HPV16-related cervical intraepithelial neoplasia. Virol J. 2022; 19(1):68. PMC: 9003970. DOI: 10.1186/s12985-022-01776-4. View

15.

Greenberg S, Kong S, Thompson E, Gulla S . Co-inhibitory T cell receptor KLRG1: human cancer expression and efficacy of neutralization in murine cancer models. Oncotarget. 2019; 10(14):1399-1406. PMC: 6402715. DOI: 10.18632/oncotarget.26659. View

16.

Judge S, Murphy W, Canter R . Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence. Front Cell Infect Microbiol. 2020; 10:49. PMC: 7031155. DOI: 10.3389/fcimb.2020.00049. View

17.

Dogra P, Rancan C, Ma W, Toth M, Senda T, Carpenter D . Tissue Determinants of Human NK Cell Development, Function, and Residence. Cell. 2020; 180(4):749-763.e13. PMC: 7194029. DOI: 10.1016/j.cell.2020.01.022. View

18.

Banga R, Procopio F, Noto A, Pollakis G, Cavassini M, Ohmiti K . PD-1(+) and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat Med. 2016; 22(7):754-61. DOI: 10.1038/nm.4113. View

19.

Lichtfuss G, Cheng W, Farsakoglu Y, Paukovics G, Rajasuriar R, Velayudham P . Virologically suppressed HIV patients show activation of NK cells and persistent innate immune activation. J Immunol. 2012; 189(3):1491-9. DOI: 10.4049/jimmunol.1200458. View

20.

Thimme R, Appay V, Koschella M, Panther E, Roth E, Hislop A . Increased expression of the NK cell receptor KLRG1 by virus-specific CD8 T cells during persistent antigen stimulation. J Virol. 2005; 79(18):12112-6. PMC: 1212638. DOI: 10.1128/JVI.79.18.12112-12116.2005. View