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Chronic HIV-1 viremia reverses NKG2A/NKG2C ratio on natural killer cells in patients with human cytomegalovirus co-infection

Brunetta, Enricoa,b; Fogli, Manuelab; Varchetta, Stefaniac; Bozzo, Luisaa; Hudspeth, Kelly Ld; Marcenaro, Emanuelae; Moretta, Alessandroe; Mavilio, Domenicoa

doi: 10.1097/QAD.0b013e3283328d1f
Basic Science

Background: The HIV-1-induced expansion of highly dysfunctional natural killer (NK) cell subsets represents a strategy to evade NK cell antiviral functions. In this context, the loss of NKG2Apos NK cells in chronic viremic HIV-1-infected individuals has also been associated with a dramatic expansion of NKG2Cpos NK cells. The viral trigger associated with high frequencies of NK cell subsets expressing NKG2C is still being debated.

Objective: To confirm that human cytomegalovirus (HCMV) infection is necessary for the expansion of NKG2Cpos NK cells and to assess whether this phenomenon affects NKG2A/NKG2C ratio on NK cells in patients coinfected with HIV-1 and HCMV.

Design: We measured the expression of NKG2A and NKG2C on NK cells from 70 healthy donors, 21 early, 96 chronic and 27 long-term nonprogressor's (LTNPs) HIV-1-infected patients using a multicolor flow cytometric approach. HCMV infection was detected by titrating the serum levels of specific circulating antibodies.

Results: A significant expansion of NKG2Cpos NK cells could be detected only in HCMV-infected patients. This phenotypic feature, together with the HIV-1-mediated downmodulation of NKG2A, pathologically reverses the ratio of NKG2A/NKG2C uniquely on NK cells from chronic viremic HIV-1-infected patients with a concomitant HCMV infection. The normalization of NKG2A/NKG2C ratio to values more than one occurred only after 24 months of suppression of HIV-1 replication following antiretroviral therapy.

Conclusion: The inversion of NKG2A/NKG2C ratio characterizes advanced stages of HIV-1 disease in patients showing a concomitant HCMV infection. This NK cell immune parameter renders this cohort of patients distinguishable from LTNPs and early HIV-1-infected individuals.

aLaboratory Clinical and Experimental Immunology, IRCCS, Istituto Clinico Humanitas, Rozzano, Milano, Italy

bLaboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

cCentre for Hepatology and Infectious Diseases, Policlinico San Matteo and University of Pavia, Italy

dDepartment of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois, USA

eDipartimento di Medicina Sperimentale, University of Genova, Genova, Italy.

Received 10 June, 2009

Revised 15 August, 2009

Accepted 21 August, 2009

Correspondence to Domenico Mavilio, Laboratory of Experimental Immunology, IRCCS, Istituto Clinico Humanitas, Via Alessandro Manzoni, 113, Rozzano, Milano, Italy. Tel: +39 02 8224 5157; fax: +39 8224 5191; e-mail:

© 2010 Lippincott Williams & Wilkins, Inc.