Expression and Function of NKG2D Is Impaired in CD8+ T Cells of Chronically HIV-1-Infected Patients Without ART.
OBJECTIVE
Increasing line of evidence indicates that the NKG2D-activating receptor plays a relevant role in the effector functions of cytotoxic lymphocytes. In this study, we investigated the expression and function of NKG2D in CD8⁺ T cells from chronically HIV-1-infected patients with or without antiretroviral therapy (ART).


METHODS
We measured by flow cytometry the expression of NKG2D on CD8⁺ T-cell subsets of ART-naive and ART patients as well as seronegative healthy subjects (HIV-neg). An intrapatient analysis before and after ART initiation was also performed. Results were correlated with viral load, CD4⁺ T-cell counts, markers of immune activation (CD38, sCD14), and soluble NKG2D ligands (sMICA and sULBP2). The function of NKG2D on CD8⁺ T cell cytotoxicity was tested by ex vivo degranulation assays.


RESULTS
We showed that NKG2D was downregulated on all CD8⁺ T-cell subsets of ART-naive patients. The expression of NKG2D on CD8⁺ T cells inversely correlated with viral load and CD38 expression but not with plasma levels of sMICA and sULBP2. Importantly, we found that NKG2D-mediated costimulation of CD8⁺ T-cell lytic activity was strongly reduced in ART-naive patients if compared with HIV-neg and ART subjects. Finally, intrapatient analysis demonstrated that effective anti-HIV-1 therapy restores NKG2D expression and NKG2D-induced cytotoxicity by CD8⁺ T cells.


CONCLUSIONS
These data underscore that NKG2D downregulation contributes to impaired CD8⁺ T-cell responses in untreated HIV-1 infection and have implications for monitoring immune functions and response to treatments, and for the development of novel anti-HIV-1 strategies combining ART with drugs that stimulate NKG2D expression and function.
*Laboratory of Immunoinfectivology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; and †Department of Medicine of Systems, Tor Vergata University, Rome, Italy.
Erica
E
Giuliani
Lia
L
Vassena
Maria Giovanna
MG
Desimio
Anna Rita
AR
Buonomini
Vincenzo
V
Malagnino
Massimo
M
Andreoni
Margherita
M
Doria
D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D000328:Adult; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry* / Q000276:immunology*; D015550:Cell Degranulation; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019562:Viral Load
C527085:KLRK1 protein, human; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1