Impaired plasmacytoid dendritic cell (PDC)-NK cell activity in viremic human immunodeficiency virus infection attributable to impairments in both PDC and NK cell function.
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections impair plasmacytoid dendritic cell (PDC) and natural killer (NK) cell subset numbers and functions, though little is known about PDC-NK cell interactions during these infections. We evaluated PDC-dependent NK cell killing and gamma interferon (IFN-gamma) and granzyme B production, using peripheral blood mononuclear cell (PBMC)-based and purified cell assays of samples from HCV- and HIV-infected subjects. CpG-enhanced PBMC killing and IFN-gamma and granzyme B activity (dependent on PDC and NK cells) were impaired in viremic HIV infection. In purified PDC-NK cell culture experiments, CpG-enhanced, PDC-dependent NK cell activity was cell contact and IFN-alpha dependent, and this activity was impaired in viremic HIV infection but not in HCV infection. In heterologous PDC-NK cell assays, impaired PDC-NK cell killing activity was largely attributable to an NK cell defect, while impaired PDC-NK cell IFN-gamma-producing activity was attributable to both PDC and NK cell defects. Additionally, the response of NK cells to direct IFN-alpha stimulation was defective in viremic HIV infection, and this defect was not attributable to diminished IFN-alpha receptor expression, though IFN-alpha receptor and NKP30 expression was closely associated with killer activity in viremic HIV infection but not in healthy controls. These data indicate that during uncontrolled HIV infection, PDC-dependent NK cell function is impaired, which is in large part attributable to defective IFN-alpha-induced NK cell activity and not to altered IFN-alpha receptor, NKP30, NKP44, NKP46, or NKG2D expression.
Conry
Sara J
SJ
Department of Medicine, Case Western Reserve University Center for AIDS Research, University Hospitals of Cleveland, OH, USA.
Milkovich
Kimberly A
KA
Yonkers
Nicole L
NL
Rodriguez
Benigno
B
Bernstein
Helene B
HB
Asaad
Robert
R
Heinzel
Frederick P
FP
Tary-Lehmann
Magdalena
M
Lederman
Michael M
MM
Anthony
Donald D
DD
D023241:Antiretroviral Therapy, Highly Active; D018899:CpG Islands; D003603:Cytotoxins / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D053804:Granzymes / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D014766:Viremia / Q000276:immunology*
D003603:Cytotoxins; D016898:Interferon-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D053804:Granzymes
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