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Journal of Virology, November 2009, p. 11175-11187, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00753-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Impaired Plasmacytoid Dendritic Cell (PDC)-NK Cell Activity in Viremic Human Immunodeficiency Virus Infection Attributable to Impairments in both PDC and NK Cell Function{triangledown}

Sara J. Conry,1 Kimberly A. Milkovich,1 Nicole L. Yonkers,1,2 Benigno Rodriguez,1 Helene B. Bernstein,3 Robert Asaad,1 Frederick P. Heinzel,1,{dagger} Magdalena Tary-Lehmann,2 Michael M. Lederman,1 and Donald D. Anthony1,2*

Departments of Medicine,1 Pathology,2 Reproductive Biology, Divisions of Infectious and Rheumatic Diseases, Case Western Reserve University Center for AIDS Research, University Hospitals of Cleveland and VA Medical Center, Cleveland, Ohio3

Received 13 April 2009/ Accepted 4 August 2009

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.

* Corresponding author. Mailing address: Biomedical Research Building 1028, Case Western Reserve University, 2109 Adelbert Rd., Cleveland, OH 44106. Phone: (216) 368-3540. Fax: (216) 368-2034. E-mail: ddA3{at}case.edu

{triangledown} Published ahead of print on 19 August 2009.

{dagger} Present address: Tampa VA Medical Center, 13000 Bruce B. Downs Blvd., Tampa, FL 33612.

Journal of Virology, November 2009, p. 11175-11187, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00753-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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