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Journal of Virology, May 2008, p. 4785-4792, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.02449-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Conferral of Enhanced Natural Killer Cell Function by KIR3DS1 in Early Human Immunodeficiency Virus Type 1 Infection{triangledown}

Brian R. Long,1 Lishomwa C. Ndhlovu,1 Jorge R. Oksenberg,2 Lewis L. Lanier,3 Frederick M. Hecht,4 Douglas F. Nixon,1 and Jason D. Barbour4*

Division of Experimental Medicine, Department of Medicine, San Francisco General Hospital, University of California, San Francisco,1 Department of Neurology, University of California, San Francisco,2 Department of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco,3 HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California4

Received 13 November 2007/ Accepted 19 February 2008

A flurry of recent reports on the role of activating and inhibitory forms of the killer cell immunoglobulin-like receptors (KIR) in natural killer (NK) cell activity against human immunodeficiency virus type 1 (HIV-1) have yielded widely divergent results. The role of the activating NK receptor encoded by the KIR3DS1 allele and its putative ligands, members of the HLA class I Bw4Ile80 cluster, in early HIV-1 disease is controversial. We selected 60 treatment-naïve adults for study from the OPTIONS cohort of individuals with early HIV-1 infection in San Francisco. We performed NK cell functional assays measuring gamma interferon (IFN-{gamma}) and CD107a expression by NK cells in the unstimulated state and after stimulation by the major histocompatibility complex class I-deficient 721.221 B-lymphoblastoid cell line. In addition, we measured CD38 expression (a T-cell activation marker) on T and NK cells. Persons who have at least one copy of the KIR3DS1 gene had higher IFN-{gamma} and CD107a expression in the unstimulated state compared to those who do not possess this gene. After stimulation, both groups experienced a large induction of IFN-{gamma} and CD107a, with KIR3DS1 carriers achieving a greater amount of IFN-{gamma} expression. Differences in effector activity correlating with KIR3DS1 were not attributable to joint carriage of HLA Bw4Ile80 and KIR3DS1. We detected a partial but not complete dependence of KIR3DS1 on the members of B*58 supertype (B*57 and B*58) leading to higher NK cell function. Possessing KIR3DS1 was associated with lower expression of CD38 on both CD8+ T and NK cells and with a loss or weakening of the known strong associations between CD8+ T-cell expression of CD38 mean fluorescence intensity and the HIV-1 viral load. We observed that possessing KIR3DS1 was associated with higher NK cell effector functions in early HIV-1 disease, despite the absence of HLA Bw4Ile80, a putative ligand of KIR3DS1. Carriage of KIR3DS1 was associated with diminished CD8+ T-cell activation, as determined by expression of CD38, and a disruption of the traditional relationship between viral load and activation in HIV-1 disease, which may lead to better clinical outcomes for these individuals.

* Corresponding author. Mailing address: HIV/AIDS Division, UCSF Box 0874, San Francisco General Hospital, University of California, San Francisco, San Francisco, CA 94143-0874. Phone: (415) 476-4082. Fax: (415) 476-6953. E-mail: jbarbour{at}php.ucsf.edu

{triangledown} Published ahead of print on 27 February 2008.

Journal of Virology, May 2008, p. 4785-4792, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.02449-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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