Increased natural killer (NK) activation has been associated with resistance to HIV-1 infection in several cohorts of HIV-1 exposed, uninfected individuals. Inheritance of protective NK receptor alleles (KIR3DS1 and KIR3DL1 high) has also been observed in a subset of HIV-1 exposed, uninfected individuals. However, the exact mechanism contributing to NK activation in HIV-1 exposed, uninfected intravenous drug users (EU-IDU) remains to be elucidated.
We investigated the role of both host genotype and pathogen-induced dendritic cell modulation of NK activation during high-risk activity in a cohort of 15 EU-IDU individuals and 15 control, uninfected donors from Philadelphia.
We assessed the activation status of NK cells and dendritic cells by flow cytometry and utilized functional assays of NK-DC cross-talk to characterize the innate immune compartment in EU-IDU individuals.
As previously reported, NK cell activation (CD69) and/or degranulation (CD107a) was significantly increased in EU-IDU individuals compared with control uninfected donors (P = 0.0056, n = 13). Genotypic analysis indicated that the frequency of protective KIR (KIR3DS1) and HLA-Bw4*80I ligands was not enriched in our cohort of EU-IDU individuals. Rather, plasmacytoid dendritic cells (PDC) from EU-IDU exhibited heightened maturation (CD83) compared with control uninfected donors (P = 0.0011, n = 12). When stimulated in vitro, both PDCs and NK cells from EU-IDU individuals maintained strong effector cell function and did not exhibit signs of exhaustion.
Increased maturation of PDCs is associated with heightened NK activation in EU-IDU individuals suggesting that both members of the innate compartment may contribute to resistance from HIV-1 infection in EU-IDU.
aThe Wistar Institute, HIV Immunopathogenesis Laboratory, Philadelphia, Pennsylvania
bCancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI Frederick, Frederick, MD 21702 and Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA
cThe University of Pennsylvania, Department of Psychiatry, HIV Prevention Division, USA
dPhiladelphia FIGHT, The Jonathan Lax Treatment Center, Philadelphia, Pennsylvania, USA.
Received 10 March, 2010
Revised 30 June, 2010
Accepted 7 July, 2010
Correspondence to Dr Luis J. Montaner, The Wistar Institute, 3601 Spruce Street, Room 480, Philadelphia, PA 19104, USA. Tel: +1 215 898 3934; fax: +1 215 573 9272; e-mail: Montaner@wistar.org