AUTHOR=Albrecht Christina , Malzahn Dörthe , Brameier Markus , Hermes Meike , Ansari Aftab A. , Walter Lutz 

TITLE=Progression to AIDS in SIV-Infected Rhesus Macaques is Associated with Distinct KIR and MHC class I Polymorphisms and NK Cell Dysfunction

JOURNAL=Frontiers in Immunology

VOLUME=5

YEAR=2014

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00600

DOI=10.3389/fimmu.2014.00600

ISSN=1664-3224

ABSTRACT=<p>Killer cell immunoglobulin-like receptors (KIR) regulate the activity of natural killer (NK) cells and have been shown to be associated with susceptibility to a number of human infectious diseases. Here, we analyzed NK cell function and genetic associations in a cohort of 52 rhesus macaques experimentally infected with SIVmac and subsequently stratified into high viral load (HVL) and low viral load (LVL) plasma viral loads at set point. This stratification coincided with fast (HVL) and slow (LVL) disease progression indicated by the disease course and critical clinical parameters including CD4+ T cell counts. HVL animals revealed sustained proliferation of NK cells but distinct loss of peripheral blood NK cell numbers and lytic function. Genetic analyses revealed that <italic>KIR</italic> genes <italic>3DL05</italic>, <italic>3DS05</italic>, and <italic>3DL10</italic> as well as <italic>3DSW08, 3DLW03</italic>, and <italic>3DSW09</italic> are correlated, most likely due to underlying haplotypes. SIV-infection outcome associated with presence of transcripts for two inhibitory <italic>KIR</italic> genes (<italic>KIR3DL02</italic>, <italic>KIR3DL10</italic>) and three activating <italic>KIR</italic> genes (<italic>KIR3DSW08</italic>, <italic>KIR3DS02</italic>, <italic>KIR3DS05</italic>). Presence of <italic>KIR3DL02</italic> and <italic>KIR3DSW08</italic> was associated with LVL outcome, whereas presence of <italic>KIR3DS02</italic> was associated with HVL outcome. Furthermore, we identified epistasis between <italic>KIR</italic> and <italic>MHC class I</italic> alleles as the transcript presence of the correlated genes <italic>KIR3DL05</italic>, <italic>KIR3DS05</italic>, and <italic>KIR3DL10</italic> increased HVL risk when <italic>Mamu-B*012</italic> transcripts were also present or when <italic>Mamu-A1*001</italic> transcripts were absent. These genetic associations were mirrored by changes in the numbers, the level of proliferation, and lytic capabilities of NK cells as well as overall survival time and gastro-intestinal tissue viral load.</p>