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

Abstract

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 KIR genes 3DL05, 3DS05, and 3DL10 as well as 3DSW08, 3DLW03, and 3DSW09 are correlated, most likely due to underlying haplotypes. SIV-infection outcome associated with presence of transcripts for two inhibitory KIR genes (KIR3DL02, KIR3DL10) and three activating KIR genes (KIR3DSW08, KIR3DS02, KIR3DS05). Presence of KIR3DL02 and KIR3DSW08 was associated with LVL outcome, whereas presence of KIR3DS02 was associated with HVL outcome. Furthermore, we identified epistasis between KIR and MHC class I alleles as the transcript presence of the correlated genes KIR3DL05, KIR3DS05, and KIR3DL10 increased HVL risk when Mamu-B*012 transcripts were also present or when Mamu-A1*001 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.

Improved full-length killer cell immunoglobulin-like receptor transcript discovery in Mauritian cynomolgus macaques

“…A growing amount of evidence suggesting the role of particular activating Mamu-KIR3DS alleles in influencing plasma viral loads in SIV-infected rhesus macaques has surfaced from associative studies (Albrect et al 2014; Chaichompoo et al 2010). Similarly, the copy number of Mamu-KIR3DS genes is speculated to influence peak viral loads following SIVmac251 infection in Indian rhesus macaques.…”

Diversification of both KIR and NKG2 natural killer cell receptor genes in macaques – implications for highly complex MHC‐dependent regulation of natural killer cells

“…identified individual KIR genes with either a protective or a detrimental effect in SIV‐infected rhesus macaques. KIR3DL02 , KIR3DSW08 and most probably also KIR3DS01 are associated with slow disease progression, longer survival times, higher numbers of blood NK cells, and higher lytic capability of NK cells . In contrast, KIR3DS02 , KIR3DL10 and KIR3DL05 were more frequently found in animals with fast disease progression, shorter survival times, lower numbers of blood NK cells, and decreased lytic capability of NK cells .…”

“…In a further study, this group demonstrated high KIR2DL4 copy numbers to be associated with a better preservation of CD4 + T cells and an increased interferon‐ γ production of stimulated CD56 − CD16 − NK cells in SIV‐infected rhesus macaques . Albrecht et al . identified individual KIR genes with either a protective or a detrimental effect in SIV‐infected rhesus macaques.…”

“…). Among the alleles with a beneficial effect in SIV infection were Mamu‐A1 alleles *001, *002, *011 and Mamu‐B alleles *008, *017, *029, *047, and *069, whereas A1*004 and B*001 were associated with susceptibility . Recently, also the presence/absence of KIR genes was included in such SIV disease association studies.…”

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…Specific interactions between KIRs of primates and MHC class I ligands are being identified and monoclonal antibodies against primate KIR proteins are being generated 220, 221. These advances are enabling phenotypic characterization of KIR expression on NK cells and T‐cell subsets in primates and investigation of KIR‐MHC biology in primate models of infectious disease 222, 223, 224…”