KIR and HLA-C Genetic Polymorphisms Influence Plasma IP-10 Concentration in Antiretroviral Therapy-Naive HIV-Infected Adult Zimbabweans

Kudakwashe Mhandire; Lynn Sodai Zijenah; Mqondisi Tshabalala; Louis-Marie Yindom; Tommy Mlambo; Doreen Zvipo Mhandire; Cuthbert Musarurwa; Kerina Duri; Sarah Rowland-Jones; Collet Dandara; Babill Stray-Pedersen

doi:10.1089/omi.2018.0147

KIR and HLA-C Genetic Polymorphisms Influence Plasma IP-10 Concentration in Antiretroviral Therapy-Naive HIV-Infected Adult Zimbabweans

OMICS. 2019 Feb;23(2):111-118. doi: 10.1089/omi.2018.0147. Epub 2019 Jan 7.

Authors

Affiliations

¹ 1 Department of Chemical Pathology, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe.
² 2 Letten Foundation Research House, Harare, Zimbabwe.
³ 3 Department of Immunology, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe.
⁴ 4 Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
⁵ 5 Division of Human Genetics, Department of Clinical Laboratory Sciences, University of Cape Town, Cape Town, South Africa.
⁶ 6 Institute of Clinical Medicine, University of Oslo and Women's Clinic, Rikshospitalet, University Hospital, Oslo, Norway.

PMID: 30614763
DOI: 10.1089/omi.2018.0147

Abstract

Past studies on the relationship between Killer cell Immunoglobulin-like Receptor (KIR) and Human Leukocyte Antigen (HLA) genetic variation and chronic immune activation (CIA) in HIV infection are not uniformly consistent. Moreover, interferon-γ-induced protein 10 (IP-10) is a soluble biomarker of immune activation, with high plasma concentrations predicting accelerated disease progression in HIV infection. Thus, we investigated the association of KIR and HLA-C genetic polymorphisms with plasma IP-10 concentration in 183 treatment-naive chronically HIV-infected adults of Bantu origin from Zimbabwe. KIR genetic variation was determined using allele-specific primer PCR while HLA-C typing was characterized by sequencing. Plasma IP-10 was quantified using enzyme-linked immunosorbent assay. The KIR2DL3 gene was significantly associated with CIA as observed from IP-10 concentrations among KIR2DL3 carriers (265.20 pg/mL, IQR: 179.99-385.19) compared with KIR2DL3 noncarriers (183.56 pg/mL; IQR: 110.98-230.81; p = 0.001) and among KIR2DL3+HLA-C2 carriers (226.23 pg/mL, IQR: 187.96-394.73) compared with KIR2DL3+HLA-C2 noncarriers (212.86 pg/mL, IQR: 160.15-344.99; p = 0.017), respectively. Similarly, IP-10 concentrations were significantly higher (p = 0.030) in the KIR3DS1 carriers (313.86 pg/mL, IQR: 230.05-469.20) compared with KIR3DS1 noncarriers (246.01 pg/mL, IQR: 169.58-373.32). Thus, KIR and HLA-C could be playing important roles in HIV-associated immune activation. The elevation of IP-10 in KIR2DL3 and KIR2DL3+C2 could potentially be explained by increased IFN-γ secretion from activated NK cell activation due to the absence of KIR2DL3's cognate C1 ligand. To the best of our knowledge, this is the first study on a potential link between KIR and HLA-C genetic determinants and plasma IP-10 concentration in this population sample. Future studies are called for in other world populations for biomarkers of disease progression and mechanisms of IP-10 variability in HIV infection.

Keywords: HIV disease progression; HLA; IP-10; KIR; biomarkers; immune activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alleles
Anti-Retroviral Agents / therapeutic use*
Biomarkers / blood
Chemokine CXCL10 / blood*
Female
Genetic Predisposition to Disease
Genotype
HIV Infections
HLA-C Antigens / genetics*
Humans
Killer Cells, Natural / metabolism
Male
Polymorphism, Genetic / genetics*
Receptors, KIR / genetics*
Zimbabwe

Substances

Anti-Retroviral Agents
Biomarkers
CXCL10 protein, human
Chemokine CXCL10
HLA-C Antigens
Receptors, KIR