Multiple Homozygous Variants in the STING-Encoding TMEM173 Gene in HIV Long-Term Nonprogressors

TY - JOUR

T1 - Multiple Homozygous Variants in the STING-Encoding TMEM173 Gene in HIV Long-Term Nonprogressors

AU - Nissen, Sara K

AU - Pedersen, Jesper G.

AU - Helleberg, Marie

AU - Kjær, Kathrine

AU - Thavachelvam, Karthiga

AU - Obel, Niels

AU - Tolstrup, Martin

AU - Jakobsen, Martin R

AU - Mogensen, Trine H

PY - 2018/5/15

Y1 - 2018/5/15

N2 - Among HIV-infected individuals, long-term nonprogressor (LTNP) patients experience slow CD4 T cell decline and almost undetectable viral load for several years after primary acquisition of HIV. Type I IFN has been suggested to play a pathogenic role in HIV pathogenesis, and therefore diminished IFN responses may underlie the LTNP phenotype. In this study, we examined the presence and possible immunological role of multiple homozygous single-nucleotide polymorphisms in the stimulator of IFN genes (STING) encoding gene TMEM173 involved in IFN induction and T cell proliferation in HIV LTNP patients. We identified LTNPs through the Danish HIV Cohort and performed genetic analysis by Sanger sequencing, covering the R71H-G230A-R293Q (HAQ) single-nucleotide polymorphisms in TMEM173. This was followed by investigation of STING mRNA and protein accumulation as well as innate immune responses and proliferation following STING stimulation and infection with replication-competent HIV in human blood–derived cells. We identified G230A-R293Q/G230A-R293Q and HAQ/HAQ homozygous TMEM173 variants in 2 out of 11 LTNP patients. None of the 11 noncontrollers on antiretroviral treatment were homozygous for these variants. We found decreased innate immune responses to DNA and HIV as well as reduced STING-dependent inhibition of CD4 T cell proliferation, particularly in the HAQ/HAQ HIV LTNP patients, compared with the age- and gender-matched noncontrollers on antiretroviral treatment. These findings suggest that homozygous HAQ STING variants contribute to reduced inhibition of CD4 T cell proliferation and a reduced immune response toward DNA and HIV, which might result in reduced levels of constitutive IFN production. Consequently, the HAQ/HAQ TMEM173 genotype may contribute to the slower disease progression characteristic of LTNPs.This work was supported by a partial Ph.D. scholarship to S.K.N. from the Faculty of Health of Aarhus University. T.H.M. received funding from the Aarhus University Research Foundation (Grant AUFF-E-2015-FLS-66) and the Danish Council for Independent Research–Medical Sciences (Grant 4004-00047B). J.G.P. received a partial Ph.D. scholarship from the Faculty of Health of Aarhus University. M.H. received funding from the Danish National Research Foundation (Grant DNRF126). M.R.J. received funding from the Danish Council for Independent Research (Grants DFF-4004-00237 and DFF-4183-00275) and the Lundbeck Foundation.

AB - Among HIV-infected individuals, long-term nonprogressor (LTNP) patients experience slow CD4 T cell decline and almost undetectable viral load for several years after primary acquisition of HIV. Type I IFN has been suggested to play a pathogenic role in HIV pathogenesis, and therefore diminished IFN responses may underlie the LTNP phenotype. In this study, we examined the presence and possible immunological role of multiple homozygous single-nucleotide polymorphisms in the stimulator of IFN genes (STING) encoding gene TMEM173 involved in IFN induction and T cell proliferation in HIV LTNP patients. We identified LTNPs through the Danish HIV Cohort and performed genetic analysis by Sanger sequencing, covering the R71H-G230A-R293Q (HAQ) single-nucleotide polymorphisms in TMEM173. This was followed by investigation of STING mRNA and protein accumulation as well as innate immune responses and proliferation following STING stimulation and infection with replication-competent HIV in human blood–derived cells. We identified G230A-R293Q/G230A-R293Q and HAQ/HAQ homozygous TMEM173 variants in 2 out of 11 LTNP patients. None of the 11 noncontrollers on antiretroviral treatment were homozygous for these variants. We found decreased innate immune responses to DNA and HIV as well as reduced STING-dependent inhibition of CD4 T cell proliferation, particularly in the HAQ/HAQ HIV LTNP patients, compared with the age- and gender-matched noncontrollers on antiretroviral treatment. These findings suggest that homozygous HAQ STING variants contribute to reduced inhibition of CD4 T cell proliferation and a reduced immune response toward DNA and HIV, which might result in reduced levels of constitutive IFN production. Consequently, the HAQ/HAQ TMEM173 genotype may contribute to the slower disease progression characteristic of LTNPs.This work was supported by a partial Ph.D. scholarship to S.K.N. from the Faculty of Health of Aarhus University. T.H.M. received funding from the Aarhus University Research Foundation (Grant AUFF-E-2015-FLS-66) and the Danish Council for Independent Research–Medical Sciences (Grant 4004-00047B). J.G.P. received a partial Ph.D. scholarship from the Faculty of Health of Aarhus University. M.H. received funding from the Danish National Research Foundation (Grant DNRF126). M.R.J. received funding from the Danish Council for Independent Research (Grants DFF-4004-00237 and DFF-4183-00275) and the Lundbeck Foundation.

KW - Adult

KW - Aged

KW - Anti-Retroviral Agents/therapeutic use

KW - Cell Line

KW - Cohort Studies

KW - Cross-Sectional Studies

KW - Female

KW - Genotype

KW - HEK293 Cells

KW - HIV Infections/drug therapy

KW - HIV Long-Term Survivors

KW - HIV-1/drug effects

KW - Homozygote

KW - Humans

KW - Immunity, Innate/genetics

KW - Lymphocyte Activation/drug effects

KW - Male

KW - Membrane Proteins/genetics

KW - Middle Aged

KW - Polymorphism, Single Nucleotide/genetics

KW - Viral Load/drug effects

U2 - 10.4049/jimmunol.1701284

DO - 10.4049/jimmunol.1701284

M3 - Journal article

C2 - 29632140

SN - 0022-1767

VL - 200

SP - 3372

EP - 3382

JO - Journal of Immunology

JF - Journal of Immunology

IS - 10

ER -