Polymorphisms in Toll-Like Receptors (TLRs)-7 and 9 Genes in Indian Population with Progressive and Nonprogressive HIV-1 Infection Nawaj Shaikh, 1 Amit Nirmalkar, 2 and Madhuri Thakar 1 Abstract The polymorphisms in Toll-like receptor (TLR) 7 and 9 genes are shown to influence HIV-1 infection. We studied HIV-1-infected Indian individuals for presence and association of TLR7 and 9 gene polymorphism with different disease outcomes. Genomic DNA from 65 HIV-infected individuals (35 long-term nonprogressors and 30 progressors) and 89 uninfected healthy donors was isolated, amplified, and sequenced for the reported polymorphisms in TLR7 [Gln11Leu (A/T); rs179008] and TLR9 (1635A/G; rs352140) genes. Of these, only the reported TLR9 single-nucleotide polymorphism [SNP; p = .017, odds ratio (OR) = 0.20] and its allele A fre- quency ( p = .038, OR = 0.41) were found to be associated with slow disease progression. Of the new SNPs observed (three TLR7 and two TLR9), the TLR7 rs2074109 G allele showed less likely association with HIV-1 acquisition ( p = .019, OR = 0.27). These findings indicate that TLR7 SNP (rs2074109) could be one of the factors for predisposition to HIV-1 and TLR9 1635A/G genotype and allele might have a role in HIV-1 disease progression in Indian population. Keywords: TLR, LTNP, HIV, disease progression, polymorphism, SNP, haplotypes, host restriction factors Introduction H ost genetic factors have been shown to influence on acquisition of Human Immunodeficiency virus (HIV) and disease progression after HIV infection. 1,2 The host restriction factors like APOBEC3G, TRIM5a, SAMHD1, BST/Tetherin, HERC5, and MHC molecules have shown to play a role in HIV infection by blocking or restricting ret- roviral replication at various stages of HIV life cycle. 2,3 While some host factors are associated with the resistance to HIV acquisition, some are associated with slower/faster disease progression. 3,4 Recently, the innate immune response has been shown to influence the HIV disease progression. 5 The Toll-like receptor (TLR) genes encode a family of transmembrane proteins essential for the innate immune rec- ognition of pathogens. 6 With the help of an extracellular do- main, TLRs identify conserved molecular motifs from a variety of organisms, including bacteria, fungi, parasites, and viru- ses. 5,7 Through the intracellular domains, TLRs interact with several adaptor proteins to activate transcription factors, leading to the production of inflammatory cytokines and the activation of the adaptive immunity. 6 Polymorphisms in TLR genes are known to be associated with increased sus- ceptibility or protection against several infections. 8,9 Stu- dies on single-nucleotide polymorphisms (SNPs) in TLR7 [Gln11Leu (A/T); rs179008] and TLR9 (1635A/G; rs352140) have shown to be associated with HIV disease progres- sion, 1,10–14 while some studies have showed that there is no such association. 15 These observations are made in Caucasian populations. Indians differ ethnically from the Caucasians and also have number of environmental influences on the innate immune responses. 16 The TLR polymorphism has not been studied in Indian population in context with the HIV disease progression. Hence, a study was planned to determine the known reported polymorphisms in TLR7 [Gln11Leu (A/T); rs179008] and TLR9 (1635A/G; rs352140) in HIV-1-infected individuals with progressive and nonprogressive HIV-1 infection and HIV-1-uninfected healthy individuals. We used the HIV-1- infected Long-Term Nonprogressors (LTNPs) as a model of absence of disease progression. Thirty five LTNPs [antiretroviral therapy (ART)-naive, asymptomatic HIV-1-infected individuals with stable CD4 count above 500 cells/mm 3 for 7 or more years without the ART] were enrolled from the ongoing cohort of LTNPs at the National AIDS Research Institute (NARI), Pune, along with 30 progressors (ART-naive HIV-1-infected individuals with CD4 < 500 cells/mm 3 and not fitting in LTNP criteria) and 89 healthy controls from the outpatient clinics of the institute. Demographic details are given in Table 1. The study was Departments of 1 Immunology and Serology and 2 Epidemiology and Biostatistics, National AIDS Research Institute, Pune, India. AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 35, Number 6, 2019 ª Mary Ann Liebert, Inc. DOI: 10.1089/aid.2019.0004 577 Downloaded by 54.162.69.248 from www.liebertpub.com at 06/26/20. For personal use only.