Association of interferon regulatory factor-1 polymorphisms with resistance to infection by HIV-1 in Kenyan female sex workers

Resistance to Human Immunodeficiency Virus-l (HIV-l) infection has been observed in multiple cohort studies including a female sex worker cohort established in Nairobi, Kenya.Both host genetic variations and HIV-1 specific immune responses have been described as important components correlating with resistance to HIV-1.Interferon regulatory factor I (IRF-l), a promoter to host immunity and also a transactivator of HIV-I, has a dual role to play in HIV/AIDS.This study reconfirmed our previous finding that 179 allele at microsatellite (MS) region in IRF-I correlated with HIV-I-resistant phenotype in this cohort.Upon this, by near-complete gene sequencing, we demonstrated that the IRF-I gene in Kenyan cohort was highly polymorphic.Fifty-three single nucleotide polymorphisms (SNP) (26 newly identified), 2 insertions and 1 deletion mutation were identified.We identified 35 consistent discrepancies between IRF-1 GenBank sequences and our population-based sequencing data, suggesting that the current GenBank reference sequences for IRF-I is incomplete.The sequence of IRF-I gene and its upstream promoter region was re- established (GenB ank: DQ7 89232).Statistical analysis revealed that, together with 179 allele at the MS region, SNPs at 619 (A/C) and 6516 (G/T) were also significantly correlated with HIV-I resistance.Despite their intronic locations, further functional investigations revealed that PBMCs from subjects with protective IRF-I genotypes/haplotlpes showed: (i) significantly depressed IRF-I protein expression at both a basal expression level and in response to exogenous IFN-y stimulation or infection by an artificially pseudotyped HIV-l construct; (2) significantly increased chances of skipping exon 2 and 3 which contain the IRF-I start codon as well as encode the DNA binding domain of IRF-I protein; (3) significantly decreased frequencies ofskipping exon 7 and 8; (4) A clear trend ofdecreased efficiency of HIV-1 replication early upon infection by HIV-1, suggestive of that these cells are less competent in supporting HIV-1 replication.This study suggests that different IRF-I genotypes/haplotypes and consequently altered expression and function of IRF-I likely compose a significant determinant for the heterogeneity of susceptibility to HIV-I in our Kenyan subject cohort.This study provides insight to natural immunity to HIV-I infection and suggests that effective anti- HIV-I strategies should target not only host immunity, but also factors important in the establishment of HIV-l infection.II Dedication More than any other, I thank my wife, Xuefen Yang, and my two daughters, Jiakai and Jiaqi, for their love, understanding and great support for my study and work.Just because of me, Xuefen gave up her career as a gynecologislObstetrician in China and came to Canada with my daughter, Jiakai.I will never forget those days you worked in Winnipeg even as a sewing machine operator for 11 months!I would say half of my achievement should belong to you, my love.Without your support, I cannot even imagine how possible it could be for me to pursue a Ph.D degree with a second language in a foreign country!We did it, together!ilI List of Tables Oligonucleotide Primers used for first round IRF-1 sequencing ...........56 Oligonucleotide Primers used for full-length IRF-I sequencing ..........61 Reagents for reverse transcriptase assay cocktail """77 Polymorphisms in theIRF-1 gene and its promoter region detected in a Kenyan population " "'85 SNPs in IRF-l gene and its promoter region submitted to dbSNP..........87 Deletion mutation identified in intron 7 of IRF-I gene.. ""'88 Complete linkage between 4227 and other SNP's within the IRF-I gene..... '.93 pairwise LD estimates for all sNPs with minor allele frequency higher than 0.l ." ""95 Consistent discrepancies between GenBank sequences and our detected sequences.....""""'97 Distributions of specific IRF-1 alleles and genotypes in HIV-1-resistant and HlV-l-susceptible subjects " """108 Distributions of specific IRF-1 haplotypes consist of variations at [RF-1 MS, 619 and 6516 in HIV-1-resistant and HIV-i-susceptible subjects ....'...116 IRF-I allele frequencies before and after 1993 ' .'.""""'122Frequencies of different exon skippings in subjects with different IRF-1 haplotypes '.."""""136 X subt)?es found mainly in West African countries such as Cameroon and Gabon.In the September 1, 1998 issue of Nature Medicine, F. Simon announced the discovery of a variant of HIV-I that fits neither the M nor O group (Simon et al., 1998).It seems to fall between the M-group and the simian immunodeficiency virus (SIV) and classified as N- group.Recombinant strains originated from co-infection of different but related strains of HIV-I have also been noted.When viruses of different subtypes co-infect the same cell and exchange their genetic materials, a new hybrid virus can be created (Burke, 1997).Many of these new strains do not survive for long, but those that are transmissible and able to infect more than one person are known as "circulating recombinant forms" or CRFs, of which at least 19 strains are currently identified(Casado et a1.,2005;Robertson et a1.,2000).The 8th Conference on Retroviruses and Opportunistic Infections in 2001 saw the publication indicating that as many as l4o/o of new infections are recombinant.HIV-I life cycle HtV-l follows a typical retrovirus life cycle as it infects target cells and reproduces.Without any intervention, a series of successive steps are followed in fulfilling the infection and replication of HIV-I.The initial step is attachment in which the virion adheres to the tzrget cell and this is mediated through the interaction between viral envelope glycoproteins (gp120 and gp41) and receptor molecules (CD4, CCR5, CXCR4) expressed on the surface of target cells.The upregulation of these molecules makes activated T cells the main targets to HIV-I infection.The second step is fusion and Figure 13 Kaplan-Meier survival analysis comparing individuals with different IRF-1 genotypes b a 6810121416 TOTAL NEGATIVE YEAR d p =0.0001 Haza¡d Ratio:0.45895% Cl: 0.305-0.689Log rank:14.81

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