The Role of Genetic Polymorphisms in the Chemokine and their Receptors and Cytokines in the Human Immunodeficiency Virus Type 1 (HIV-1) Infection (original) (raw)
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The Journal of Infectious Diseases, 2010
High-throughput genome-wide techniques have facilitated the identification of previously unknown host proteins involved in cellular human immunodeficiency virus (HIV) infection. Recently, 3 independent studies have used small interfering RNA technology to silence each gene in the human genome to determine the importance of each in HIV infection. Genes conferring a significant effect were termed HIV-dependency factors (HDFs).
Role of chemokine and cytokine polymorphisms in the progression of HIV1 disease
Biochemical and Biophysical Research Communications, 2010
Allelic variants of the genes for chemokine receptors and their natural ligands, the chemokines, and cytokines can affect HIV-1 disease progression. This study investigates the level of expression of the CCR5-Δ32, CCR2b-641, RANTES In1.1C, SDF-1 3′A, IL-10-5′–592A and IL-4–589T alleles in two unique HIV-1 infected patient cohorts that represent the two distinct stages of disease progression, namely rapid progressors (RPs) and long term non-progressors (LTNPs) (n = 12/group) were recruited. Quantitation of the gene expression of CCR5-Δ32, CCR2b-641, RANTES In1.1C, SDF-1 3′A, IL-10-5′−592A and IL-4–589T in peripheral blood mononuclear leukocytes (PBML) isolated from patients was performed by real time, quantitative (Q)-PCR using DNA was isolated from PBML. We observed that expression of these HIV-protective alleles was generally greater in the LTNP cohort than the RP cohort. LTNPs expressed more of the protective chemokine, SDF-1α than RPs, and no statistically significant difference was observed in RANTES production between the LTNPs and RPs. The LTNPs expressed significantly less amounts of cytokines IL-10 and IL-4 as compared to the RPs. Our results demonstrate that gene polymorphisms for CCR5-Δ32, CCR2b-641, RANTES In1.1C, SDF-1 3′A, IL-10-5′−592A and IL-4–589T may be used as clinical markers to predict progression of HIV-1 infections.
Current Medicinal Chemistry, 2007
The natural history and pathogenic processes of infection by the human immunodeficiency virus type 1 (HIV-1) are complex, variable, and dependent upon a multitude of viral and host factors and their interactions. The CCR5-∆32 allele remains the most important genetic factor known to be associated with host resistance to the HIV-1 infection. However, other mutations in the CCR5, CCR2, CX 3 CR1, CXCL12 (SDF1), and CCL5 (RANTES) genes have been identified and associated with host resistance and/or susceptibility to HIV-1 infection and disease progression. Some studies have also suggested that chemokine receptor gene polymorphisms may affect response to potent antiretroviral therapy. This article reviews the polymorphisms already described in the mutant chemokine receptors or ligands and their impact on the host susceptibility to HIV-1 infection and on the clinical course of the disease, as well as the development of new anti-HIV therapies that takes into account these potential targets in the host. These genetic polymorphisms could be used as genetic markers to detect individuals at higher risk of developing either a faster disease progression or therapeutic failure. Once these individuals are identified, therapeutic strategies based on either different, more aggressive drugs or combinations of drugs can be used, either alone or in combination with shorter intervals for therapeutic monitoring. Pharmacogenetics is very likely to underlie future therapies for HIV-1 infection, and current patients with multi-resistance to the existing antiretroviral agents could also benefit from this approach. These developments also underscore the importance of continuing the investigation of new therapies targeted to the host in order to inhibit the HIV-1 entry into the host cells.
Genetic determinants of HIV-1 infection and progression to AIDS: immune response genes
Tissue Antigens, 2009
Genomic studies involving well-defined multicenter cohorts of HIV-1/AIDS covering multiple populations have led to a greater understanding of the role of host determinants in viral acquisition, disease progression, transmission, and response to anti-retroviral therapy. Similarly, recent knowledge on the virus genetic diversity has helped in elucidating mechanisms leading to the evolution of viral escape mutants and the role played by host immune determinants, in particular the major histocompatibility complex (MHC) associated genes. At least two alleles, HLA-B*27 and B*57, have been identified as 'protective' against HIV-1 while B*35 and B*53 act as susceptibility favoring factors. How human leukocyte antigen (HLA)-mediated selection drives the evolution of HIV-1 and which circulating variants are more likely to evade immune surveillance of the population are now beginning to become clear. Importantly, the rare HLA alleles in a population bear a selective advantage to the host because these can induce immune responses against pre-adapted viruses. It is conceivable that previously established protective HLA associations are shifting with the evolving cytotoxic T lymphocyte (CTL) epitopes and may not remain protective in future. At the same time, this process is unraveling novel subdominant epitopes of the virus which could now be incorporated as the dominant target CTL epitopes. An insight into the population-specific correlates of protection is hence necessary for designing future anti-HIV therapeutic and/or prophylactic vaccine formulation(s).
Modulating influence on HIV/AIDS by interactingRANTESgene variants
Proceedings of the National Academy of Sciences, 2002
RANTES (regulated on activation normal T cell expressed and secreted), a ligand for the CC chemokine receptor 5, potently inhibits HIV-1 replicationin vitro. We tested the influence of fourRANTESsingle nucleotide polymorphism (SNP) variants and their haplotypes on HIV-1 infection and AIDS progression in five AIDS cohorts. Three SNPs in theRANTESgene region on chromosome 17 (403Ain the promoter,In1.1Cin the first intron, and3′222Cin the 3′ untranslated region) are associated with increased frequency of HIV-1 infection. The commonIn1.1CSNP allele is nested within an intronic regulatory sequence element that exhibits differential allele binding to nuclear proteins and a down-regulation of gene transcription. TheIn1.1Callele or haplotypes that includeIn1.1Cdisplay a strong dominant association with rapid progression to AIDS among HIV-1-infected individuals in African-American, European-American, and combined cohorts. The principalRANTESSNP genetic influence on AIDS progression derives f...
Journal of Virology, 2005
Humans differ substantially with respect to susceptibility to human immunodeficiency virus type 1 (HIV-1). We evaluated variants of nine host genes participating in the viral life cycle for their role in modulating HIV-1 infection. Alleles were assessed ex vivo for their impact on viral replication in purified CD4 T cells from healthy blood donors (n ؍ 128). Thereafter, candidate alleles were assessed in vivo in a cohort of HIV-1-infected individuals (n ؍ 851) not receiving potent antiretroviral therapy. As a benchmark test, we tested 12 previously reported host genetic variants influencing HIV-1 infection as well as single nucleotide polymorphisms in the nine candidate genes. This led to the proposition of three alleles of PML, TSG101, and PPIA as potentially associated with differences in progression of HIV-1 disease. In a model considering the combined effects of new and previously reported gene variants, we estimated that their effect might be responsible for lengthening or shortening by up to 2.8 years the period from 500 CD4 T cells/l to <200 CD4 T cells/l.
The American Journal of Human Genetics, 2006
CCL3 (MIP-1a), CCL4 (MIP-1b), and CCL18 (DC-CK1/PARC/AMAC-1) are potent chemoattractants produced by macrophages, natural killer cells, fibroblasts, mast cells, CD4 + T cells, and CD8 + T cells. CCL3 and CCL4 are natural ligands for the primary human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and are also known to activate and enhance the cytotoxicity of natural killer cells. Genomic DNAs from 13,000 participants enrolled in five United Statesbased natural-history cohorts with acquired immunodeficiency syndrome (AIDS) were genotyped for 21 single-nucleotide polymorphisms (SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18. All 21 SNPs were polymorphic in African Americans (AAs), whereas 7 of the 21 had minor-allele frequencies !0.01 in European Americans (EAs). Substantial linkage disequilibrium was observed in a 37-kb interval containing 17 SNPs where many pairwise D values exceeded 0.70 in both racial groups, but particularly in EAs. Four and three haplotype blocks were observed in AAs and EAs, respectively. Blocks were strongly correlated with each other, and common haplotype diversity within blocks was limited. Two significant associations are reported that replicate an earlier study. First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (). Second, seven highly correlated SNPs spanning P p .02-.03 36 kb and containing all three genes were significantly associated with more-rapid disease progression among EAs enrolled in the Multicenter AIDS Cohort Study cohort (). These results reiterate the importance of chemokine gene P p .01-.02 variation in HIV-1/AIDS pathogenesis and emphasize that localized linkage disequilibrium makes the identification of causal mutations difficult.