Association Between Polymorphisms Of CCR5Gene And HIV Infection, Disease Progression:Systematic Review

Background:AIDS (Acquired Immune Deficiency Syndrome. AIDS) is a chronic infectious disease which caused by the human immunodeficiency virus (HIV). HIV destroys the human immune system, causes the acquired immune deficiency syndrome, and eventually leads to death by infecting the CD4+cells. The researches show that the different people have different susceptibility to HIV, and the HIV-infected patients reveal different progression-rate. The phenomena may be related to the host genetic background. A large number of studies focus on chemokine receptor and ligand gene polymorphisms, and the relationship with HIV infection and disease progression. More attention is on the chemokine receptor5(CC-chemokine receptor, CCR5) gene, which is the co-receptor of HIV into CD4T cells. Numerous polymorphisms exist in the gene regulatory region and the coding region, influent the expression of CCR5in CD4+cell surface, thus affecting the HIV infecting CD4+cells, and ultimately affect the host’s susceptibility to HIV and the rate of disease progression. At present, there were the multitudinous studies on the relationship between polymorphisms of CCR5gene and HIV infection, disease progression, but the conclusions still had some controversies.Objective:A systematic review had been performed for evaluating comprehensively the past literatures about the association between CCR5gene polymorphism and HIV infection, disease progression which were included. We expected to clear if the host CCR5gene polymorphisms play an important role in the course and disease progression of HIV infection or not, as well as the influencing factors, in order to provide reliable evidence for the formulation of AIDS prevention and treatment strategies.Methods:Evidence-based medicine systematic review was performed to develop the technical route, the following major elements:1. Literature search:Using MeSH(Medical Subject Headings) and free words to search at the same time. Developing a search strategy which followed with the integrity as the premise and taked the specificity into account. The search terms included three aspects:(1) AIDS-related vocabularies;(2) CCR5-related vocabularies;(3) Susceptibility-related, Polymorphisms-related and Disease progression-related vocabularies. The main search databases included PubMed. EMBASS, CBM and VIP and so on. Other search channels include references, network search engines, and AIDS-related professional journals and Web sites.2. Criteria for inclusion and exclusion of the literatures:The inclusion criteria included all of the studies about the CCR5gene polymorphisms and HIV infection and disease progression. Exclusion criteria were non-population-based studies and non-detailed data required studies.3. Screening and evaluating the quality of the literatures:Two reviewers screened and assessed the quality of literatures at the same time, using the CASP (Critical Appraisal Skills Programme) and NOS (Newcastle-Ottawa Scale)4. Analyzing the heterogeneity of the literatures:Evaluating the heterogeneity among the various researches by using the Q test, I2test and H test. The sources of heterogeneity were analyzed.5. Combining effect size:If there existed no heterogeneity among studies, using a fixed effect model to combine the effect size. If there was heterogeneity among studies, using subgroup analysis according to the sources of heterogeneity or using the random affects model. If the studies had small amount or the heterogeneity was large, just using descriptive analysis.6. The sensitivity analysis:Analyzing factors that may affect the stability of results, excluding this factor to re-examine the stability of the results. Or using the fixed effect model and random effects model simultaneously to combine of effect size, and examining the stability of the results.7. Publication bias analysis:using of Begg’s and Egger’s test and the nonparametric trim and fill method integratedly to examine the publication bias.8. The statistical analysis of data was performed with Stata10.0statistical package.Results:Section one:the association between CCR5gene polymorphisms and HIV infection.1. A total of37literatures were included. CCR5gene polymorphisms in the studies included the A32polymorphism in the coding region, the promoter region’s59029A/G,59353T/C,59356C/T,59402A/G and59653C/T et al. The designs of the studies were case-control study and the quality of research was basically in line with the case-control study of the evaluation criteria.2. The association between CCR5gene Δ32polymorphisms in coding region and HIV infection.(1) There were20studies in which control groups were the general population. The total numbers of cases were4397and the controls were5776. Two CCR5Δ32/Δ32homozygous cases were detected in the case groups with the detection rate was0.05%and control groups was37cases with the detection rate was0.64%. Compared with the wild homozygote, the pooled OR and95%CI of CCR5Δ32/Δ32mutation homozygote were0.172(0.069～0.434), the pooled OR and95%CI of CCR5Δ32/WT heterozygote were1.033(0.829～1.288).(2) There were9studies in which control groups were the long-term exposure but uninfected people. The total numbers of cases were1793and the controls were655. None of CCR5Δ32/Δ32homozygote was detected in case groups, but9 CCR5Δ32/A32homozygous cases were detected in the long-term exposure uninfected groups with a detection rate of1.37%. Compared with the wild homozygote, the pooled OR and95%CI of CCR5A32/A32homozygote were0.057(0.008～0.420), the pooled OR and95%CI of CCR5A32/WT heterozygote were0.900(0.648to1.252).(3) There were9studies in which the objects were children (all be born with HIV-positive mothers). The total numbers of cases were1388and the controls were1928. One CCR5A32/A32homozygous was detected in the case groups with a detection rate of0.07%and control groups was4cases with a detection rate of0.2%. Compared with the wild homozygote, the pooled OR and95%CI of CCR5A32/A32homozygote were0.438(0.097～1.974), the pooled OR and95%CI of CCR5Δ32/WT heterozygote were1.019(0.781～1.329)3. The association between CCR5promoter gene polymorphisms and HIV infection.(1) The relationship of the promoter59029A/G polymorphisms with HIV infection in7studies were analyzed, the total number of the cases was1282and the controls was1194. Allelic frequency of59029G were39～43%in European and55～61%in Asian. In the European population,59029G allele might increase the risk of HIV infection (G/G&G/A vs AA:OR=1.478,95%CI:1.033～2.115), but in Africa populations (G/G&G/A vs AA:OR=0.711,95%CI:0.523～0.948) and in the Asian population (Indian)(G/G&G/A vs AA:OR=0.489,95%CI:0.257～0.931), the59029G mutation might reduce the risk of HIV infection.(2) The relationship of the59353T/C polymorphisms with HIV infection were analyzed in7studies, the total number of cases was751and the controls was1023. Allelic frequency of59353C were52～57%in European and39～42%in Asian. Overall, there was no association between the59353T/C polymorphisms and the susceptibility of HIV. But in the children subgroup, the pooled OR and95%CI of (C/C&C/T vs T/T) were0.712(0.522～0.971).(3) The relationship of59356C/T polymorphisms with HIV infection were analyzed in5studies(the objects were children in studies), the total number of the cases were553and the controls were982. Allelic frequency of59356T was7～12%in children and2%in adult (Indian). In the children population.59356T/T homozygous genotype might increase the risk of HIV infection, the pooled OR and95%CI were3.718(1.777～7.777).(4) The relationship between the59402A/G polymorphisms and HIV infection were analyzed in6studies, the total number of the cases was846and the controls was1440. Allelic frequency of59402G were24～28%in children, were43～51%(Asian) and13%(African) in adult. Meta-analysis result showed that neither in the children group nor adult group,59402A/G polymorphisms was correlated with the susceptibility to HIV.(5) The relationship between the59653C/T polymorphisms and HIV infection were analyzed in6studies, the total number of the cases was1013and the controls was977. Allelic frequencies of59653T were9～17%, but59653T was not detected in Indian population. Meta-analysis result showed that59653C/T polymorphisms were not correlated with the susceptibility to HIV.Section two:The association between CCR5gene polymorphisms and HIV disease progression.1. A total of24studies on the relationship between CCR5gene polymorphisms and HIV disease progression were included, the study designs were case-control study and survival analysis. CCR5gene polymorphisms included the Δ32in the coding region, the59029A/G and59353C/T in the promoter region.2. The relationship between the CCR5A32polymorphisms and HIV disease progression.(1) There were11studies which explored distribution differences of CCR5Δ32/WT genetype among LTNP group, TP group and RP group. The total numbers of cases were671in LTNP group,1088in TP group and413in RP group. Comparison of LTNP group and TP group (11studies), the pooled OR and its95%CI was0.460(0.308～0.686). Stratified by race, the pooled OR and its95%CI was0.423(0.262～0.684) in European population. Stratified by age, the pooled OR and its95% CI were0.470(0.300-0.739) in adults, and was0.331(0.124-0.886) in children. Comparison of LTNP group and RP group (6studies), the pooled OR and its95%CI was0.237(0.106～0.529). Stratified by race, the pooled OR and its95%CI was0.217(0.092～0.510) in European population. Stratified by age, the pooled OR and its95%CI was0.274(0.122～0.613) in adults, and was0.145(0.006～3.290) in children. Comparison of TP group and RP group (6studies), the pooled OR and its95%CI was0.4960.225～1.093). Stratified by race, the pooled OR and its95%CI was0.455(0.195～1.059) in European population. Stratified by age, the pooled OR and its95%CI was0.544(0.232-1.272) in adults, and was0.362(0.027～4.780) in chileren. The results showed that the distribution of CCR5Δ32/WT genotype between the TP and RP populations was not significantly difference (Z=1.74, P=0.082).(2) There were8studies which explored hazard ratio(HR) of CCR5A32/WT vs CCR5WT/WT from HIV infection progression to AIDS. Stratified by race, the pooled HR and its95%CI was0.629(0.471～0.840) in European population. The results showed the HIV infected patients who carried CCR5Δ32/WT and had the risk of progression to AIDS was62.9%, compare to those who carried CCR5WT/WT homozygous wild type in European population.3. The association between CCR5promoter polymorphisms and HIV disease progression(1) There were3studies which explored distribution differences of CCR5promoter59029A/G genetype among the LTNP group, the RP group and the TP group. The total numbers of the LTNP group was348, the RP group was175and the TP group was404. Comparison of the LTNP group and the RP group, after excluding the CCR5Δ32mutation and the CCR2-64I mutation, the pooled OR and its95%CI of59029(A vs. the G) and (the AA&AG, vs. the GG) were1.863(1.010～3.437) and2.112(1.235～3.614). Comparison of the LTNP group and the TP group, after excluding the CCR5Δ32mutation and the CCR2-64I mutation, the pooled OR and95%CI of all comparison models included1, the P values of hypothesis testing were greater than0.05. Comparison of the RP group and the TP group, after excluding the CCR5A32mutation and the CCR2-64I mutation, the pooled OR and95%CI of59029(A vs G) model was1.442(1.050～1.980),59029(AA vs GG) model was2.120(1.102～4.080),59029(AA&AG vs GG)model was1.772(1.060-2.963).3studies analyzed that the risk of progression to AIDS or death in HIV-infected individuals who carried the59029A/A or A/G genotype compared to59029G/G genotype. The results showed that in European populations the risk of HIV-infected patients who carried the59029A/A genotype was higher than those who carried the59029G/G.(2) There were3studies which analyzed distribution differences of CCR5promoter59353T/C genetype among the LTNP group, the RP group and the TP group. The total number of LTNP group was123and the RP group was125, the TP group was199. The frequency of C/C genotype in the RP group was significantly higher than in the LTNP group and the TP group. The risk of progression to AIDS (CD4+T <200) of HIV infected who carried59353(C/C&C/T) genotype was higher than those who carried the59353T/T genotype.Conclusions:Section one:the association between CCR5gene polymorphisms and HIV infection1. CCR5A32mutation was mainly distributed in the Caucasian population. Allelic frequency of CCR5A32was9.34%in Caucasian and was rarely in other races. Therefore there was important significant in the European population to assess relationship between HIV infection and CCR5A32.2. CCR5Δ32/Δ32mutation homozygous was rarely detected in HIV infected patients, but the heterozygous could be frequently detected.3. In the adult, whether the general population controls, or long-term exposure uninfected controls, CCRΔ32/Δ32homozygous could reduce the risk of HIV infection, while the CCR5A32/WT heterozygotes and HIV susceptibility was not relevant. Therefore it can be concluded that CCR5Δ32/A32mutation homozygotes can prevent HIV transmission in the adults (route of transmission including sexually transmission and injection-drug transmission). 4. Either the CCR5A32/A32homozygous or heterozygous CCR5A32/WT, the risk of HIV vertical transmission had been reduced in children. Therefore we can think that HIV transmission mechanism in the adults might be different of in vertical transmission.5. The CCR5gene promoter59029G allelic mutations might reduce the risk of HIV infection in the Africa-Americans and Indians.6. The CCR5gene promoter59353C allelic mutations might reduce the risk of HIV infection in children.7. With C/C homozygotes compared, CCR5gene promoter59356T/T homozygote increased the risk of HIV infection in children.8. In general, the CCR5gene promoter59402G allelic mutations and susceptibility to HIV was not related, but a single study showed that59402G allelic mutations may reduce the risk of HIV infection in children and adult.9. CCR5gene promoter59653C/T polymorphisms and susceptibility to HIV was not related.Section two:the association between CCR5gene polymorphisms and HIV disease progression.1. In the European population, HIV-infected patients who carried CCR5A32/WT heterozygous had a significantly higher risk than those who carried the homozygous wild-type. In the LTNP group, the frequency of CCR5A32/WT heterozygous genotype was significantly higher than in the TP population and RP population, but between the TP group and RP group the CCR5A32/WT heterozygous genotype frequency was not significantly different. This showed that CCR5A32/WT heterozygous genotype played a role to prevent HIV disease progression in LTNP population, but once the disease begin to progress, block effect may be limited.2. The frequency of CCR5promoter59029A in the RP group was significantly higher than in the LTNP group and TP group, while between the LTNP group and TP group, genetype frequency was not significantly different, which showed that the59029A related to HIV rapid progression. The survival analysis also showed that HIV-infected patients who carried59029A/A genotype had a significantly increased risk on the infection with HIV progress to AIDS in European, but the risk of progress to death had no significant increase. In addition, the results revealed that people infected with HIV carried CCR5promoter59353C/C genotype had a significantly increased risk on the progress to AIDS.59029A and59353C were associated with rapid progression of HIV disease because that they linked tightly on the chromosome.