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1.  F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort 
Background
Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk.
Design and Methods
Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed.
Results
H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development.
Conclusion
H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.
doi:10.1111/hae.12004
PMCID: PMC3521089  PMID: 22958194
F8 haplotype; FVIII inhibitors; haplotype mismatch
2.  Role of GB Virus C in Human Immunodeficiency Virus Type-1- and Hepatitis C Virus-infected Hemophiliac Children and Adolescents 
Journal of acquired immune deficiency syndromes (1999)  2012;61(2):10.1097/QAI.0b013e31826218e1..
Background
GBV-C has been associated with a better prognosis of HIV-1 disease in adults. Little is known about prevalence and interaction between GBV-C, HIV-1, and/or HCV in hemophiliac children and adolescents.
Methods
A well characterized cohort of HIV-1-infected and -uninfected hemophiliac children and adolescents followed in the Hemophilia Growth and Development Study (HGDS) were evaluated using qRT-PCR to detect GBV-C RNA in samples from baseline and last follow-up visit.
Results
HIV-1-infected (n=202) and -uninfected (n=119) patients had a low prevalence of GBV-C infection at baseline (0.9 and 0%), which increased at time of last follow-up visit to 25.2% and 26.3%, respectively. In addition, at the time of the follow-up GBV-C measurement, those GBV-C-infected had been followed longer and had higher CD4+ cell counts and lower HIV-1 viral loads than those GBV-C-uninfected. These beneficial effects of GBV-C were no longer significant after controlling for CD4+ cell count and HIV-1 RNA at baseline. HCV RNA clearance was more common amongst those who were not GBV-C infected than those who became GBV-C-viremic.
Conclusions
This study confirms a positive association of GBV-C with milder course of HIV-1 infection. GBV-C infection was associated with a higher likelihood of persistent HCV infection.
doi:10.1097/QAI.0b013e31826218e1.
PMCID: PMC3548052  PMID: 23007118
GB Virus C; Hepatitis Virus C; Humane Immunodeficiency Virus; co-infection; hemophilia
3.  Genome wide association study of spontaneous resolution of hepatitis C virus infection 
Annals of internal medicine  2013;158(4):235-245.
Background
Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person’s lifetime risk of cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and in persons with a genetic variant near IL28B, the genetic basis is not well understood.
Objective
To evaluate the host genetic basis for spontaneous resolution of HCV infection.
Design
Two-stage genome wide association study (GWAS).
Setting
13 international multicenter study sites.
Patients
919 individuals with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 individuals with serum HCV antibodies and RNA (persistence).
Measurements
Frequencies of 792,721 SNPs.
Results
Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL28B and included rs12979860 (overall per-allele OR = 0.45, P = 2.17 × 10−30) and 10 additional SNPs spanning 55,000 bases. On chromosome 6, allele frequency differences localized near genes for class II human leukocyte antigens (HLA) and included rs4273729 (overall per-allele OR= 0.59, P = 1.71 × 10−16) near DQB1*03:01 and an additional 116 SNPs spanning 1,090,000 base pairs. The associations in chromosomes 19 and 6 were independent, additive, and explain an estimated 14.9% (95% CI: 8.5–22.6%) of the variation in HCV resolution in those of European-Ancestry, and 15.8% (95% CI:4.4–31.0%) in individuals of African-Ancestry. Replication of the chromosome 6 SNP, rs4272729 in an additional 746 individuals confirmed the findings (p=0.015).
Limitations
Epigenetic effects were not studied.
Conclusions
IL28B and HLA class II are independently associated with spontaneous resolution of HCV infection and SNPs marking IL28B and DQB1*03:01 may explain ~15% of spontaneous resolution of HCV infection.
doi:10.7326/0003-4819-158-4-201302190-00003
PMCID: PMC3638215  PMID: 23420232
4.  APOBEC3B Deletion and Risk of HIV-1 Acquisition 
The Journal of infectious diseases  2009;200(7):1054-1058.
The human APOBEC3 family of cytidine deaminases provides intrinsic immunity to retroviral infection. A naturally occurring 29.5-kb deletion removes the entire APOBEC3B gene. We examined the impact of the APOBEC3B gene deletion in >4000 individuals from five HIV-1 natural history cohorts. The hemizygous genotype had no effect on either infection or progression. However, the homozygous deletion was significantly associated with unfavorable outcomes for HIV-1 acquisition (OR=7.37, P=0.024), progression to AIDS (RH = 4.01, P=0.03), and viral set-point (P=0.04). These findings suggest that the loss of APOBEC3B may increase host susceptibility to HIV-1/AIDS and warrant further study.
doi:10.1086/605644
PMCID: PMC3690486  PMID: 19698078
5.  Role of Exonic Variation in Chemokine Receptor Genes on AIDS: CCRL2 F167Y Association with Pneumocystis Pneumonia 
PLoS Genetics  2011;7(10):e1002328.
Chromosome 3p21–22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV-1. Although the genetic association of CCR5 and CCR2 variants with HIV-1 pathogenesis is well known, the role of variation in other nearby chemokine receptor genes remain unresolved. We genotyped exonic single nucleotide polymorphisms (SNPs) in chemokine receptor genes: CCR3, CCRL2, and CXCR6 (at 3p21) and CCR8 and CX3CR1 (at 3p22), the majority of which were non-synonymous. The individual SNPs were tested for their effects on disease progression and outcomes in five treatment-naïve HIV-1/AIDS natural history cohorts. In addition to the known CCR5 and CCR2 associations, significant associations were identified for CCR3, CCR8, and CCRL2 on progression to AIDS. A multivariate survival analysis pointed to a previously undetected association of a non-conservative amino acid change F167Y in CCRL2 with AIDS progression: 167F is associated with accelerated progression to AIDS (RH = 1.90, P = 0.002, corrected). Further analysis indicated that CCRL2-167F was specifically associated with more rapid development of pneumocystis pneumonia (PCP) (RH = 2.84, 95% CI 1.28–6.31) among four major AIDS–defining conditions. Considering the newly defined role of CCRL2 in lung dendritic cell trafficking, this atypical chemokine receptor may affect PCP through immune regulation and inducing inflammation.
Author Summary
Human chemokine receptors are cell surface proteins that may be utilized by HIV-1 for entry into host cells. DNA variation in the HIV-1 major coreceptor CCR5 affects HIV-1 infection and progression. This study comprehensively assesses the role of genetic variation of multiple chemokine receptor genes clustered in the chromosome 3p21 and 3p22 on HIV-1 disease outcomes in HIV-1 natural history cohorts. The multivariate survival analyses identified functional variants that altered disease progression rate in CCRL2, CCR3, and CCR8. CCRL2-F167Y affects the rate to AIDS development through a specific protection against pneumocystis pneumonia (PCP), a common AIDS–defining condition. Our study identified this atypical chemokine receptor CCRL2 as a key factor involved in PCP, possibly through inducing inflammation in the lung.
doi:10.1371/journal.pgen.1002328
PMCID: PMC3203199  PMID: 22046140
6.  KIR2DL2 Enhances Protective and Detrimental HLA Class I-Mediated Immunity in Chronic Viral Infection 
PLoS Pathogens  2011;7(10):e1002270.
Killer cell immunoglobulin-like receptors (KIRs) influence both innate and adaptive immunity. But while the role of KIRs in NK-mediated innate immunity is well-documented, the impact of KIRs on the T cell response in human disease is not known. Here we test the hypothesis that an individual's KIR genotype affects the efficiency of their HLA class I-mediated antiviral immune response and the outcome of viral infection. We show that, in two unrelated viral infections, hepatitis C virus and human T lymphotropic virus type 1, possession of the KIR2DL2 gene enhanced both protective and detrimental HLA class I-restricted anti-viral immunity. These results reveal a novel role for inhibitory KIRs. We conclude that inhibitory KIRs, in synergy with T cells, are a major determinant of the outcome of persistent viral infection.
Author Summary
Hepatitis C virus (HCV) and human T-cell leukemia virus (HTLV-I) infect millions of people worldwide. Some HCV-infected individuals spontaneously clear the virus and many HTLV-1-infected people remain asymptomatic; however, in both cases the infection can lead to serious illness such as cancer. The factors which determine outcome are still elusive. We have found that a gene that encodes a receptor (KIR2DL2) enhances both protective and detrimental HLA class I-mediated immunity to HCV and HTLV-1. Strikingly, although KIRs are primarily associated with innate immunity, our observations suggest that they also have a major impact on the efficiency of the adaptive immune response. This work helps to explain why one individual infected with a virus remains healthy but another, infected with the same virus develops disease; it also helps to explain why particular HLA class I molecules do not always protect or cause susceptibility as expected. Interestingly, the impact of the KIR is entirely context dependent: if an HLA class I molecule is protective then protection is enhanced, but in the context of a detrimental HLA then susceptibility is enhanced. This study reveals a novel role for inhibitory KIRs in adaptive immunity.
doi:10.1371/journal.ppat.1002270
PMCID: PMC3192839  PMID: 22022261
7.  Multiple-cohort genetic association study reveals CXCR6 as a new chemokine receptor involved in long-term nonprogression to AIDS 
The Journal of Infectious Diseases  2010;202(6):908-915.
Background. The compilation of previous genomewide association studies of AIDS shows a major polymorphism in the HCP5 gene associated with both control of the viral load and long-term nonprogression (LTNP) to AIDS.
Methods. To look for genetic variants that affect LTNP without necessary control of the viral load, we reanalyzed the genomewide data of the unique LTNP Genomics of Resistance to Immunodeficiency Virus (GRIV) cohort by excluding “elite controller” patients, who were controlling the viral load at very low levels (<100 copies/mL).
Results. The rs2234358 polymorphism in the CXCR6 gene was the strongest signal (P = 2.5 × 10−7; odds ratio, 1.85) obtained for the genomewide association study comparing the 186 GRIV LTNPs who were not elite controllers with 697 uninfected control subjects. This association was replicated in 3 additional independent European studies, reaching genomewide significance of Pcombined = 9.7 × 10−10. This association with LTNP is independent of the combined CCR2-CCR5 locus and the HCP5 polymorphisms.
Conclusion. The statistical significance, the replication, and the magnitude of the association demonstrate that CXCR6 is likely involved in the molecular etiology of AIDS and, in particular, in LTNP, emphasizing the power of extreme-phenotype cohorts. CXCR6 is a chemokine receptor that is known as a minor coreceptor in human immunodeficiency virus type 1 infection but could participate in disease progression through its role as a mediator of inflammation.
doi:10.1086/655782
PMCID: PMC3601691  PMID: 20704485
8.  Genetic variation in IL28B and spontaneous clearance of hepatitis C virus 
Nature  2009;461(7265):798-801.
Hepatitis C virus (HCV) infection is the most common blood borne infection in the U.S. with estimates of 4 million HCV-infected individuals in the U.S. and 170 million worldwide1. The majority (70%–80%) of HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma2. Epidemiological, viral, and host factors have been associated with the differences in HCV clearance or persistence and studies have demonstrated that a strong host immune response against HCV favors viral clearance3,4. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3kb upstream of the IL28B gene, which encodes the type III interferon IFN-λ3, was shown to associate strongly with more than a 2-fold difference in response to HCV drug treatment5. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (N = 388) or had persistent infection (N = 620). We show that the C/C genotype strongly enhances resolution of HCV infection amongst individuals of both European and African ancestry (European: OR = 0.38, p = 10−7; African: OR = 0.32, p = 10−4; combined: OR = 0.33, p <10−12). To date, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.
doi:10.1038/nature08463
PMCID: PMC3172006  PMID: 19759533
9.  High frequencies of exposure to the novel human parvovirus, PARV4 in haemophiliacs and injecting drug users detected by a serological assay for PARV4 antibodies 
The Journal of infectious diseases  2009;200(7):1119-1125.
Background
PARV4 is a human parvovirus first detected and cloned from an individual with a HIV seroconversion-like illness and which subsequently persists in lymphoid tissue and bone marrow. In contrast to B19V, PARV4 infections are most frequently detected in injecting drug users (IDUs), particularly those co-infected with HIV-1. To investigate its transmission routes and whether infections are acquired through plasma-derived blood products, we developed a novel anti-PARV4 ELISA to determine seroprevalence in parenterally exposed and non-exposed subjects.
Methods
PARV4 VP2 was expressed and used as antigen in an indirect ELISA to detect anti-PARV4 IgG.
Results
All 50 non-parenterally exposed adult controls were anti-PARV4 negative, in contrast to 67% and 33% antibody frequencies in HIV-positive and –negative IDUs respectively. Predominantly parenteral transmission was confirmed by the finding of similar infection frequencies (11/20 and 4/15) among HIV-coinfected and –uninfected haemophiliacs treated with non-virally inactivated FVIII/IX, whereas all but one of their 35 non-haemophiliac siblings were seronegative (despite close household contact).
Conclusions
This study provides convincing evidence that PARV4 is primarily transmitted parenterally. Evidence for widespread infection of haemophiliacs treated with non-virally inactivated clotting factor creates fresh safety concerns for plasma-derived blood products, particularly as parvoviruses are relatively resistant to virus inactivation.
doi:10.1086/605646
PMCID: PMC2914696  PMID: 19691429
PARV4; parvovirus; haemophilia; serology
10.  Association of Y chromosome haplogroup I with HIV progression, and HAART outcome 
Human genetics  2009;125(3):281-294.
The host genetic basis of differential outcomes in HIV infection, progression, viral load set point and highly active retroviral therapy (HAART) responses was examined for the common Y haplogroups in European Americans and African Americans. Accelerated progression to acquired immune deficiency syndrome (AIDS) and related death in European Americans among Y chromosome haplogroup I (Y-I) subjects was discovered. Additionally, Y-I haplogroup subjects on HAART took a longer time to HIV-1 viral suppression and were more likely to fail HAART. Both the accelerated progression and longer time to viral suppression results observed in haplogroup Y-I were significant after false-discovery-rate corrections. A higher frequency of AIDS-defining illnesses was also observed in haplogroup Y-I. These effects were independent of the previously identified autosomal AIDS restriction genes. When the Y-I haplogroup subjects were further subdivided into six I subhaplogroups, no one subhaplogroup accounted for the effects on HIV progression, viral load or HAART response. Adjustment of the analyses for population stratification found significant and concordant haplogroup Y-I results. The Y chromosome haplogroup analyses of HIV infection and progression in African Americans were not significant. Our results suggest that one or more loci on the Y chromosome found on haplogroup Y-I have an effect on AIDS progression and treatment responses in European Americans.
doi:10.1007/s00439-008-0620-7
PMCID: PMC2885350  PMID: 19169712
11.  Evaluation of IL10, IL19, and IL20 gene polymorphisms and chronic hepatitis B infection outcome 
Summary
Hepatitis B viral infection remains a serious global health problem despite the availability of a highly effective vaccine. Approximately 5% of HBV-infected adults develop chronic hepatitis B, which may result in liver cirrhosis or hepatocellular carcinoma. Variants of interleukin-10 (IL10) have been previously associated with chronic hepatitis B infection and progression to hepatocellular carcinoma. Single nucleotide polymorphisms (SNPs, n = 42) from the IL10, IL19, and IL20 gene regions were examined for an association with HBV infection outcome, either chronic or recovered, in a nested case-control study of African Americans and European Americans. Among African Americans, three nominally statistically significant SNP associations in IL10, two in IL20, and one haplotype association were observed with different HBV infection outcomes (P = 0.005–0.04). The SNP, rs1518108, in IL20 nominally deviated significantly from Hardy-Weinberg equilibrium in African Americans, with a large excess of heterozygotes in chronic HBV-infected cases (P = 0.0006), which suggests a strong genetic effect. Among European Americans, a nominally statistically significant SNP association in IL20, as well as an IL20 haplotype were associated with HBV recovery (P = 0.01–0.04). These results suggest that IL10 and IL20 gene variants influence HBV infection outcome and encourage the pursuit of further studies of these cytokines in HBV pathogenesis.
doi:10.1111/j.1744-313X.2008.00770.x
PMCID: PMC2874896  PMID: 18479293
Interleukin-10; Inflammation; African American; Immunogenetics; Hepatitis b; HIV co-infection
12.  Naturally occurring dominant resistance mutations to HCV protease and polymerase inhibitors in treatment-naïve patients 
Hepatology (Baltimore, Md.)  2008;48(6):1769-1778.
Resistance mutations to HCV NS3 protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant STAT-C resistance mutations in the population we analyzed HCV genome sequences from 507 treatment-naïve HCV genotype 1 infected patients from the US, Germany and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication competent, drug resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir, the NS5B polymerase inhibitor AG-021541, and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multi-drug resistance. Collectively, however, 8.6% of the genotype 1a and 1.4% of the genotype 1b infected patients carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug resistant viral strains might achieve replication levels comparable to non-resistant viruses in vivo.
Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in HCV genotype 1 infected treatment-naïve patients. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous non-response to peginterferon and ribavirin.
doi:10.1002/hep.22549
PMCID: PMC2645896  PMID: 19026009
NS3 protease inhibitor; NS5B polymerase inhibitor; Telaprevir; Boceprevir
13.  Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance 
The Journal of infectious diseases  2008;198(8):1159-1165.
The immune response is critical in determining the outcome of hepatitis C virus (HCV) infection. Interleukin (IL)-18 is a pivotal mediator of Th1/Th2 driven immune response. Two IL-18 promoter polymorphisms (-607 C/A and -137 G/C) and their haplotypes were known to affect the IL-18 expression. We examined the role of these polymorphisms in determining HCV clearance or persistence. Genotyping was performed among African American injecting drug users (IDUs) with HCV clearance (n = 91) and HCV persistence (n = 182), and among European American hemophiliacs mainly infected through plasma transfusion. Among IDUs, IL18 -607A (Odds ratio [OR], 3.68; 95% confidence interval [CI],1.85–7.34) and IL18 -137C (OR, 2.33; 95% CI, 1.24–4.36) were significantly associated with HCV clearance. A haplotype carrying -607A and -137C (OR, 4.53, 95% CI, 1.77–11.6) was also strongly associated with viral clearance. No association was found among hemophiliacs. These results suggest that IL18 promoter polymorphism may affect the outcome of HCV infection in certain groups.
doi:10.1086/592047
PMCID: PMC2674361  PMID: 18781864
Interleukin-18; Hepatitis C virus; Single nucleotide polymorphisms
14.  Mitochondrial DNA Haplogroups influence AIDS Progression 
AIDS (London, England)  2008;22(18):2429-2439.
Objective
Mitochondrial function plays a role in both AIDS progression and highly active antiretroviral therapy (HAART) toxicity, therefore we sought to determine whether mitochondrial (mt) DNA variation revealed novel AIDS Restriction Genes (ARGs), particularly as mtDNA single nucleotide polymorphisms (SNPs) are known to influence regulation of oxidative phosphorylation, reactive oxygen species (ROS) production, and apoptosis.
Design
Retrospective cohort study.
Methods
We performed an association study of mtDNA haplogroups among 1833 European American HIV-1 patients from five US cohorts, the Multicenter AIDS Cohort Study (MACS), the San Francisco City Clinic Study (SFCC), Hemophilia Growth and Development Study (HGDS), the Multicenter Hemophilia Cohort Study (MHCS), and the AIDS Linked to Intravenous Experiences (ALIVE) cohort to determine whether the mtDNA haplogroup correlated with AIDS progression rate.
Results
MtDNA haplogroups J and U5a were elevated among HIV-1 infected people who display accelerated progression to AIDS and death. Haplogroups Uk, H3, and IWX appeared to be highly protective against AIDS progression.
Conclusions
The associations found in our study appear to support a functional explanation by which mtDNA variation among haplogroups influencing ATP production, ROS generation, and apoptosis is correlated to AIDS disease progression, however repeating these results in cohorts with different ethnic backgrounds would be informative. These data suggest that mitochondrial genes are important indicators of AIDS disease progression in HIV-1 infected persons.
doi:10.1097/QAD.0b013e32831940bb
PMCID: PMC2699618  PMID: 19005266
Mitochondria; AIDS; HIV-1; apoptosis; disease
15.  Regulatory Polymorphisms in the Cyclophilin A Gene, PPIA, Accelerate Progression to AIDS 
PLoS Pathogens  2007;3(6):e88.
Human cyclophilin A, or CypA, encoded by the gene peptidyl prolyl isomerase A (PPIA), is incorporated into the HIV type 1 (HIV-1) virion and promotes HIV-1 infectivity by facilitating virus uncoating. We examined the effect of single nucleotide polymorphisms (SNPs) and haplotypes within the PPIA gene on HIV-1 infection and disease progression in five HIV-1 longitudinal history cohorts. Kaplan-Meier survival statistics and Cox proportional hazards model were used to assess time to AIDS outcomes. Among eight SNPs tested, two promoter SNPs (SNP3 and SNP4) in perfect linkage disequilibrium were associated with more rapid CD4+ T-cell loss (relative hazard = 3.7, p = 0.003) in African Americans. Among European Americans, these alleles were also associated with a significant trend to more rapid progression to AIDS in a multi-point categorical analysis (p = 0.005). Both SNPs showed differential nuclear protein-binding efficiencies in a gel shift assay. In addition, one SNP (SNP5) located in the 5′ UTR previously shown to be associated with higher ex vivo HIV-1 replication was found to be more frequent in HIV-1-positive individuals than in those highly exposed uninfected individuals. These results implicate regulatory PPIA polymorphisms as a component of genetic susceptibility to HIV-1 infection or disease progression, affirming the important role of PPIA in HIV-1 pathogenesis.
Author Summary
Individual risk of acquiring HIV type 1 (HIV-1) infection and developing AIDS is not equal; some people are more prone to HIV/AIDS than others. Susceptibility to HIV-1/AIDS is likely determined by a combination of environmental, viral, and host genetic factors. Genetic variations in host cellular factors involved in HIV-1 cell entry, replication, and host defense have been found to affect susceptibility to HIV-1/AIDS. In this report, we focused on the gene PPIA that encodes cyclophilin A, a human cellular protein that is incorporated into the HIV-1 virion and promotes viral replication. We studied genetic variation in the PPIA gene in persons with different susceptibility levels to HIV-1 infection or different rates of disease progression. We found that individuals who processed two functional variants in the promoter region of PPIA had higher risk of CD4+ T-cell loss or progression to AIDS-defining diseases. We also observed that an additional variant occurred more frequently in HIV-1-infected individuals compared to HIV-1-exposed, but uninfected, individuals. These results suggest that genetic variation in PPIA may influence host susceptibility to HIV-1 infection or disease progression and targeting PPIA might provide therapeutic benefit.
doi:10.1371/journal.ppat.0030088
PMCID: PMC1894826  PMID: 17590083
16.  Polymorphisms of CUL5 Are Associated with CD4+ T Cell Loss in HIV-1 Infected Individuals 
PLoS Genetics  2007;3(1):e19.
Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (Apobec3) antiretroviral factors cause hypermutation of proviral DNA leading to degradation or replication-incompetent HIV-1. However, HIV-1 viral infectivity factor (Vif) suppresses Apobec3 activity through the Cullin 5-Elongin B-Elongin C E3 ubiquitin ligase complex. We examined the effect of genetic polymorphisms in the CUL5 gene (encoding Cullin 5 protein) on AIDS disease progression in five HIV-1 longitudinal cohorts. A total of 12 single nucleotide polymorphisms (SNPs) spanning 93 kb in the CUL5 locus were genotyped and their haplotypes inferred. A phylogenetic network analysis revealed that CUL5 haplotypes were grouped into two clusters of evolutionarily related haplotypes. Cox survival analysis and mixed effects models were used to assess time to AIDS outcomes and CD4+ T cell trajectories, respectively. Relative to cluster I haplotypes, the collective cluster II haplotypes were associated with more rapid CD4+ T cell loss (relative hazards [RH] = 1.47 and p = 0.009), in a dose-dependent fashion. This effect was mainly attributable to a single cluster II haplotype (Hap10) (RH = 2.49 and p = 0.00001), possibly due to differential nuclear protein–binding efficiencies of a Hap10-specifying SNP as indicated by a gel shift assay. Consistent effects were observed for CD4+ T cell counts and HIV-1 viral load trajectories over time. The findings of both functional and genetic epidemiologic consequences of CUL5 polymorphism on CD4+ T cell and HIV-1 levels point to a role for Cullin 5 in HIV-1 pathogenesis and suggest interference with the Vif-Cullin 5 pathway as a possible anti-HIV-1 therapeutic strategy.
Author Summary
Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 G (Apobec3G) is an innate antiviral protein that inhibits HIV type 1 (HIV-1) replication by causing deleterious mutations in the HIV-1 genome. Unfortunately, HIV-1 has a strategy to defeat the antiviral activity of Apobec3G. The HIV-1 viral infectivity factor (Vif) binds to Apobec3G leading to the degradation of Apobec3G through a complex containing Cullin 5 and the proteins Elongin B and Elongin C. Since Cullin 5 directly interacts with Vif and is critical to the Apobec3G degradation pathway, the authors asked if genetic variation of CUL5 could tip the balance between HIV-1 and Apobec3G and modify the course of HIV-1 infection. They showed that genetic variation in the CUL5 gene encoding Cullin 5 affected the rate of CD4+ T cell loss in patients infected with HIV-1. CUL5 haplotypes formed two clusters of evolutionarily related haplotypes with opposing effects—cluster I delayed and the cluster II accelerated CD4+ T cell loss. The effect was mainly attributable to a single haplotype or its tagging-SNP, which demonstrated differential binding of transcription factors. This finding highlights the epidemiologic importance of the HIV-1 and Cullin 5 interaction and suggests that the factors in the HIV-1 Vif-Apobec3G degradation pathway may be targets for antiviral drugs.
doi:10.1371/journal.pgen.0030019
PMCID: PMC1781497  PMID: 17257057
17.  APOBEC3G Genetic Variants and Their Influence on the Progression to AIDS†  
Journal of Virology  2004;78(20):11070-11076.
The cytosine deaminase APOBEC3G, in the absence of the human immunodeficiency virus type 1 (HIV-1) accessory gene HIV-1 viral infectivity factor (vif), inhibits viral replication by introducing G→A hypermutation in the newly synthesized HIV-1 DNA negative strand. We tested the hypothesis that genetic variants of APOBEC3G may modify HIV-1 transmission and disease progression. Single nucleotide polymorphisms were identified in the promoter region (three), introns (two), and exons (two). Genotypes were determined for 3,073 study participants enrolled in six HIV-AIDS prospective cohorts. One codon-changing variant, H186R in exon 4, was polymorphic in African Americans (AA) (f = 37%) and rare in European Americans (f < 3%) or Europeans (f = 5%). For AA, the variant allele 186R was strongly associated with decline in CD4 T cells (CD4 slope on square root scale: −1.86, P = 0.009), The 186R allele was also associated with accelerated progression to AIDS-defining conditions in AA. The in vitro antiviral activity of the 186R enzyme was not inferior to that of the common H186 variant. These studies suggest that there may be a modifying role of variants of APOBEC3G on HIV-1 disease progression that warrants further investigation.
doi:10.1128/JVI.78.20.11070-11076.2004
PMCID: PMC521814  PMID: 15452227

Results 1-17 (17)