Detecting AIDS restriction genes: From candidate genes to genome-wide association discovery

Laboratory of Genomic Diversity, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Vaccine (Impact Factor: 3.62). 07/2008; 26(24):2951-65. DOI: 10.1016/j.vaccine.2007.12.054
Source: PubMed


The screening of common genetic polymorphisms among candidate genes for AIDS pathology in HIV exposed cohort populations has led to the description of 20 AIDS restriction genes (ARGs), variants that affect susceptibility to HIV infection or to AIDS progression. The combination of high-throughput genotyping platforms and the recent HapMap annotation of some 3 million human SNP variants has been developed for and applied to gene discovery in complex and multi-factorial diseases. Here, we explore novel computational approaches to ARG discovery which consider interacting analytical models, various genetic influences, and SNP-haplotype/LD structure in AIDS cohort populations to determine if these ARGs could have been discovered using an unbiased genome-wide association approach. The procedures were evaluated by tracking the performance of haplotypes and SNPs within ARG regions to detect genetic association in the same AIDS cohort populations in which the ARGs were originally discovered. The methodology captures the signals of multiple non-independent AIDS-genetic association tests of different disease stages and uses association signal strength (odds ratio or relative hazard), statistical significance (p-values), gene influence, internal replication, and haplotype structure together as a multi-facetted approach to identifying important genetic associations within a deluge of genotyping/test data. The complementary approaches perform rather well and predict the detection of a variety of undiscovered ARGs that affect different stages of HIV/AIDS pathogenesis using genome-wide association analyses.

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    • "This communicability is, in part, reflected by infectivity of the host as measured by the plasma RNA viral load (VL) [1], [2], [3], [4], [5], [6]. However, we and others have demonstrated that susceptibility and communicability are dictated, in part, by polymorphisms in genes that influence HIV-AIDS susceptibility ([7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23] and reviewed in [24], [25], [26], [27], [28], [29]). For this reason, we hypothesized that the inherent variability among individuals in host genes that influence HIV-AIDS susceptibility, when translated to the level of a population, might influence the epidemic spread of HIV in that population and, by extension, might contribute to the observed heterogeneous distribution of HIV among populations [3], [30], [31], [32], [33], [34], [35], [36], [37], [38]. "
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    ABSTRACT: Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of these genetic factors on the epidemic spread of HIV, as well as on its prevention. Ro, the basic reproductive number, is a fundamental concept in explaining the emergence and persistence of epidemics. By modeling sexual transmission among HIV+/HIV- partner pairs, we find that Ro estimates, and concordantly, the temporal and spatial patterns of HIV outgrowth are highly dependent on the infecting partners' CCL3L1-CCR5 genotype. Ro was least and highest when the infected partner possessed protective and detrimental CCL3L1-CCR5 genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high CCL3L1 gene dose and protective CCR5 genotypes, the spread of HIV might be minimal. Additionally, Pc, the critical vaccination proportion, an estimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was <1 only when the infected partner had a protective CCL3L1-CCR5 genotype. Since in practice Pc cannot be >1, to prevent epidemic spread, population groups defined by specific CCL3L1-CCR5 genotypes might require repeated vaccination, or as our models suggest, a vaccine with an efficacy of >70%. Further, failure to account for CCL3L1-CCR5-based genetic risk might confound estimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of CCL3L1-CCR5 genotype of only 25 (5%) subjects between placebo and vaccine arms results in a relative error of approximately 12% from the true vaccine efficacy. CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observed heterogeneous global distribution of HIV infection. As Ro is lowest when the infecting partner has beneficial CCL3L1-CCR5 genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in halting epidemic spread. Further, CCL3L1-CCR5 genotype may provide critical guidance for optimizing the design and evaluation of HIV-1 vaccine trials and prevention programs.
    PLoS ONE 02/2008; 3(11):e3671. DOI:10.1371/journal.pone.0003671 · 3.23 Impact Factor
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    ABSTRACT: Sebastiaan Bol ging op zoek naar humane eiwitten die hiv-vermenigvuldiging ondersteunen of remmen, met name in macrofagen. Deze cellen leven lang, gaan niet dood als gevolg van hiv-infectie en zijn - doordat ze zich veelal in weefsels bevinden - lastig bereikbaar voor hiv-remmers. Hierdoor vormen hiv-geïnfecteerde macrofagen één van de belangrijke barrières voor het genezen van mensen met hiv. Bol infecteerde macrofagen van honderden gezonde donoren met hiv en zocht naar verbanden tussen de mate waarin het virus zich vermenigvuldigde en variaties in het DNA (SNPs) van de betreffende proefpersonen. Hij identificeerde SNPs die coderen voor twee eiwitten die wellicht betrokken zijn bij hiv-replicatie in macrofagen. De SNP in één daarvan lijkt ook geassocieerd met ziektebeloop.
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