Single Nucleotide Polymorphism in Gene Encoding Transcription Factor Prep1 Is Associated with HIV-1-Associated Dementia

BACKGROUND: Infection with HIV-1 may result in severe cognitive and motor impairment, referred to as HIV-1-associated dementia (HAD). While its prevalence has dropped significantly in the era of combination antiretroviral therapy, milder neurocognitive disorders persist with a high prevalence. To identify additional therapeutic targets for treating HIV-associated neurocognitive disorders, several candidate gene polymorphisms have been evaluated, but few have been replicated across multiple studies. METHODS: We here tested 7 candidate gene polymorphisms for association with HAD in a case-control study consisting of 86 HAD cases and 246 non-HAD AIDS patients as controls. Since infected monocytes and macrophages are thought to play an important role in the infection of the brain, 5 recently identified single nucleotide polymorphisms (SNPs) affecting HIV-1 replication in macrophages in vitro were also tested. RESULTS: The CCR5 wt/Δ32 genotype was only associated with HAD in individuals who developed AIDS prior to 1991, in agreement with the observed fading effect of this genotype on viral load set point. A significant difference in genotype distribution among all cases and controls irrespective of year of AIDS diagnosis was found only for a SNP in candidate gene PREP1 (p = 1.2 × 10(-5)). Prep1 has recently been identified as a transcription factor preferentially binding the -2,518 G allele in the promoter of the gene encoding MCP-1, a protein with a well established role in the etiology of HAD. CONCLUSION: These results support previous findings suggesting an important role for MCP-1 in the onset of HIV-1-associated neurocognitive disorders

Genome-Wide Association Study Identifies Single Nucleotide Polymorphism in DYRK1A Associated with Replication of HIV-1 in Monocyte-Derived Macrophages

Background: HIV-1 infected macrophages play an important role in rendering resting T cells permissive for infection, in spreading HIV-1 to T cells, and in the pathogenesis of AIDS dementia. During highly active anti-retroviral treatment (HAART), macrophages keep producing virus because tissue penetration of antiretrovirals is suboptimal and the efficacy of some is reduced. Thus, to cure HIV-1 infection with antiretrovirals we will also need to efficiently inhibit viral replication in macrophages. The majority of the current drugs block the action of viral enzymes, whereas there is an abundance of yet unidentified host factors that could be targeted. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages. Methodology/Principal Findings: Monocyte-derived macrophages from 393 blood donors were infected with HIV-1 and viral replication was determined using Gag p24 antigen levels. Genomic DNA from individuals with macrophages that had relatively low (n = 96) or high (n = 96) p24 production was used for SNP genotyping with the Illumina 610 Quad beadchip. A total of 494,656 SNPs that passed quality control were tested for association with HIV-1 replication in macrophages, using linear regression. We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16×10-5). While the association was not genome-wide significant (p<1×10-7), we could replicate this association using monocyte-derived macrophages from an independent group of 31 individuals (p = 0.0034). Combined analysis of the initial and replication cohort increased the strength of the association (p = 4.84×10-6). In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048). Conclusions/Significance: These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo. © 2011 Bol et al

Polymorphism in HIV-1 dependency factor PDE8A affects mRNA level and HIV-1 replication in primary macrophages

AbstractFour genome-wide RNAi screens have recently identified hundreds of HIV-1 dependency factors (HDFs). Previously, we reported a large variation in the ability of HIV-1 to replicate in monocyte-derived macrophages (MDM) derived from >400 healthy seronegative blood donors. Here we determined whether SNPs in genes encoding newly identified HDFs were associated with this variation in HIV-1 replication. We found a significant association between the minor allele of SNP rs2304418 in phosphodiesterase 8A (PDE8A) and lower HIV-1 replication (p=2.4×10−6). The minor allele of SNP rs2304418 was also significantly associated with lower PDE8A mRNA levels in MDM (p=8.3×10−5). In accordance with this, overexpression of PDE8A in HEK293T cells resulted in increased HIV-1 replication, while subsequent knock-down of PDE8A decreased replication. This study links host genetic variation in a newly identified HDF to variation in HIV-1 replication in a relevant primary target cell for HIV-1 and may provide new leads for treatment of this infection

Overview of all common genetic variants tested for association with HIV-1-associated neurocognitive disorders.

<p>HAND, HIV-1-associated neurocognitive disorders; HAD, HIV-1-associated dementia; HIVE, HIV-1 encephalitis.</p

Genotype distribution among HAD (cases) and non-HAD (controls) HIV-1-infected patients for all polymorphisms tested.

1<p>Polymorphisms selected from earlier studies that tested for association between genotype and HAD.</p>2<p>In the case of <i>APOE</i> AA, AB and BB refer to no APO E4, one APO E4 allele and two APO E4 alleles, respectively.</p>3<p>SNPs selected from a previous study that found associations between these SNPs and HIV-1 replication in macrophages.</p><p>*Significant difference after correction for multiple testing (n = 12); Bonferroni threshold <i>p</i> = 4.2×10⁻³.</p

Comparison of AIDS survival between HAD cases and non-HAD controls.

<p>(<b>A</b>) Kaplan Meier analysis for time from AIDS to death with start cART as censor (vertical lines), for both HAD cases (grey line) and non-HAD AIDS patients as controls (black line). (<b>B</b>) Kaplan Meier analysis for time from AIDS to death with start cART as censor (vertical lines) for the controls (black line) and for time from AIDS to HAD for the HAD cases (grey line). cART, combination antiretroviral therapy; HAD, HIV-1-associated dementia.</p

Characteristics of the studied population consisting of AIDS patients with or without HAD.

<p>N.A., not applicable; HAD, HIV-1-associated dementia; IDU, injecting drug user.</p>1<p>Mann Whitney test.</p>2<p>Time to develop HAD after AIDS diagnosis among the cases was compared to the time from AIDS diagnosis to death or to start cART in the control group.</p>3<p>unpaired t test.</p>4<p>CD4+ T cell counts within 6 months to the date of AIDS diagnosis.</p>5<p>Fisher's exact test.</p