Abstract
BackgroundHIV-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 FindingsMonocyte-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/SignificanceThese findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo.
Highlights
The development of highly active antiretroviral therapy (HAART) has been the biggest achievement in HIV/AIDS medicine
Association between single nucleotide polymorphism in the kinase DYRK1A and HIV-1 replication in monocytederived macrophages A total of 494,656 SNPs passing quality control were tested for association with levels of HIV-1 replication in monocyte-derived macrophages (MDM) using linear regression
The two SNPs in Phosphodiesterase 8A (PDE8A) were found to be in high linkage disequilibrium (LD; r2 = 0.97), whereas only a moderate degree of LD was found between rs1046099 and rs1270629 in MOAP1 (r2 = 0.54) (Table 2)
Summary
The development of highly active antiretroviral therapy (HAART) has been the biggest achievement in HIV/AIDS medicine. HAART does not affect cells that are latently infected because in these cells the virus is not actively replicating. Activation of this viral reservoir of latently infected resting CD4+ T cells [5] and residual replication in monocytes/macrophages (reviewed in [6]) is believed to be responsible for the increase in plasma viral RNA levels that is observed after discontinuing HAART. 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. To cure HIV-1 infection with antiretrovirals we will need to efficiently inhibit viral replication in macrophages. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages
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