Susceptibility to HIV-1 infection varies greatly between individuals, with disease progression rates determined not only by viral properties but also host factors. The central hypothesis of this proposal is that the extensive diversification of the APOBEC3 (A3) family of restriction factors contributes to the high degree of variability in HIV-1 replication in vivo. There is growing evidence that genomic variation - ranging from single nucleotide polymorphisms (SNPs) to large structural variants - influences the efficacy of host antiviral defenses. Indeed, we have evidence that naturally occurring SNPs modulate the antiviral activity of A3F and A3H. Moreover, we have identified three regions near and within the A3 locus itself that show copy number variations among HapMap populations (based on data from 450 individuals of West-African, Asian and European ancestry). These copy number variants (CNV) overlap with A3B, A3E and A3F exons and possibly upstream regulatory sequences of the APOBEC locus. Preliminary data indicate that the APOBEC loci from HIV-1 infected long-term non-progressors (LTNP) are enriched for A3 copy number variants, suggesting a protective role of A3 copy number variation. Conversely, we have shown that cells homozygous for A3-CNV2 copy loss (complete deletion of the A3B gene) are more susceptible to HIV-1 infection in vitro. Collectively, our preliminary data strongly support the notion that A3 regions are structurally polymorphic and that the resulting A3 variants exert a key impact on HIV-1 replication.
In specific aim 1 (CNV discovery and mapping), we will interrogate the A3 gene family cluster at very high resolution using cutting edge technologies to capture the wide range of CNVs embedded in this locus. For this purpose, we will use samples from ethnically diverse (18 different groups) or phenotypically selected (LTNP) populations.
In specific aim 2 (gene expression), we will determine the mRNA expression pattern specific for A3-CNV genotypes and identify protein variants associated with the panel of rearranged A3 loci. We will also compare the transcriptional regulation of A3 genomic variants in lymphocytes and dendritic cells of LTNPs and treated progressors.
In specific aim 3 (gene function), the impact of A3-CNVs and SNPs on viral restriction will be tested, using lymphocytes from individuals with known A3 genotypes, as well as model cell-lines expressing gene products representing naturally circulating A3 genomic variants. These experiments will integrate genomic variation data of the A3 region with an understanding of the regulation and antiviral functions of A3 deaminases. This comprehensive investigation into the functional consequences of the high variability in A3 genomic architecture should help identify new biomarkers to be tested in future epidemiological studies of retroviral infections. In addition, understanding the functional diversity of intrinsic defense factors has the potential to create novel treatment strategies aimed at a long- lasting suppression of HIV/AIDS disease.
Susceptibility to HIV-1 infection and AIDS disease progression varies greatly among individuals. The goal of this proposal is to determine the degree of structural genomic variation within the APOBEC 3 locus, and to assess how variability of these intrinsic resistance genes impacts on HIV-1 replication.
|Dahabieh, Matthew S; Ooms, Marcel; Brumme, Chanson et al. (2014) Direct non-productive HIV-1 infection in a T-cell line is driven by cellular activation state and NF?B. Retrovirology 11:17|
|Manganaro, Lara; Pache, Lars; Herrmann, Tobias et al. (2014) Tumor suppressor cylindromatosis (CYLD) controls HIV transcription in an NF-?B-dependent manner. J Virol 88:7528-40|
|Opaluch, Amanda M; Schneider, Monika; Chiang, Chih-yuan et al. (2014) Positive regulation of TRAF6-dependent innate immune responses by protein phosphatase PP1-?. PLoS One 9:e89284|
|Alvarez, Raymond A; Hamlin, Rebecca E; Monroe, Anthony et al. (2014) HIV-1 Vpu antagonism of tetherin inhibits antibody-dependent cellular cytotoxic responses by natural killer cells. J Virol 88:6031-46|
|Brinzevich, Daria; Young, George R; Sebra, Robert et al. (2014) HIV-1 interacts with human endogenous retrovirus K (HML-2) envelopes derived from human primary lymphocytes. J Virol 88:6213-23|
|Letko, Michael; Silvestri, Guido; Hahn, Beatrice H et al. (2013) Vif proteins from diverse primate lentiviral lineages use the same binding site in APOBEC3G. J Virol 87:11861-71|
|Ooms, Marcel; Brayton, Bonnie; Letko, Michael et al. (2013) HIV-1 Vif adaptation to human APOBEC3H haplotypes. Cell Host Microbe 14:411-21|
|Morrison, Juliet; Laurent-Rolle, Maudry; Maestre, Ana M et al. (2013) Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling. PLoS Pathog 9:e1003265|
|Gokcumen, Omer; Tischler, Verena; Tica, Jelena et al. (2013) Primate genome architecture influences structural variation mechanisms and functional consequences. Proc Natl Acad Sci U S A 110:15764-9|
|Gokcumen, Omer; Zhu, Qihui; Mulder, Lubbertus C F et al. (2013) Balancing selection on a regulatory region exhibiting ancient variation that predates human-neandertal divergence. PLoS Genet 9:e1003404|
Showing the most recent 10 out of 20 publications