title: Reactivation of latently infected HIV-1 viral reservoirs and correction of aberrant alternative splicing in the LMNA gene via AMPK activation: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome.
abstract: Although the use of antiretroviral therapy (ART) has proven highly effective in controlling and suppressing HIV-1 replication, the persistence of latent but replication-competent proviruses in a small subset of CD4(+) memory T cells presents significant challenges to viral eradication from infected individuals. Attempts to eliminate latent reservoirs are epitomized by the 'shock and kill' approach, a strategy involving the combinatorial usage of compounds that influence epigenetic modulation and initiation of proviral transcription. However, efficient regulation of viral pre-mRNA splicing through manipulation of host cell splicing machinery is also indispensible for HIV-1 replication. Interestingly, aberrant alternative splicing of the LMNA gene via the usage of a cryptic splice site has been shown to be the cause of most cases of Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic condition characterized by an accelerated aging phenotype due to the accumulation of a truncated form of lamin A known as progerin. Recent evidence has shown that inhibition of the splicing factors ASF/SF2 (or SRSF1) and SRp55 (or SRSF6) leads to a reduction or an increase in progerin at both the mRNA and protein levels, respectively, thus altering the LMNA pre-mRNA splicing ratio. It is also well-established that during the latter stages of HIV-1 infection, an increase in the production and nuclear export of unspliced viral mRNA is indispensible for efficient HIV-1 replication and that the presence of ASF/SF2 leads to excessive viral pre-mRNA splicing and a reduction of unspliced mRNA, while the presence of SRp55 inhibits viral pre-mRNA splicing and aids in the generation and translation of unspliced HIV-1 mRNAs. The splicing-factor associated protein and putative mitochondrial chaperone p32 has also been shown to inhibit ASF/SF2, increase unspliced HIV-1 viral mRNA, and enhance mitochondrial DNA replication and oxidative phosphorylation. It is our hypothesis that activation of AMPK, a master regulator of cellular metabolism which has been shown to activate PKC-theta (θ) and is essential for T cell activation, may modulate the splicing activities of SRp55 as well as enhance a p32-mediated inhibition of ASF/SF2-induced alternative splicing, potentially correcting aberrant alternative splicing in the LMNA gene and reactivating latent viral HIV-1 reservoirs. Moreover, similar epigenetic modifications and cell cycle regulators also characterize the analogous stages of premature senescence in progeroid cells and latency in HIV-1 infected T cells. AMPK-activating compounds including metformin and resveratrol may thus embody a novel treatment paradigm linking the pathophysiology of HGPS with that of HIV-1 latency.
authors.affiliation: Finley BioSciences, Houston, TX 77042-4539, United States. Electronic address: jfinley4@alumni.jh.edu.
authors.forename: Jahahreeh
authors.initials: J
authors.lastname: Finley
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D017398:Alternative Splicing; D004197:Disease Reservoirs; D004789:Enzyme Activation; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D011371:Progeria / Q000235:genetics*; D014775:Virus Activation; D017735:Virus Latency
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D000263:Adenylate Kinase