"Hutchinson-Gilford Progeria Syndrome" by The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. Scaffidi P, Gordon L, Misteli T; https://commons.wikimedia.org/wiki/File:HIV-budding-Color.jpg#/media/File:HIV-budding-Color.jpg. "HIV-budding-Color" by Photo Credit: C. Goldsmith. Content Providers: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus.
And here I am again. Post number two, come forth! As you can imagine from the title of the post (Common Mechanism Linking HIV-1 and Progeria), some of the things that I'm going to propose in this post (that is the subject of a paper I authored and published in 2015, accessible via the link below with references) will definitely raise a few eyebrows.
Anyway, if you're anything like me when I first started to research this and place together the pieces of the puzzle, you may be asking yourself: What on earth does HIV-1 have to do with the gene splicing and accelerating aging disease Hutchinson-Gilford progeria syndrome (HGPS for short)? Well, as it turns out, quite a bit! If you look back at my prior post on how gene splicing is altered in HGPS, you'll see that I went into quite a bit of detail on how a specific splicing factor, SRSF1, causes the gene "cutting crew" to recognize and bind predominantly to a cryptic splice site in the LMNA gene as opposed to binding to the normal splice site, producing a toxic protein called progerin that induces accelerating aging. That post also described how a natural endogenous inhibitor of SRSF1, called p32, is also essential for mitochondrial biogenesis (birth of new mitochondria) and autophagy/mitophagy (disposal of worn-out mitochondria and cellular components). As mitochondrial biogenesis and autophagy have been repeatedly shown to be critical in improving lifespan and healthspan, and because the activation of the master metabolic regulator AMPK leads to increased mitochondrial biogenesis, autophagy, and increased lifespan and healthspan, I proposed that AMPK activation may act as a central mediator for correcting gene splicing by regulating the activity of p32 and thus decreasing the activity of SRSF1. And sure enough, several chemically distinct compounds that have been shown to correct accelerated aging defects in HGPS cells, including rapamycin, methylene blue, sulforaphane, and retinoic acid, have all been shown to activate AMPK!
Once again, as I was poking around in the research literature (the PubMed Mobile App is pretty awesome), SRSF1 kept popping up as also being associated with viral infections. Huh?@#? Of course, further investigation was at hand. As it turns out, the splicing activity of SRSF1 is actually what prevents a dormant HIV-1 virus in a T cell from being reactivated, preventing the immune system from detecting and destroying the virus. Because the HIV-1 virus is lying dormant in mostly CD4+ memory T cells, which can lay dormant for decades, a person infected with HIV-1 will be incapable of riding him or herself of the virus and will always be HIV-1+ unless the T cell (and the virus within it) can be sufficiently activated.
Sounds a little heavy, but some background information should help clear things up. When HIV-1 initially infects T cells and starts to replicate, most of the CD4+ T cells are eventually killed. However, a minority of those T cells, with the HIV-1 virus integrated into the DNA of the T cell, may convert to CD4+ memory T cells and become dormant and long-lived, awaiting an appropriate stimulus to reactivate it (there are other mechanisms involved, but this is the general gist). Although a combination of anti-retroviral drugs (ARTs) can reduce viral load to below detectable levels by targeting actively infected cells, these drugs are incapable of targeting and killing CD4+ memory T cells that harbor latent (i.e. dormant) HIV-1 because the virus is not actively replicating.
And here comes SRSF1, rearing its head once again. Interestingly, a number of studies now report that the splicing activity of endogenous SRSF1 in a memory T cell leads to excessive splicing of the HIV-1 genome that is integrated in the host cell genome (i.e. memory T cell genome). This causes the virus to not produce enough unspliced HIV-1 mRNA. Unspliced HIV-1 mRNA is needed to efficiently reactivate the virus, thus allowing immune system detection and destruction or self-destruction of the T cell itself.
Hmmm...Now that's interesting:-) SRSF1 splicing activity prevents the reactivation of HIV-1 as well as promotes toxic progerin production in HGPS by increasing the usage of the LMNA cryptic splice site. But a wait minute. True, SRSF1 activity inhibits reactivation of the HIV-1 virus. However, studies also show that the only truly effective way to purge the virus out of the dormant T cell in order to kill it (also known as the "shock and kill" approach) is to activate the T cell itself. Question: Does increased SRSF1 activity also prevent T cell activation??
No doubt!! Several studies have shown that SRSF1 activity significantly decreases on T cell activation in normal T cells that are not infected with HIV-1. Also, the splicing of certain genes (essential for T cell activation) by SRSF1 is inhibited on T cell activation, indicating that SRSF1 indeed inhibits both latent HIV-1 reactivation as well as T cell activation.
Now, time for a side-by-side comparison. As noted in the last post, the induction of autophagy by rapamycin and sulforaphane, both AMPK activators, lead to the correction of accelerating aging defects in HGPS cells by disposing of the toxic protein progerin. Is autophagy activated on and essential for T cell activation as well?? You bet!! Several studies have demonstrated that inhibition of autophagy leads to an inefficient activation of T cells and T cell activation leads to an upregulation of autophagic flux.
But wait, there's more:-) The prior post also noted that mitochondrial biogenesis is upregulated by methylene blue in HGPS cells, leading to correction of accelerated aging defects. Indeed, mitochondrial biogenesis and oxidative phosphorylation (process of making ATP in the mitochondria) have been shown to be severely impaired in HGPS cells. Is mitochondrial biogenesis/functionality necessary for efficient T cell activation as well?? Most definitely!! Again studies have shown that an initial burst of energy in the form of ATP is necessary during the initiation of T cell activation and mitochondria also congregate around the connection between a T cell and the cell that presents to the T cell a piece of a foreign invader in order to activate the T cell.
Okay, heavy stuff. Now its time to connect the dots. If SRSF1, which prevents the reactivation of latent HIV-1, is downregulated on T cell activation, and mitochondrial biogenesis/functionality and autophagy are enhanced on T cell activation, could the activation of AMPK, and thus an increase in the activity of p32, facilitate T cell activation and latent HIV-1 reactivation??
But of course!! Studies have shown, similar to the mechanisms that are involved in HGPS, when a memory T cell that's latently infected with HIV-1 is efficiently activated, the levels of SRSF1 are decreased and the activity of p32 is enhanced, leading to an increase of unspliced HIV-1 mRNA, increased mitochondrial functionality, and enhanced autophagy, leading to efficient HIV-1 reactivation!!
BUT, here's the real kicker, studies now indicate that AMPK activation is critical for the activation of T cells generally, as knockdown of AMPK significantly inhibits the immune response to viral and bacterial infections. Because AMPK enhances autophagy and mitochondrial biogenesis and because p32 is critical for autophagy, mitochondrial biogenesis, and inhibits SRSF1 activity, a beautiful molecular portrait begins to emerge: AMPK activation leads to mitochondrial biogenesis, autophagy, and alteration of gene splicing in both HGPS and HIV-1, leading to a correction of aging defects in HGPS and reactivation of latent HIV-1!
However, the proof is in the pudding, as they say. If AMPK is central
to both HGPS and latent HIV-1 reactivation, compounds that have been
shown to be effective in HGPS should also have some immune enhancing/T cell
activating effects. Indeed, retinoic acid signaling has been shown to be
essential for efficient T cell activation, methylene blue has been shown
to reactivate latent HIV-1 via photo-oxidation, and sulforaphane has been shown
to have immune-enhancing effects. Each of these compounds has also been shown
to correct accelerated aging defects in HGPS cells.
Check back for additional posts on individual compounds. I promise you won’t be disappointed!!
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.
https://www.linkedin.com/pulse/common-mechanism-linking-hiv-1-progeria-jahahreeh-finley?trk=mp-reader-card
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.
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