AMPK activator Metformin to begin clinical trials to reactivate latent HIV-1 and reduce the amount of hidden virus in the body

"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.

Here's an interesting update I recently posted on LinkedIn (check the link below).  It looks as if my ideas of AMPK activation possibly being effective in reducing the amount of hidden HIV-1 virus and potentially leading to a cure are going to be tested in humans.  McGill University (prestigious Canadian University whose alumnus co-founded the Johns Hopkins School of Medicine) is sponsoring a clinical trial (listed on ClinicalTrials.gov) to determine, in their words, if the AMPK activator metformin is able to "reduce the amount of hidden virus in the body”, resulting in a “decrease in the size of the HIV reservoir.” They’re also looking to determine if metformin is able to boost the activity of CD8+ T cells, cells that are crucial in the immune response against viruses, bacteria, and other pathogens.  As laid out in my prior posts and in my publications, AMPK activation is necessary for T cell activation generally and AMPK activation leads to an enhanced formation of CD8+ memory T cells. AMPK is also activated by a bewildering number of compounds (natural and synthetic), including metformin (Galega plant), sulforaphane (broccoli sprouts), retinoic acid (vitamin A), rapamycin (bacteria), and methylene blue. Considering that metformin also beneficially alters gene splicing in genetic disorders and in normal humans, and considering that sulforaphane, retinoic acid, rapamycin, and methylene blue reverses accelerated cellular aging defects in Progeria, the connection between HIV-1 latency and Progeria is becoming much more clear. It looks as if someone has been listening to (or reading up on) me:-)

Clinical Trial Official Title: The Effect of Metformin on HIV Reservoir Size in Non-diabetic Antiretroviral Therapy (ART) Treated Participants: the Lilac Study

As my prior posts and recent publication on the connection between Hutchinson-Gilford progeria syndrome (HGPS) and HIV-1 latency have alluded to, the activation of the master metabolic regulator AMPK by compounds as chemically distinct as metformin, rapamycin, sulforaphane, methylene blue, retinoic acid, and possibly many others may act synergistically to both beneficially alter gene splicing in normal humans and children diagnosed with HGPS as well as reactivate latent HIV-1 in CD4+ memory T cells, thus allowing detection and destruction by the immune system or induction of a self-destruct mechanism.

Interestingly, first received by ClinicalTrials.gov on January 15, 2016, McGill University Health Center, one of the largest medical institutions in Canada and affiliated with McGill University (a prestigious Canadian University a part of the Association of American Universities and whose alumnus co-founded the Johns Hopkins School of Medicine) is sponsoring a clinical trial to determine if metformin is able to “reduce the amount of hidden virus in the body”, resulting in a “decrease in the size of the HIV reservoir.”

The trial is a phase I trial with an estimated enrollment of 22 patients with a start date of March 2016 and an estimated completion date of October 2017.  A portion of the details of the clinical trial are reproduced below with a link provided as well.

Another interesting detail about this trial is the secondary outcome measure of determining a “change in the percentage of activated CD8 T-cells”.  AMPK activation has been well documented to be critical in the activation of T cells generally.  AMPK has also been shown to be activated by  both metformin and bryostatin and, when combined, synergistically reactivates latent HIV-1 [1,2]. AMPK has also been shown to be essential for appropriate immune responses to bacterial and viral challenges and the activation of AMPK leads to the formation of CD8+ memory T cells, facilitating accelerated pathogen clearance [3,4]. 

As metformin is a prototypical AMPK activator, the potential results and implications from this trial are both exciting and consequential: The synergistic actions of various AMPK activators may not only reactivate latent HIV-1, but also but boost the formation and activity of CD8+ memory T cells, potentially riding the virus from the body and providing a cure.  Because metformin and AMPK activation also beneficially alters gene splicing in genetic disorders and in normal humans, the figure I drafted below may indeed become much more salient with time [5].

https://www.linkedin.com/pulse/ampk-activator-metformin-begin-clinical-trials-latent-finley?published=t

Excerpt from: Metformin Immunotherapy in HIV Infection


Official Title: The Effect of Metformin on HIV Reservoir Size in Non-diabetic Antiretroviral Therapy (ART) Treated Participants: the Lilac Study

Sponsor: McGill University Health Center
Information provided by (Responsible Party): Jean-Pierre Routy, McGill University Health Center
ClinicalTrials.gov Identifier: NCT02659306

First received: January 15, 2016
Last updated: January 19, 2016
Last verified: January 2016

Estimated Enrollment: 22
Study Start Date: March 2016
Estimated Study Completion Date: October 2017
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)

The purposes of this study are to find out if:

1. metformin can be combined with anti-HIV drugs to reduce the amount of hidden virus in the body;
2. metformin can be combined with anti-HIV drugs to improve immune function.
3. metformin can be combined with anti-HIV drugs to impact CD4 T cell count and CD4/CD8 T cell ratio during treatment and after its discontinuation
4. metformin can change the composition of the bacteria in the gut which may improve inflammation.

Further study details as provided by McGill University Health Center:

Primary Outcome Measures:

• Decrease in the size of the HIV reservoir [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

• Change in the percentage of activated CD8 T-cells [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]

References:   

1. Tamás P, Hawley SA, Clarke RG, et al. Regulation of the energy sensor AMP activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med 2006;203(7):1665–70.
2. Mehla R, Bivalkar-Mehla S, Zhang R, et al. Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner. PLoS One. 2010 Jun 16;5(6):e11160.
3. Blagih J, Coulombe F, Vincent EE, et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity. 2015 Jan 20;42(1):41-54.
4. Rolf J, Zarrouk M, Finlay DK, Foretz M, Viollet B, Cantrell DA. AMPKα1: a glucose sensor that controls CD8 T-cell memory. Eur J Immunol. 2013 Apr;43(4):889-96.
5. Laustriat D, Gide J, Barrault L, et al. In Vitro and In Vivo Modulation of Alternative Splicing by the Biguanide Metformin. Mol Ther Nucleic Acids. 2015 Nov 3;4:e262.