Anti-aging drug and AMPK activator Rapamycin currently in clinical trials to reduce the latent HIV-1 reservoir

"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 the evidence continues to mount in support of my publication:-) Below is another LinkedIn post I authored detailing a clinical trial that began late last year to determine if the anti-aging drug rapamycin can reduce the latent/dormant HIV-1 reservoir as well as increase the levels of CD8+ T cells to kill the virus once it’s reactivated.  Just like metformin (Galega plant), sulforaphane (broccoli sprouts), artemisinin (Nobel Prize winning drug derived from the Artemisia plant), retinoic acid (vitamin A metabolite), methylene blue, and many others, rapamycin has recently been shown to be a potent AMPK activator and, similar to sulforaphane, retinoic acid, and methylene blue, reverses cellular aging defects in Progeria.  Interestingly, activation of AMPK by these compounds (and countless other naturally-occurring compounds) boosts the levels of cytotoxic CD8+ T cells.  These cells are extremely important in mounting a powerful immune response that kills viruses, bacteria, pathogens, and cancer cells.  Are diseases as seemingly disparate as HIV-1, Progeria, and cancer possibly connected by a common pathway ? I wouldn't bet against it:-)

Clinical Trial Official Title: Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy

In line with the recent filing by McGill University with ClinicalTrials.gov (January 2016; see last post) to determine if the AMPK activator metformin is able to “reduce the amount of hidden virus in the body”, “decrease the size of the HIV reservoir”, and induce a “change in the percentage of activated CD8 T-cells”, a clinical trial registration, first received by ClinicalTrilas.gov on April 6, 2015 and sponsored by the AIDS Clinical Trials Group in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), seeks to determine whether the anti-aging drug and AMPK activator rapamycin (also known as sirolimus) is capable of reducing the latent HIV-1 reservoir in patients currently on suppressive anti-retroviral therapy.

This is a PhaseI/II study (determining both safety and efficacy) with an estimated enrollment of 30 patients with a start date of August 2015, an estimated primary completion date of September 2016 (final data collection date for primary outcome measure), and an estimated study completion date of January 2017. The study is being chaired by physicians from the University of California, San Francisco and Brigham and Women's Hospital, with patient recruitment from institutions including the Johns Hopkins University, Cornell University, Columbia University, and the University of Pennsylvania.  A portion of the details of the clinical trial are reproduced below with a link provided as well.

It is very interesting to note that the sponsors of this study are seeking to determine the efficacy of rapamycin for “HIV Reservoir Reduction”  in patients with “plasma HIV-1 RNA below the level of quantification (e.g., <20, <40, <50, or <75 copies/mL depending on the assay) for ≥24 months.” (see Inclusion Criteria on the website). HIV-1 RNA below these levels indicate that anti-retroviral therapy has been successful in treating productively infected cells, but CD4+ T cells latently infected with HIV-1 (i.e. dormant) still persist and must be selectively and safely reactivated to potentially effectuate a cure. 

Another interesting detail is that the sponsors are seeking to determine, as a primary outcome measure, if rapamycin affects the “frequency of HIV-1 Gag-specific CD8+ T-cells” and whether rapamycin affects “HIV-1-specific CD4+ T-cell responses and HIV-1-specific CD8+ T-cell      responses” as a secondary outcome measure.

Studies have shown that efficient reactivation of latent HIV-1 involves a reduction in the splicing of the HIV-1 genome by the splicing factor SRSF1, an upregulation in the activity of the splicing-associated protein p32, the production of unspliced HIV-1 mRNA (also known as HIV-1 Gag), and the processing of Gag into the HIV-1 p24 antigen, an antigen that is an endpoint that is frequently measured to determine if efficient reactivation of latent HIV-1 by a candidate compound was successful [1,2]. The activation of T cells generally have been shown to be critically dependent on AMPK activation and the activity of the splicing factor SRSF1 is downregulated during both latent HIV-1 reactivation and in activation of T cells not infected with HIV-1  [1,3,4].

AMPK is critical for the formation of memory CD8+ T cells, a memory T cell population that is instrumental in mounting an effective immune response to both pathogens and cancer cells [5].  Interestingly, the knockdown of AMPK significantly inhibits the immune response to both viral and bacterial challenges and metformin and rapamycin have both been shown to increase the formation of CD8+ memory T cells [6-8]. 

Lastly, and perhaps most importantly, is the recent study that convincingly demonstrates that rapamycin, similar to metformin, is a potent activator of AMPK in vivo (i.e. in a living organism) in normal elderly mice [9]. Because both metformin and rapamycin activate AMPK in vivo and AMPK has been shown to be essential for T cell activation and the formation of CD8+ memory T cells, the activation of AMPK appears to be “a common yet indirect mechanism of action” shared by many compounds that likely underlies the reactivation of latent HIV-1 reservoirs as well the creation and enhancement of CD8+ memory T cells. As proposed in my most current paper, this mechanistic commonality of AMPK activation also likely explains the actions of rapamycin in the amelioration of accelerated cellular aging defects in Hutchinson-Gilford progeria syndrome.  Again, the figure I recently drafted below is illustrative of both disease interconnectedness and the common mechanism of action of chemically distinct compounds to treat those diseases.  

https://www.linkedin.com/pulse/anti-aging-drug-ampk-activator-rapamycin-currently-clinical-finley?published=u 

Excerpt from: https://clinicaltrials.gov/ct2/show/NCT02440789?term=rapamycin+hiv&rank=1

Official Title: Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy

Sponsor: AIDS Clinical Trials Group

Collaborator: National Institute of Allergy and Infectious Diseases (NIAID)

Information provided by (Responsible Party): AIDS Clinical Trials Group

ClinicalTrials.gov Identifier:

NCT02440789

First received: April 6, 2015

Last updated: January 29, 2016

Last verified: January 2016

Estimated Enrollment: 30

Study Start Date: August 2015

Estimated Study Completion Date: January 2017

Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)

Further study details as provided by AIDS Clinical Trials Group: 

Primary Outcome Measures:

• Number of participants who met the study-defined composite safety endpoint [ Time Frame: 44 weeks ] [ Designated as safety issue: Yes ]The study-defined primary safety endpoint is a composite endpoint. A participant is considered to have met the endpoint if the participant 1) experienced a new Grade ≥3 AE, including signs/symptoms, lab toxicity or clinical event, that is definitely, probably or possibly related to study treatment, as judged by the core team, or 2) had a change in CD4+ cell count ( confirmed >50% decline or to 300 cells/mm3) while on sirolimus
• Efficacy - Immunologic [ Time Frame: 32 weeks ] [ Designated as safety issue: No ]Frequency of HIV-1 Gag-specific CD8+ T-cells by intracellular staining for IFN-gamma at baseline and at week 32 (20 weeks on sirolimus)
  
• Efficacy - Virologic [ Time Frame: 32 weeks ] [ Designated as safety issue: No ]CD4+ T-cell-associated HIV-1 RNA and plasma HIV-1 RNA by SCA at baseline and at week 32 (20 weeks on sirolumus) 

Secondary Outcome Measures:

• Measurement of CD4+ T-cell counts [ Time Frame: Measured through Week 44 ] [ Designated as safety issue: Yes ]CD4+ T-cell counts at baseline and at weeks 14, 16, 20, 24, 32 (2, 4, 8, 12, 20 weeks on sirolimus) and 44
  
• Measurement of HIV-1 RNA levels [ Time Frame: Measured through Week 44 ] [ Designated as safety issue: Yes ]HIV-1 RNA levels by conventional assay at baseline and at weeks 16, 20, 24, 32 (4, 8, 12, 20 weeks on sirolimus) and 44
  
• Measurement of CD4+/CD8+ T-cell responses [ Time Frame: Measured through Week 44 ] [ Designated as safety issue: No ]HIV-1-specific CD4+ T-cell responses and HIV-1-specific CD8+ T-cell responses (other than gag) at baseline and at weeks 13, 16, 24, 32 (1, 4, 12, 20 weeks on sirolimus) and 44
  
• T-cell activation and proliferation [ Time Frame: Measured through Week 44 ] [ Designated as safety issue: No ]T-cell activation and proliferation (% CD4+ and CD8+ T cells CD38+/HLA-DR+, CD25+, PD-1+, Ki67+ and PD-L1 expression) at baseline and at weeks 13, 16, 24, 32 (1, 4, 12, 20 weeks on sirolimus) and 44
  
• Cell-associated HIV-1 DNA levels in total CD4+ cells [ Time Frame: Measured through Week 44 ] [ Designated as safety issue: No ]HIV-1 DNA levels in CD4+ T-cells at baseline and at weeks 13, 16, 24, 32 (1, 4, 12, 20 weeks on sirolimus) and 44.           

References:

1. Berro R, Kehn K, de la Fuente C, et al. Acetylated Tat regulates human immunodeficiency virus type 1 splicing through its interaction with the splicing regulator p32. J Virol. 2006 Apr;80(7):3189-204.

2. Spina CA, Anderson J, Archin NM, et al. An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog. 2013;9(12):e1003834.

3. 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.

4. Moulton VR, Gillooly AR, Tsokos GC. Ubiquitination regulates expression of the serine/arginine-rich splicing factor 1 (SRSF1) in normal and systemic lupus erythematosus (SLE) T cells. J Biol Chem. 2014 Feb 14;289(7):4126-34.

5. 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.

6. 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.

7. Pearce EL, Walsh MC, Cejas PJ, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009 Jul 2;460(7251):103-7.

8. Araki K, Turner AP, Shaffer VO. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009 Jul 2;460(7251):108-12.

9. Chiao YA, Kolwicz SC, Basisty N, et al. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY). 2016 Feb;8(2):314-27.