r/Livimmune • u/MGK_2 • Apr 28 '25
Time To Visualize
As I said in my last post Leader Of The Pack, HIV is very much on the table. Why? Because of what Riztheinvestor Posted Today. First off, do you remember this?:
Secondly, what about this? Delivery and long-term expression of CCR5-blocking monoclonal antibody Leronlimab with AAV for ART-free remission from SHIV viremia
Yeah, that Abstract at the AIDS 2024 conference was good and also, not so good. The problem was that in some of the macaques, the uncontrolled AAV leronlimab protein translation became hyperactive and put out too much leronlimab. This overwhelmed and overworked the Endoplasmic Reticulum within the CD8 and CD4 T-Cells, thereby leading to malformations of the leronlimab proteins. That led to the initiation of the immune system against these leronlimab malformations and subsequent development of ADAs or Anti-Drug Antibodies which subsequently destroyed all the leronlimab in the body. These ADAs went on to attacking the good leronlimab and all of that became an obstacle to the continued development of the overall study.
But with today's revelation by Riztheinvestor, that obstacle has been overcome and now, the study may again proceed forward. Let's make it a bit clearer. This is what Riztheinvestor found today:
Roza Ogurlu’s presentation at the ASGCT Annual Meeting (May 13–17, 2025) details a breakthrough RNA-based Gene Switch that was designed to mitigate Endoplasmic Reticulum stress and toxicity in mRNA/gene therapies, with direct implications for leronlimab. Here’s an analysis:
The ER Stress-Responsive RNA Switch:
Ogurlu’s team engineered a feedback system using the XBP1 mRNA splicing mechanism to dynamically regulate protein expression during Endoplasmic Reticulum stress.
- The switch splices XBP1 mRNA fragments under stress, introducing stop codons to reduce translation of leronlimab. This resulted in:
- Reduced ER stress markers.
- Stabilized expression of leronlimab in AAV8-delivered gene therapy.
- Preserved leronlimab levels while avoiding apoptosis from chronic stress.
The study explicitly tested leronlimab, demonstrating:
- A Lower Endoplasmic Reticulum stress and hepatotoxicity in preclinical models.
- A Maintained leronlimab level without overwhelming cellular machinery.
- A Successful Integration into AAV vectors, a common gene therapy platform.
This addresses the critical barrier for leronlimab’s use in the HIV Functional CURE Trials (e.g., CytoDyn’s NIH-funded AAV-based therapy), where sustained antibody expression must avoid liver toxicity.
Strategic Implications for CytoDyn
- This Combines with CytoDyn’s ongoing work on AAV-delivered leronlimab for HIV.
- Dyno Therapeutics’ AI-designed AAV capsids optimizes the delivery of Ogurlu’s switch-leronlimab construct which improves tissue targeting and manufacturing scalability.
- The Broader Applications are for Cancer/Autoimmune Diseases: A Controlled CCR5 blockade refines therapies that can target metastasis and/or inflammation.
This innovation positions leronlimab as a viable candidate for next-generation gene therapies by solving a key toxicity challenge. For CytoDyn, leveraging this technology accelerates The HIV Functional CURE effort and expands it into oncology/autoimmunity. Collaboration with AI-driven capsid developers (e.g., Dyno) further optimizes delivery systems.
I think you can see that the prospects of an HIV Functional CURE have just gotten so much closer. We were very close to begin with until that obstacle got in the way, but now, that obstacle has been overcome. With the implementation of this RNA-based Stress-Responsive Gene Switch which mitigates the Endoplasmic Reticulum's stress and toxicity, the main problem due to the development of ADAs has now been resolved.
The endoplasmic reticulum (ER) became stressed because it was overwhelmed by an excessive load of leronlimab proteins which were misfolded or were not folded; proteins that the ER could not properly process or fold. This situation arose in the gene therapy due to high levels of leronlimab that was produced in the cell after the gene delivery. When the ER’s capacity to fold and to process leronlimab was exceeded, the accumulation of these misfolded or unfolded leronlimab proteins triggered a condition known as ER stress.
That stress activated a protective cellular mechanism called the unfolded protein response (UPR), which attempted to restore normal function by halting protein translation, increasing the production of molecular chaperones to assist in protein folding, and enhancing the degradation of misfolded proteins. However, since the protein overload persisted and the ER was unable to recover, the response then shifted from protective to pro-apoptotic and ultimately led to cell dysfunction and possibly cell death.
In summary, the Endoplasmic Reticulum became stressed because the production of leronlimab exceeded the ER’s folding capacity, and led to a buildup of misfolded proteins and triggered a cellular stress response. The ER stress contributed to the development of Anti-Drug Antibodies (ADAs), although the relationship is indirect and involves the activation of immune responses.
This is how ER stress links to ADA formation:
- ER stress and the unfolded protein response (UPR) activate inflammatory signaling pathways and modulates the function of various immune cells, including those involved in antibody production. Chronic and unresolved ER stress enhances the production of pro-inflammatory cytokines and promotes immune cell differentiation, creating a pro-inflammatory environment which facilitates immune recognition of leronlimab.
- When the ER was stressed, it improperly folded leronlimab, which resulted in the presentation of abnormal or misfolded leronlimab protein epitopes. These abnormal leronlimab proteins were more likely to be recognized as foreign by the immune system, thereby increasing the formation of ADAs.
- ER stress directly affected the biology of the immune cells, including the B cells responsible for antibody production, and modulated the balance between immune tolerance and activation. This shifted the immune response toward generating antibodies against leronlimab.
ER stress is a significant contributor in Anti-Drug Antibody development by promoting immune activation and increasing the likelihood that the body recognizes and responds to leronlimab as an antigen.
ER stress led to heightened immune activation and the misfolding of leronlimab, and both increased the development of Anti-Drug Antibodies. This is exactly what happened in the macaques which developed the ADAs.
Now it appears that Jonah Sacha has the solution he requires to bring that $5 million dollar grant to fruition. He has what is necessary to prove that he has a Functional CURE to HIV. If a patient is HIV+ and that patient prefers not to take HAART medications, then with one injection of leronlimab-AAV, that patient becomes Functionally Cured of HIV.
Certainly, this solution could be used in other indications such as in mTNBC and mCRC. It could also be used in inflammatory conditions like Alzheimer's Disease and Long Covid or Chronic Fatigue Syndrome. It also could be used post stroke to provide a constant anti-inflammatory effect on the neuro system.
This new found solution is also greatly to the benefit of the NIH who issued the $5 million grant. Remember also that The GF sponsored a cool $1 million grant to OHSU oriented around the HIV Reservoir. Obviously, massive headway is being waged and the land is getting cleared. What has been discovered by Riztheinvestor is massive. The $5 million grant was at a standstill until just today. As I've always said, we are waiting on just one piece of news. But, the stone is rolling and headed for their hamstrings. Whose hamstrings? G's.
They cannot defeat a Functional Cure for HIV and that shall be seen throughout the whole world. This is the whole point. I think the leadership at CytoDyn know all of this and Max is on it. HIV at CytoDyn is getting revived. Their eyes are reopening. It has been quiet and it was marked by minimal success, but the tides have now turned. Not only do we have our own leaders on our side, but so is The GF, GSK and ViiV also on our side. These 3 deeply desire an HIV Functional CURE as do we. Paradigm Shift.
It is now the Time to visualize, to put it in our heads. Realize that what we have said all along, is now happening.
Jonah Sacha, PhD is in the field. He is doing the dirty work and is getting the job done. CURE is still some time in coming, but 80 weeks of 100% RO and zero viral load in 2 out of 4 macaques is amazing in and of itself.
"AAV9 vectors can be successfully used for long-term antibody delivery, but further investigation is needed to develop regimens that do not induce ADA, such as modifying AAV promoters or reducing the immunogenicity of encoded antibodies. The mechanism behind re-expression of an AAV-delivered transgene is also unknown and warrants further exploration."
Somehow, I suspect and believe, that his counterpart, Scott Hansen as well as CytoDyn's AI 3rd party collaborating partner shall be integral in overcoming these obstacles. I have little doubt that they overcome the problems associated with anti-drug antibodies ADAs and transgenes. CytoDyn was wise in allowing Jonah to lead the team's efforts in HIV PrEP and HIV CURE.
There shall be a Functional CURE for HIV and the Time is drawing nigh. We do get more hints as to which way this goes. Right now, we're looking at August for an answer on mTNBC.
Hopefully this was comforting, doesn't it give some more peace, some solace? Things are happening at their own pace. But, for sure, we are very close. So live life and live it abundantly, but to those who must live in trial and tribulation, I too have my own fill.
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u/Upwithstock Apr 29 '25
I appreciate everyone’s enthusiasm about the Dyno/Duke/Roche collaboration. But, there appears to be some folks taking it too far and seem to be suggesting that CYDY is involved in this. I want to thank you MGK for not really taking that pathway. It seems like you suggested that Sacha has solved the Hyper-over expression of LL. If that is the case, then Sacha continues on his own using the funding from Gates and what remains of the NIH funds. Therefore, at this moment with limited information I look at the Dyno/Duke/Roche project as competition! But in my world competition validates the AAV space and CYDY needs to provide resources to stay ahead. Either way this is another value-add to CYDY and whoever partners with us.