Planet Of The Apes
Jonah Sacha's Presentation at HIVR4P October 9, 2024
Planet of the Apes with Slides
Jonah Sacha 01:25: Thank you for that introduction Michaela. Thank you for the opportunity to speak today.
Before I begin, I need to let you know that I consult for and serve as :
01:43, So our main question was:
Main Question: Could we prevent/clear reservoir seeding in infants soon after HIV is acquired?
What we found?: That the combination of broadly HIV neutralizing antibodies with CCR5 blockade and under the cover of antiretroviral therapy, we could prevent reservoir establishment in SHIV infected macaque infants.
Why is it important?: Because it reveals a previously unknown Synergy between HIV broadly neutralizing antibodies and CCR5 blockade. Because all of these are in clinical development, this is a real clinical option that we can take forward.
So despite major advances, about 150,000 children still become infected each year, the majority of which are infected vertically through breast feeding and so my colleague Dr. Nancy Haigwood developed this fantastic infant macaque model in pediatric HIV infection. These infants are born naturally in the wild vaginal birth. They are allowed to suckle for up to 7 days. Their mother, at 30 days old are challenged with a high dose of oral SHIV. This results in a 100% infection rate. You can see by these animals here:
02:53 Jonah Sacha: High Virema, Rapid Pathogenesis and if left untreated, 75% will come to infection within 6 months. So this is a robust model of infant infection.
03:05: And so, working in collaboration with Dr. Haglund, showed that if you take these infants at 24 hours post infection, then administer a combination of bNAbs as shown on the bottom, you can completely prevent seeding of the viral reservoir in this model. Again, this is at 24 hours.
03:24: So in work that is partially published or unpublished, we went to find the window of opportunity for treatment, and again, this is using the same bNAb cocktail, we administered either at 30, 48 or 72 hours post oral inoculation, you can see at 30 hours, there is complete protection, begin to lose that protection at 48 hours and by 72 hours post infection, the die is cast. Every animal presents with viremia and is productively infected.
03:53: And so, we use this moving forward, timing 72 hours post infection. And we asked the question, "Whether at 72 hours, could we treat these animals short term ART as shown on the left or ART + bNAbs, could we prevent seeding of the reservoir?" and the answer in both of these groups was a resounding No. You can see on the left, in the short term, ART and also ART + bNAbs on the right, 4 out of the 6 animals had productive infection and the other 2 were infected in spite of blipping throughout.
04:24: So, that led to the question of whether we could use CCR5 blockade alone or in combination with bNAbs to be effective at 72 hours post infection. And so we turned to leronlimab. This is a humanized monoclonal IgG4 antibody that targets CCR5. Specifically, it binds to the N-terminus and extra-cellular domain 2 of CCR5. These are the same regions that the HIV envelope binds to. So, it is a competitive inhibitor of CCR5 binding with HIV. It is currently in clinical trials and has been tested in over 1,000 people and has a decently high safety profile. Most importantly, we showed recently that in the macaque model, if we use this pre-exposure prophylaxis, leronlimab by itself, could prevent rectal transmission of SHIV.
05:14 And so this is the outline of the study. We had 2 concurrent untreated Controls to insure that our challenge stock was still functioning as expected. We had 2 concurrent controls ART + bNAbs given at that day 3. And then for our experimental groups, we had ART + leronlimab, 6 animals, starting at day 3 with 2 weekly doses at 50mg/kg followed by weekly 10mg/kg doses through week 8. And then finally, we had the triple therapy group where we combined all of them: ART, bNAbs and leronlimab. In this group, there were 8 animals. And then we continued our ART through 27 weeks to allow for washout and then did ART release.
05:54: So these are the Plasma Viral Loads. You can see that in the untreated controls, as expected, we get infection was very high, progressive of viral infection. In the ART + bNAbs, concurrent controls, get infected, blips the virus, then, subsequently controlled by ART. Same story for ART + Leronlimab and Triple Therapy Group. Something, I will point out though, interestingly, I don't know if this is stochastic or if there is something to this, the Viral Loads that we saw in the acute phase, right when we initiate treatment were much higher in the triple therapy group than in the other groups. But again, all the animals become infected and then the virus is controlled.
06:36: So why 27 weeks? We had to wait for leronlimab to wash out. Looking on top, this is free leronlimab in plasma. And the bottom is CCR5 Receptor Occupancy. CCR5 on the surface of CD4 cells for blood. And you can see that by 27 weeks, leronlimab is completely washed out from the plasma and off the surface of the CD4 T-Cells.
06:56 That is the same story with our bNAbs. They are also washed out. So at this point, week 27, we proceeded to ART release.
07:01: In our untreated controls, one animal succumbed to infection in this time period. The other one continued on with high levels of viremia. As expected, the 2 concurrent controls of ART + bNAbs both rebounded with viremia. The leronlimab + ART group looked surprisingly similar to bNAbs with ART with 4 out of 6 animals that rebounded with viremia. Interestingly, the other 2 animals never rebounded. But all of this is in very stark contrast to the triple therapy group where not a single animal, 0 out of 8 rebounded with positive viremia. And this data is now through 7.5 months off of ART. (At time of this transcript, 1/27/25, it is 11 months off of ART). So, during this time period, we never saw any evidence of any rebound of plasma viremia in any of these triple therapy treated animals.
07:44: We also measured Cell Associated Viral loads DNA. Unseeded controls. We see it transiently in the ART + bNAbs group and again when the virus rebounds. We don't see any in the ART + leronlimab group and then again, in the triple therapy group, we never see any evidence, we did not have a single positive at any time point, in any of these 8 animals. Suggesting that perhaps, the virus reservoir had been cleared.
08:25: So at week 56, we took a blood draw and lymph node biopsy, assay for virus specific T-Cells, you can see that in the controls in black, this is the ART + bNAbs controls, we see specific T-Cells in the lymph nodes of PBMC (peripheral blood), but if we look in the 8 triple therapy groups in Lilac, we don't see any evidence of a T-Cell response in peripheral blood or lymph node. And then we took, isolated CD-4 T-Cells, and did a higher sensitivity assay, and again shown in lilac with the open symbols, none of these are positive. We did not have a single positive hit in any of the triple therapy treated animals suggesting that the virus reservoir had potentially been cleared.
09:07: So finally, at week 60, we initiated the gold standard CD8 depletion. And you can see here, looking at the CD8 levels in peripheral blood. In the control, untreated control on the left are 2 bNAb animals in the middle, and all 8 of the triple therapy on the right, CD-8 T-cells are removed from the blood. In the untreated controls, see a log rise in plasma viremia. We see a rebound of the virus in the ART + bNAb group, so again, we see the presence of the virus. Striking contrast, we don't see any rebound of virus in any of the CD 8 depleted treated triple therapy animals. So, cumulatively, this data suggests that the virus reservoir was indeed actually cleared in these animals. Difficult to prove in the negative, but all the data seems to support that.
09:50: So what do we take away from this? 1st is that there seems to be a previously unappreciated synergy between CCR5 blockade with broadly Neutralizing Anti-bodies bNAbs. In this model of infant macaques, treated early, at 72 hours, it is insufficient to treat with bNAbs or leronlimab by itself, but, if you combine them, together, they are able to, what appears to be, clear the reservoir and prevent reservoir seeding. As far as the mechanism of this, we actually don't know, so I would love to hear your thoughts on this. One idea is that it is a combination of anti-viral efficacy. Going at the virus through its CCR5 receptor, and also through bNAbs and neutralization, OR, as shown nicely in this review of by Anne Seruti who was speaking momentarily, trafficking of the infected cells model is really critical and we know that CCR5 is a trafficking signal. So are we actually altering trafficking of the infected cells early on? Whatever mechanism, this needs to be investigated in much greater detail.
11:00 And with that I'd like to thank the individuals who did this work. Dr. Nancy Haigwood and her group. Animal staff at UC Davis. NIH who funded this work. Thank you.
Posted Jan 27, 2025, 9:00 PM UTC