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Author Topic: MS drug Tysabri shows promise in efforts to combat HIV's 'viral reservoirs'  (Read 1292 times)

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Offline tryingtostay

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Link

A drug used to treat patients with Crohn's disease and multiple sclerosis has helped scientists confirm how "viral reservoirs" form in patients living with HIV and also proven effective in animal trials at blocking the pathways to those reservoirs in the brain and gut, a team of researchers reported recently in the journal PLOS Pathogens.

The drug, a humanized antibody called natalizumab, is produced by Biogen Idec Inc. under the brand name Tysabri and prescribed to patients suffering from Crohn's disease and relapse of multiple sclerosis. In their experiments, university researchers found the antibody effectively blocks a molecule that two types of white blood cells use to travel to the brain and the gut, where they collect in viral reserves linked to debilitating illnesses that strike people living with HIV, said Boston College Professor of Biology Ken Williams, a senior author of the report.

The researchers found a three-week course of natalizumab, applied four weeks after infection, reversed lesions on the central nervous system. Furthermore, the experiments showed for the first time that the traffic of the virus to the brain - transported in disease-fighting cells known as monocytes and macrophages - could be physically blocked, Williams said.

In a parallel trial, a three-week course of treatment with natalizumab at the time of experimental infection completely blocked the traffic of the virus to the brain and the gut in animal subjects, according to the report. These tests confirmed the roles of monocytes in seeding the central nervous system with the virus and leukocytes leading to the infection of the gut - both precursors to a range of illnesses.

"We actually stopped all traffic and showed that if you physically block monocytes and macrophages, the virus does not enter the brain," said Williams, whose research focuses on the long-term impact of the immune system's response to HIV/AIDS infection. "And even if full and major lesions of the central nervous system are present, application of the antibody can heal that damage and eliminate the virus, underscoring the necessity for continued traffic of cells to the central nervous system and the gut to maintain infection and lesions."

The team - which included additional researchers from Boston College, as well as colleagues at Harvard Medical School, Cornell University, and the University of Florida College of Medicine - studied the antibody based on earlier research that showed natalizumab blocked monocyte traffic in laboratory mice in trials focused on the treatment of multiple sclerosis, Williams said.

"So our question was if we can do that with HIV, does it stop virus replication in the brain, stop seeding and does it reverse injury?" said Williams. "The answer to each of those questions, we now know, is 'yes'."

The findings suggest that potential treatment regimens for humans at the time of HIV infection could include the use of the antibody in combination with antiretroviral drugs, a pairing that could serve to halt the seeding of HIV reservoirs in the brain and gut, while traditional antiretroviral therapies can target lymphoid organs to contain infection, Williams said. Human clinical trials would have to be conducted to pave the way for that potential use of the drug by patients, he said.

The latest report is viewed as a critical step in the effort to combat illnesses linked to HIV infection, including nerve damage, cardiac disease, gut disorders and dementia, which strike patients living with HIV and AIDS even though they are largely symptom free thanks to treatment from antiretroviral drugs.

Despite drug therapies that help hold HIV/AIDS symptoms in check, researchers have centered on the presence of viral reservoirs that persist in the brain and the gut. Earlier research from the Williams lab has shown that cells and molecules from these stockpiles are present in illnesses such as neuropathy in the hands and feet, AIDS-related dementia, "leaky gut" syndrome and heart inflammation in people living with HIV and AIDS.

The Williams lab is also involved in a $39-million human clinical trial led by researchers at Massachusetts General Hospital and funded by the National Institute of Allergy and Infectious Diseases to determine whether treatment with a statin drug can reduce the elevated risk of cardiovascular disease in individuals infected with HIV. The REPRIEVE trials are slated to begin this spring.

As calls grow louder for a push to a "cure" for HIV/AIDS, researchers have focused on monocytes and macrophages - as well as T-cells - as another route to the development of new drug therapies that can fully arrest the damaging impact of the virus.

"When people talk about a 'cure' for aids, it's really about eradicating these viral reservoirs," said Williams

Offline leatherman

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viral reserves linked to debilitating illnesses that strike people living with HIV


Earlier research from the Williams lab has shown that cells and molecules from these stockpiles are present in illnesses such as neuropathy in the hands and feet, AIDS-related dementia, "leaky gut" syndrome and heart inflammation in people living with HIV and AIDS.
I don't understand these two sentences from this article.

I don't know that I've ever read that PLWH are "struck" with debilitating illnesses because of viral reserves. While there is certainly long-term systemic inflammation due to reservoirs (not just the presence of these reservoirs in the system, but also the occasional "spill-over" over virus),  this virus is usually latent and in relatively small amounts. I can't imagine that a small amount of "latent" virus is striking down PLWH with "debilitating illnesses".

Then when some of these "debilitating illnesses" are listed, there are a couple of issues. "leaky gut syndrome" isn't really a thing and it's inclusion is suspect. Plus I don't understand the inclusion of "AIDS-related dementia", instead of listing HAND (HIV-associated neurocognitive disorder). Doesn't "AIDS-related" imply that it's related to an AIDS condition (ie low CD4, high VL) and not caused by controlled latent viral reservoirs?

monocytes and macrophages - could be physically blocked,
what's the effect of stopping monocytes and macrophages from crossing over to my brain? Blocking my immune system from working sounds problematic to me. LOL

of course the time from animal trials to human consumption is a very long path and many potential-looking strategies fall apart after more study. :-\
leatherman (aka mIkIE)


chart from 1992-2013; updated 2/09/13  Reyataz/Norvir/Truvada

Offline JakaTingkir

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of course the time from animal trials to human consumption is a very long path and many potential-looking strategies fall apart after more study. :-\

Well if this drugs was safe to be used for MS, i think it will go to phase IIb or III. But, I dont know if this pharma company will interest with this finding, thats the problem....:-)

Offline leatherman

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Well if this drugs was safe to be used for MS,
umm, this drug is not all that safe. The drug is linked with causing PML and death. It is only on the market because it's a drug of last resort for people living with Chrons or MS

Quote
Natalizumab was approved in 2004 by the U.S. Food and Drug Administration (FDA) after years of testing. It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy (PML) when administered in combination with interferon beta-1a, another immunosuppressive drug often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. As of June 2009, ten cases of PML were known. However, twenty-four cases of PML had been reported since its reintroduction by October 2009, showing a sharp rise in the number of fatalities and prompting a review of the chemical for human use by the European Medicines Agency.[1][2][3] By January 2010, 31 cases of PML were attributed to natalizumab.[4] The FDA did not withdraw the drug from the market because its clinical benefits outweigh the risks involved.[5] In the European Union, it has been approved for human use only for the treatment of multiple sclerosis and only then as a monotherapy because the initial cases of PML, and later the fatalities, were said by the manufacturers to be linked to the use of previous medicines by the patients.
http://en.wikipedia.org/wiki/Natalizumab
leatherman (aka mIkIE)


chart from 1992-2013; updated 2/09/13  Reyataz/Norvir/Truvada

Offline JakaTingkir

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Good points leatherman..i think there will be no clinical trial on this drug, the fatalities outweigh the benefits...

But there is a candidate that could inhibit virus in macrophage or monocyte such as drugs thats developed by biotron...i hope its more effective than using MS drug to overcome the virus in the brain. Last update was still in phase IIa... :)

Offline DJS1980

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Have scientist been able to locate these 'viral reservoirs' or they part on the DNA or RNA of that person blood, organs, bone marrow, etc etc? I understand that a person could have a undectable VL but the virus remains IE as viral reservoirs and if treatment is stop VL can rise again.

If someone can link me too any research articles or papers that would be great. I work with radioactive sources and tools. I know the effects these tools and radioactive source can do to a persons DNA, no I'm not saying what a lot of you are thinking!!.

Offline leatherman

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Have scientist been able to locate these 'viral reservoirs'
Latent reservoirs of HIV are located throughout the body, including the brain, gut, lymph tissue, bone marrow, and genital tract.

here's a bunch of science-y info, circa 2012
http://www.projectinform.org/pdf/AIDS_0312.pdf

Quote
Most of the latent virus in resting CD4(+) T cells is found in cells of the memory phenotype. The half-life of this latent reservoir is extremely long (44 months). At this rate, eradication of this reservoir would require over 60 years of treatment.
http://www.ncbi.nlm.nih.gov/pubmed/10837072

well there you go! I usually do learn something new everyday and that was it ;)
sweet! I come from a line of people who have all lived into their late 90s and early 100s. Since I've been on meds 20+ years, that leaves about 40+ more years until my meds could cure me. So if you add those 40 years to the 53 yrs I just celebrated on PI Day and I'll only be 93 when I'm HIV-free and still have nearly a decade to go. LOL :D
leatherman (aka mIkIE)


chart from 1992-2013; updated 2/09/13  Reyataz/Norvir/Truvada

Offline Andy Velez

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DJS, I appreciate your interest in this thread. However there are rules here and as a person who is NOT HIV+ the only forum you are permitted to write in is AM I INFECTED, with the exception sometimes of SOMEONE I LOVE IS +.

I am leaving this thread as is for the timebeing but don't write here again.

Thanks for your cooperation. 
Andy Velez

Offline Matts

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The " Kick and kill" is not so easy as believed.  The PKC activator "ingenol-3-hexanoate" (Ing-B) - a derivative from the plant Euphorbia tirucalli can wake up the latent cells.
But in an animal model the monkeys had to be killed because the brain was flooded with activated HIV reservoirs and the monkeys got a serious Encephalitis. It is possible to activate the latent cells, but the body cant handle this enormous number of activated viruses.

Problems and more problems:)

http://www.croiconference.org/sessions/latency-reversing-agents-activate-latent-reservoirs-brain-siv-infected-macaques

Quote
Background: Our group has been testing the PKC activator ingenol-3-hexanoate (Ing-B) as a potential candidate for a “Kick and Kill” HIV eradication strategy. Preliminary data show that Ing-B treatment caused a temporary but significant increase in plasma viral load (VL) of two virally suppressed SIVmac251-infected cART-treated rhesus macaques. After interrupting the drug regimen (cART and Ing-B), VL stayed undetectable for 45 days before rebounding to pre-cART levels. Here we report results from Ing-B treatment in our consistent and accelerated SIV macaque model for HIV/AIDS and HAND.

Methods: Three pigtailed macaques were dual inoculated with SIVΔB670 and SIV/17E-Fr, and treated at 12 days p.i. with CNS-penetrant cART (TNF, ATZ, RTN, L-870812). After 500 days of viral suppression, one animal was kept as control while two macaques received daily oral doses of Ing-B for 40 days. After a 2-week washout, the same animals received a 10-day treatment of Ing-B in combination with vorinostat (4 daily IV doses in 10 days). Animals were kept on cART until necropsy. SIV RNA was quantitated in plasma and CSF by ddPCR. SIV DNA was assessed in tissues by qPCR. In situ hybridization (ISH) for SIV RNA was performed in samples from brain and mesenteric lymph node. Resting CD4+ T cells were collected before and after latency reversing agents (LRA) treatment for quantitative viral outgrowth assay.

Results: LRA induction caused a significant increase of plasma and CSF VL in one of the LRA-treated macaques. CSF viral load was 10x higher than in plasma, and the animal had to be euthanized due to encephalitis-related symptoms. SIV RNA could be detected by ISH in occipital cortex, despite undetectable levels of SIV DNA measured by qPCR. No change was observed in the other LRA-treated macaque. However, the number of SIV-infected resting CD4+ T cells was reduced after LRA-induction in both treated animals when compared to control.

Conclusions: Treatment with LRAs led to a decrease in latent reservoirs in SIV-infected cART-treated macaques. In one animal, treatment activated viral genomes in basal ganglia, leading to CNS disease, indicating that the brain harbors latent virus and should be seriously considered when novel "Kick and Kill” strategies are designed for HIV eradication.
triumeq

 


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