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Author Topic: UF Research: Macrophages as latent reservoirs, mutation catalysts  (Read 2520 times)

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Offline carpediem98

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Here's an article from Science Daily discussing research out of the University of Florida regarding the role of macrophages in mutation and persistent infection.  Along with the targeted "reawakening" of resting lymphocytes that has been shown to be possible with Zolinza/vorinostat/SAHA, a drug that targets these macrophages might get us that much closer to the reality of total eradication of HIV.

Link to original article is http://www.sciencedaily.com/releases/2009/05/090527181544.htm.

New Cellular Targets For HIV Drug Development

ScienceDaily (May 28, 2009) — Focusing HIV drug development on immune cells called macrophages instead of traditionally targeted T cells could bring us closer to eradicating the disease, according to new research from University of Florida and five other institutions.

In the largest study of its kind, researchers found that in diseased cells — such as cancer cells — that are also infected with HIV, almost all the virus was packed into macrophages, whose job is to "eat" invading disease agents.

What's more, up to half of those macrophages were hybrids, formed when pieces of genetic material from several parent HIV viruses combined to form new strains.

Such "recombination" is responsible for formation of mutants that easily elude immune system surveillance and escape from anti-HIV drugs.

"Macrophages are these little factories producing new hybrid particles of the virus, making the virus probably even more aggressive over time," said study co-author Marco Salemi, Ph.D., an assistant professor in the department of pathology, immunology and laboratory medicine at the UF College of Medicine. "If we want to eradicate HIV we need to find a way to actually target the virus specifically infecting the macrophages."

At least 1.1 million people in the United States and 33 million in the world are living with HIV/AIDS, according to the Kaiser Family Foundation.

The researchers set out to see if HIV populations that infect abnormal tissues are different from those that infect normal ones, and whether particular strains are associated with certain types of illness.

They tackled the question using frozen post-autopsy tissue samples, pathology results and advanced computational techniques. They analyzed 780 HIV sequences from 53 normal and abnormal tissues from seven patients who had died between 1995 and 2003 from various AIDS-related conditions, including HIV-associated dementia, non-Hodgkin's lymphoma and generalized infections throughout the body. Four patients had been treated with highly active antiretroviral therapy, called HAART, at or near the time of death.

The researchers compared brain and lymphoma tissues, which had heavy concentrations of macrophages, with lymphoid tissues — such as from the spleen and lymph nodes— that had a mix of HIV-infected macrophages and T cells.

The analyses revealed great diversity in the HIV strains present, with different tissues having hybrid viruses made up of slightly different sets of genes. A high frequency of such recombinant viruses was also found in tissues generally associated with disease processes, such as the meninges, spleen and lymph nodes.

The researchers concluded that HIV-infected macrophages might be implicated in tumor-producing mechanisms.

The higher frequency of recombinant virus in diseased tissues likely is because macrophages multiply as a result of an inflammatory response, the researchers said.

"The study points to macrophages as a site of recombination in active disease," said neurobiologist Kenneth C. Williams, Ph.D., a Boston College associate professor and AIDS expert who was not involved in the study. "So people can say this is one spot where these viruses come from."

T cells — the so-called conductors of the immune system orchestra, whose decline is the hallmark of HIV disease — are an obvious target for HIV drug development because they die soon after infection, and are readily sampled from the blood and cultured. But although current drugs are effective at blocking infection of new cells and lowering viral loads to barely detectable levels, they never reduce the viral level in an infected person to zero.

"Where is it coming from?" said Michael S. McGrath, the University of California, San Francisco, professor who led the research team. "We believe it's coming from these macrophages."

Macrophages, like T cells, can be infected multiple times by HIV. But unlike T cells, when they get infected, they don't die within days, but live for several months, all the while being re-infected with multiple viruses of different genetic makeup. That situation is ripe for the emergence of hybrids.

"Most people who look at viral sequences assume that evolution of the virus is linear. In the real world that doesn't happen — large parts of the virus are swapped in and out. This group has shown that in this model," Williams said. "It sort of overturns the old way of trying to match virus sequence with pathology."

McGrath's group is now developing macrophage-targeting drugs that, through a grant from the National Institute of Mental Health, should be in human clinical trials in a few years.

"This is one of the last frontiers — killing off what we believe is a so far untouched reservoir," he said.

The work was published recently in the journal PLoS One.

University of Florida (2009, May 28). New Cellular Targets For HIV Drug Development.
« Last Edit: May 28, 2009, 05:20:11 PM by carpediem98 »

Offline veritas

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Re: UF Research: Macrophages as latent reservoirs, mutation catalysts
« Reply #1 on: May 29, 2009, 05:13:55 AM »


Here's somemore info on machrophages and HIV. Notice how the virus enters and leaves the cell in the diagram.
Exciting stuff:


Any infected cell exposes ps.


Offline Inchlingblue

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Re: UF Research: Macrophages as latent reservoirs, mutation catalysts
« Reply #2 on: May 29, 2009, 06:04:42 PM »
There's an older thread here that mentions a drug in development that targets Macrophage reservoirs

"Another drug on show was Biotron's BIT225. The drug recently began Phase I clinical trials and is designed to attack HIV in macrophage reservoir cells. The Australian biotech company maintains that, although most of the virus originates from the T cells, it also 'hides' from the immune system in reservoirs, making it difficult to completely clear from the body. It is these back-up supplies of virus that the company is hoping to destroy (some other antiretroviral therapies also affect these reservoirs, but none target them specifically)."



Below is an update presented at the latest CROI:

Biotron presented a paper at the 16th Conference on Retroviruses and Opportunistic Infections ('CROI')
in Montreal, demonstrating that BIT225 stops integration of HIV-1 into cells by more than 99% and
reduces release of virus from cells by more than 95%.  

The study was performed in human macrophage cells infected in vitro with HIV-1.  In addition, data
was also presented showing that BIT225 significantly inhibits transfer of HIV-1 virus from
macrophages to T cells.  This is significant as, during HIV infection in humans, HIV-infected
macrophages are responsible for ongoing re-infection of T cells.  Current approved antiretroviral drugs
do not target HIV in macrophages whereas BIT225 specifically targets HIV in these cells.



They're doing a Phase Ib/IIa trial on HCV patients with results expected at end of March 2009, I couldn't find anything published with the results.
« Last Edit: May 29, 2009, 06:14:22 PM by Inchlingblue »

Offline Inchlingblue

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Re: UF Research: Macrophages as latent reservoirs, mutation catalysts
« Reply #3 on: June 11, 2009, 02:38:19 PM »
HIV-1 infected macrophage-specific anti-viral therapy

Pauline Chugh, Birgit Bradel-Tretheway, Carlos M.R. Monteiro-Filho, Vicente Planelles, Sanjay B Maggirwar email, Stephen Dewhurst and Baek Kim
Retrovirology 2008, 5:11doi:10.1186/1742-4690-5-11Background

ABSTRACT (Provisional)

Unlike CD4+ T cells, HIV-1 infected macrophages exhibit extended life span even upon stress, consistent with their in vivo role as long-lived HIV-1 reservoirs. Results: Here, we demonstrate that PI3K/Akt inhibitors, including clinically available Miltefosine, dramatically reduced HIV-1 production from long-living virus-infected macrophages. These PI3K/Akt inhibitors hyper-sensitize infected macrophages to extracellular stresses that they are normally exposed to, and eventually leads to cell death of infected macrophages without harming uninfected cells. Based on the data from these Akt inhibitors, we were able to further investigate how HIV-1 infection utilizes the PI3K/Akt pathway to establish the cytoprotective effect of HIV-1 infection, which extends the lifespan of infected macrophages, a key viral reservoir. First, we found that HIV-1 infection activates the well characterized pro-survival PI3K/Akt pathway in primary human macrophages, as reflected by decreased PTEN protein expression and increased Akt kinase activity. Interestingly, the expression of HIV-1 or SIV Tat is sufficient to mediate this cytoprotective effect, which is dependent on the basic domain of Tat - a region that has previously been shown to bind p53. Next, we observed that this interaction appears to contribute to the downregulation of PTEN expression, since HIV-1 Tat was found to compete with PTEN for p53 binding; this is known to result in p53 destabilization, with a consequent reduction in PTEN protein production. Conclusions: Since HIV-1 infected macrophages display highly elevated Akt activity, our results collectively show that PI3K/Akt inhibitors may be a novel therapy for interfering with the establishment of long-living HIV-1 infected reservoirs.


« Last Edit: June 11, 2009, 04:47:01 PM by Inchlingblue »


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