Researchers identify new mechanism to disrupt HIV latency

March 8, 2018

HIV, the virus that causes AIDS, has a secret life. Though anti-retroviral therapy can reduce its numbers, the virus can hide and avoid both treatments and the body's immune response.
Researchers at UC Davis Health, together with colleagues at UC San Francisco and the University of North Carolina at Chapel Hill, have found that increased crotonylation, an epigenetic mechanism that governs gene expression, might be the key to making HIV come out of hiding and become susceptible to anti-HIV drugs. Their study is published in The Journal of Clinical Investigation.
"We have been working on mechanisms that could be used to disrupt HIV latency," said Satya Dandekar, chair of the UC Davis Department of Medical Microbiology and Immunology and senior author on the paper. "The goal is to force the virus to be expressed so it is visible to the immune system and can be targeted through immuno-therapeutics. This is the first study to identify histone crotonylation as a driver for HIV transcription and de-crotonylation of histone as an epigenetic marker for HIV silencing."
While medical science has transformed HIV/AIDS from a deadly disease to a chronic one, there are still millions of people living with the virus. HIV's ability to become dormant makes it invisible to both the immune system and treatments. Researchers have dedicated years to deciphering the mechanisms that help HIV hide and finding ways to reverse that process.
In this study, the researchers focused on histone crotonylation, an epigenetic mechanism that modifies the proteins that package DNA, affecting gene expression.
"Histone crotonylation regulates HIV latency," said UC Davis associate project scientist Guochun Jiang, first author on the paper. "If we can modulate that, the virus can be more efficiently flushed out."
To better understand this mechanism, the team focused on an enzyme called ACSS2, which plays an important role in fatty acid metabolism in the gut. HIV has often been linked to impairment of lipid metabolism, making ACSS2 a promising potential target for an HIV cure.

To test it out, the researchers studied peripheral blood samples from HIV-infected patients and several HIV latency cell models. Activating the ACSS2 enzyme increased viral transcription manifold. The results from patient samples were particularly encouraging.
"We examined well-characterized cell models of HIV latency and immune cells from HIV patients who had been undergoing antiretroviral therapy and had undetectable viral loads," Dandekar said. "In those samples, we were able to disrupt the HIV silencing by inducing histone crotonylation."
To further validate the results, the researchers treated samples with an ACSS2 inhibitor, which reduced detectable virus levels, highlighting the important role of decrotonylation in establishing HIV latency.
One of the more intriguing findings in the study was that increasing histone crotonylation works synergistically with other known anti-HIV latency molecules, such as the protein kinase C agonist PEP005 and the HDAC inhibitor vorinostat. Dandekar and her colleagues are now searching for more molecules that attack viral latency to develop an overall strategy of combining therapeutic agents to compel HIV expression.
"We are looking for synergistic disruption, by combining histone crotonylation with other mechanisms to reactivate HIV," Dandekar said. "This research positions us to screen and identify small molecules, which can be optimized to carry out HIV modification."

 http://www.ucdmc.ucdavis.edu/publish/news/newsroom/12717

Dimethandrolone Undecanoate (DMAU). A promising once a day male birth control pill,

The birth control pill has been available to women for a long time since FDA-approved it in  1960 but an oral contraceptive for men has not yet hit the market.Scientists are in look out for a male birth control pill which is as effective and acceptable like female birth control pill. But progress toward a male birth control pill has been stymied because available oral forms of testosterone cause liver inflammation and clear the body too quickly for once-daily dosing, thus requiring two doses a day.Stephanie Page,  professor of medicine at the University of Washington, Seattle, Wash, and colleagues have conducted a study and found out a new birth control pill for men that appears to be safe when used daily for a month with hormone responses consistent with effective contraception. The results of the study have been presented at ENDO 2018, the Endocrine Society’s 100th annual meeting in Chicago, Ill.

According to researchers the experimental male oral contraceptive–called dimethandrolone undecanoate, or DMAU–combines activity of an androgen (male hormone) like testosterone, and a progestin, and is taken once a day like a pill for women. DMAU  contains undecanoate, a long-chain fatty acid  which slows this clearance required for once a day dose and is being developed by the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development.”DMAU is a major step forward in the development of a once-daily ‘male pill’,” Page said. “Many men say they would prefer a daily pill as a reversible contraceptive, rather than long-acting injections or topical gels, which are also in development.”

The study included 100 healthy men, ages 18 to 50 years, and took place at the University of Washington Medical Center and at Harbor-UCLA Medical Center in Torrance, CA (led by co-author Christina Wang, M.D.). The investigators tested three different doses of DMAU (100, 200, and 400 milligrams, or mg) and two different formulations inside the capsules (castor oil and powder). Each dose group included five subjects who were randomly assigned to receive an inactive placebo and another 12 to 15 men who received DMAU. Subjects took the drug or placebo for 28 days once daily with food. DMAU must be taken with food to be effective, Page noted.

A total of 83 men completed the study, including giving blood samples, for hormone and cholesterol testing, on the first and last days of the study.

At the highest dose of DMAU tested, 400 mg, subjects showed “marked suppression” of levels of their testosterone and two hormones required for sperm production. The low levels, Page said, are consistent with effective male contraception shown in longer-term studies.

“Despite having low levels of circulating testosterone, very few subjects reported symptoms consistent with testosterone deficiency or excess,” Page said.

All groups taking DMAU did have weight gain and decreases in HDL (“good”) cholesterol, both of which Page said were mild. All subjects passed safety tests, including markers of liver and kidney function.

“These promising results are unprecedented in the development of a prototype male pill,” Page said. “Longer term studies are currently under way to confirm that DMAU taken every day blocks sperm production.”

The experts feel that the ongoing research has brought them  one step closer to expanding the options for male birth control, providing the world’s 7.6 billion people with a much-needed option for safe and reversible contraception.

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4,548 + 697, Doctors may Lose Registration

4,548 Doctors Lose Registration For Not Serving In Rural Areas

 Mumbai:  The Maharashtra government cancelled the registration of over 4,500 doctors for failing to serve in rural areas for a year, which is mandatory, a Directorate of Medical Education and Research (DMER) official said.

The decision to cancel their registration was taken by DMER after it found that these doctors have refused to work in rural areas for a year - a mandatory provision made by the state government.

According to DMER, these doctors have even failed to pay the penalty incurred for not serving in rural areas.

In all, 4,548 doctors have faced action. They graduated from government-run medical colleges in the state between 2005 and 2012 and have neither served in rural areas nor paid the fine, it said.

A DMER official said, "If the doctors do not serve the bond, they must pay a penalty, which is Rs. 10 lakh for an MBBS, Rs. 50 lakh for post-graduates and Rs. 2 crore for superspeciality doctors."

Head of DMER Dr Pravin Shingare said all the doctors who have faced action, had been given sufficient time to honour their commitment to serve in rural areas or pay the penalty.

"We took this firm step as these doctors violated both the clauses," he said.

     
A senior official of the state medical education department, said every medical practitioner needs to renew his or her registration with the Maharashtra Medical Council.

Without the registration, these doctors will be called bogus and may invite legal action, he said.

"The objective of the bond is to give doctors exposure to complicated cases. It is a highly educative and learning experience for newly-graduated doctors. Hence, we want them to go to rural areas and work for at least a year," the official said.

The government also provides reasonable allowances for doctors serving in tribal areas. The wages are also high, he said.

Dr Sagar Mundada, the chairman of the youth wing of Indian Medical Association (IMA), said, "Nobody is complaining about remuneration, but the real issue is poor infrastructure at primary health centres, where these doctors serve as a part of their bond."

"Except for a handful of medicines, no other drugs are supplied. Other essential materials provided are of low quality and in poor quantity. The quarters provided to these doctors are poorly maintained and still they are expected to stay there for a year," he said

697 Doctors To Lose Registration: MCI To Lash Whip

The registration of 697 doctors lies in jeopardy as the Uttarakhand State government has cracked whip on doctors who received subsidized education in government medical colleges but DID NOT complete their bond of serving for some years in the health department. The names of each and every doctor would be sent to MCI to cancel their registration.
Uttarakhand government medical colleges provides subsidized education to students after signing a bond to work with the health department for a specific number of years. The penalty for not serving the bond is Rs. 30 lakhs for PG students and Rs. 15 lakhs for MBBS students.
The state medical education department had issued notices to 783 doctors, out of which, only 86 doctors have joined health department.
The govt is not at all happy about these doctors and has formed a six-member committee to identify all missing doctors. A list of these doctors will be sent to MCI and legal notices sent again to the offenders.
On one side, doctors are continuously protesting for their ‘rights’ and ‘justice’.
How can these doctors take benefits from government and then fail to pay back?
Why do these doctors are turning their backs to their own duties?
Source: Times Of India