Novel method for dating 'hibernating' HIV strains

Researchers at the BC Centre for Excellence in HIV/AIDS (BC-CfE) and Simon Fraser University (SFU), in partnership with University of British Columbia (UBC) and Western University, have developed a novel way for dating "hibernating" HIV strains, in an advancement for HIV cure research in the province. Published in the Proceedings of the National Academy of Sciences (PNAS), the BC-CfE's first major scientific contribution to the area of HIV cure research confirms that dormant HIV strains can persist in the body for decades.

"If you can't identify it, you can't cure it. This research provides further essential clues in the pursuit of an HIV cure -- which will ultimately require the complete eradication of dormant or 'latent' HIV strains," said Dr. Zabrina Brumme, Director, Laboratory with BC-CfE and lead author on the study. "Scientists have long known that strains of HIV can remain essentially in hibernation in an individual living with HIV, only to reactivate many years later. Our study confirms that the latent HIV reservoir is genetically diverse and can contain viral strains dating back to transmission."

 

"The BC-CfE has consistently been a national and global leader on research on HIV and on the implementation of its pioneering Treatment as Prevention® strategy. The addition of molecular biologist Dr. Zabrina Brumme as Director of the innovative BC-CfE Laboratory ensures the BC-CfE will play a significant role in HIV cure research," said Dr. Julio Montaner, Director of the BC-CfE. "Curative strategies will need to address this new study's key findings. I want to acknowledge the study participants and thank them for helping to increase our knowledge on the origins of the latent HIV reservoir."

"By creating family trees of viruses using a technique called molecular phylogenetics, we can reconstruct the evolutionary history of HIV within a person," said Brad Jones, a Ph.D. student with UBC at the BC-CfE and the first author on the study. "In essence, we created a highly calibrated 'time machine' that gives us a specific time stamp for when each dormant HIV strain originally appeared in a person."

Dormant HIV strains, which have integrated their DNA into that of the body's cells, can persist for years and are unreachable by antiretroviral treatments and the immune system. They can reactivate at any time, which is why HIV treatment needs to be maintained for life.

Through advances in antiretroviral therapy, an individual living with HIV can now live a longer, healthier life on treatment. Treatment works by stopping HIV from infecting new cells. On sustained treatment, individuals can achieve a level of virus that is undetectable by standard blood tests. An undetectable viral load means improved health and that the virus is not transmittable to others -- the concept behind Treatment as Prevention®.

"Previous research had already revealed that the HIV reservoir was genetically complex. With our method, we can now understand that complexity with greater granularity, pinpointing exactly when each unique HIV strain originally appeared in a person," said Dr. Jeffrey Joy, Research Scientist at the BC-CfE and co-author on the study.

"In order to eradicate HIV from a person's body, you first need to know the characteristics of HIV in the latent reservoir," said Dr. Art Poon, Assistant Professor in Pathology and Laboratory Medicine at Western University, also a co-author on the study. "We are providing a method for better measuring the timeline of virus latency and evolution within an individual living with HIV."

In order to "date" dormant HIV strains within the viral reservoir, researchers needed to compare these strains to those that evolved within an individual living with HIV over the entire history of their infection. The BC-CfE is one of a handful of institutions worldwide capable of such research, thanks to its maintenance of a historical repository of blood specimens from individuals diagnosed with HIV in BC. These specimens date back to 1996 and were originally collected for viral load and drug resistance testing. The BC-CfE Laboratory has provided HIV drug resistance genotyping for virtually all Canadian provinces and territories since 1998, as well as for many countries worldwide.

This research was funded by the Canadian Institutes of Health Research (CIHR) in partnership with the Canadian Foundation for AIDS Research (CANFAR) and the International AIDS Society (IAS) through its support of the Canadian HIV Cure Enterprise (CanCURE), as well as the US National Institutes of Health (NIH) through its support of the Martin Delaney BELIEVE Collaboratory.

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Source: https://www.sciencedaily.com/releases/2018/09/180905142037.htm

Antiviral Compound "Viperin" Found in the Human Body

The human body can make a compound with a special power to fight viruses; viperin is an enzyme made naturally in many mammals. Scientists have found that it has an antiviral effect on a variety of pathogens including hepatitis C, rabies and West Nile viruses. The enzyme aids the chemical reaction that generates ddhCTP, a molecule that can prevent viruses from replicating their genetic material, halting the expansion of the viral population. This work, which was reported in Nature, could have important implications in antiviral drug development.

"We knew viperin had broad antiviral effects through some sort of enzymatic activity, but other antivirals use a different method to stop viruses," explained study author Craig Cameron, a professor and the Eberly Chair in Biochemistry and Molecular Biology at Penn State. "Our collaborators at the Albert Einstein College of Medicine, led by senior authors Tyler Grove and Steven Almo, revealed that viperin catalyzes an important reaction that results in the creation of a molecule called ddhCTP. 

“Our team at Penn State then showed the effects of ddhCTP on a virus's ability to replicate its genetic material. Surprisingly, the molecule acts in a similar manner to drugs that were developed to treat viruses like HIV and hepatitis C. With a better understanding of how viperin prevents viruses from replicating, we hope to be able to design better antivirals."

Viruses usually have small genomes and lack critical cell components found in normal cells, so they hijack the cellular machinery they lack, using nucleotide bases from their host to build new genetic material - viral RNA. The ddhCTP chemical can mimic nucleotides, the foundations of DNA and RNA, and these 'nucleotide analogs' get incorporated into the new viral RNA that is made. Then they can interfere with the extension of the genetic strand, which stops the virus from making new copies of itself.

"Long ago, the paradigm was that in order to kill a virus, you had to kill the infected cell," said Cameron. "Such a paradigm is of no use when the virus infects an essential cell type with limited capacity for replenishment. The development of nucleotide analogs that function without actually killing the infected cell changed everything."

Usually, nucleotide analogs are synthetic and come with risks. Nucleotides are important in many ways, so they can have dangerous side effects.

"The major obstacle to developing therapeutically useful antiviral nucleotides is unintended targets," noted study author Jamie Arnold, associate research professor of biochemistry and molecular biology at Penn State. "For example, a few years ago we discovered that a nucleotide analog under development for [the] treatment of hepatitis C could interfere with the production of RNA in mitochondria, subcellular organelles important for energy production in the patient's own cells. That meant people with mitochondrial dysfunction are predisposed to any negative effects of this unintended interference."

However, ddhCTP appears to be safe so far; it does not seem to have unintended targets.

"Unlike many of our current drugs, ddhCTP is encoded by the cells of humans and other mammals," said Cameron. "We have been synthesizing nucleotide analogs for years, but here we see that nature beat us to the punch and created a nucleotide analog that can deal with a virus in living cells and does not exhibit any toxicity to date. If there's something out there that's going to work, nature has probably thought of it first. We just have to find it."

The researchers tested ddhCTP against West Nile, Zika and dengue viruses, and found that the ddhCTP could stop the replication of Zika in live cells.

"The molecule directly inhibited replication of three different strains of Zika virus," said study author Joyce Jose, assistant professor of biochemistry and molecular biology at Penn State. "It was equally effective against the original strain from 1947 as it was against two strains from the recent 2016 outbreak. This is particularly exciting because there are no known treatments for Zika. This study highlights a new avenue of research into natural compounds like ddhCTP that could be used in future treatments."

The researchers have shown that ddhCTP has a lot of potential as a therapeutic, although it was not effective against a class of viruses called picornaviruses; that group includes polio and rhinovirus. The researchers would like to find out why and determine if a vulnerable virus might gain resistance against ddhCTP.

"Development of resistance to an antiviral agent is always an issue," said Cameron, "Having some idea of how resistance happens, or being able to prevent it from happening, will be critical if this is to be used as a broad-spectrum therapy."

Source: https://www.labroots.com/trending/microbiology/11860/antiviral-compound-found-human-body

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Integrase Inhibitors: An Overview

Integrase inhibitors (also known as integrase strand transfer inhibitors, or INSTIs) are a powerful class of antiretroviral drug which prevents HIV from integrating its genetic coding (genome) into the DNA of the infected host cell. It does so by blocking an enzyme called integrase and, by doing so, makes it impossible for HIV to replicate.

As a class of drugs, integrase inhibitors are considered advantageous in treating HIV infection, with easier dosing requirements, lower side effects, improved resistance profiles, and greater durability.

Current guidance from the U.S. Department of Health and Human Services places integrase inhibitors as a preferred, first-line agent for persons newly treated for HIV. In fact, of the six treatment options currently recommended for newly treated patients, five contain an integrase inhibitor as their backbone drug agent.

Mechanism

HIV integrates its viral genome into the host cell's DNA in a five-step process:
The integrase enzyme binds to HIV DNA, the latter of which is created in a process called reverse transcription.

The HIV DNA is then prepared for integration in a process called cleaving, which literally cleaves the viral genetic strand, leaving open gaps in its structure.

The cleaved strand is then inserted into the host cell's nucleus through a nuclear pore.

Once inside the nucleus, the HIV DNA is transferred into the host DNA in is what's called a strand transfer reaction. In this stage, the viral DNA the literally attacks the host cell's DNA, separating the bonds that hold the host DNA together and attaching itself through the chemical gaps in the viral DNA strand.

The attack then incites a natural protective response called gap repair, in which the host cell will automatically repair any damage to the DNA, essentially facilitating the takeover of its genetic coding.

Simply by blocking the integrase enzyme, the entire integration process is stopped, effectively ending the virus' life cycle. However, as integration is only one of several stages of the HIV life cycles, other drugs are taken to inhibit other stages, further preventing HIV from replicating and ensuring that viral activity is fully suppressed (as measured by the HIV viral load).

Side Effects and Considerations

Unlike other classes of HIV drug, integrase inhibitors work directly on the viral mechanisms themselves rather than on cells. As such, they tend have far fewer side effect, primarily diarrhoea, nausea, fatigue, headache, and insomnia.

Most of these side effects, however, are transient and usually resolve on their own. With that being said, if you experience any adverse event while taking an integrase inhibitor drug combination, advise your doctor or clinic immediately. Do not stop treatment without at least speaking to a qualified professional. Stopping and changing prematurely can do more harm than good.

Similarly, while integrase inhibitors are less to prone to premature drug resistance, you should avoid missing doses or gaps in treatment. Resistance occurs when drug levels in the blood begin to fall, allowing mutant viruses to emerge and proliferate. When this happens, your drugs will not be able to work as well as before and may, in some cases, fail.

Since integrase inhibitors remain in the blood stream for longer periods of time, they are able to suppress HIV mutants even when doses are occasionally missed. But it's important to understand that prolonged interruptions are ill advised and that daily adherence remain key to treatment success.

Source: https://www.verywellhealth.com/integrase-inhibitors-48802
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Monthly Once: HIV Drugs on the Horizon

One of the main barriers to HIV drug success is the high level of adherence needed to attain the clinical goals of therapy. For some, the daily task of taking antiretroviral drugs can be overwhelming, particularly when accompanied by emotional or functional issues that can adversely impact the lives—and adherence—of people with living HIV. 

So profound are these issues that, in the U.S. today, more than 20% of people on antiretroviral therapy are able to maintain an undetectable viral load, the measure for treatment success.

In response, scientists have now begun to explore long-acting drugs, as well as drug delivery systems, that may eventually allow for once-monthly—or even once-quarterly—dosing, either to treat HIV infection or to prevent it.

Long-Lasting Investigational Drugs

In 2013, two long-acting antiretroviral agents were introduced at the 7th annual International AIDS Society (IAS) Conference in Kuala Lumpur. The investigational drugs were both developed as injectable nanosuspensions, wherein tiny crystals of active drug are suspended in liquid, allowing for the slow and steady release of the medication into the system.

The first, cabotegravir (also known as GSK1265744) belongs to a class of drugs called integrase inhibitors, which blocks an enzyme called integrase that HIV needs to multiply. The second, TMC278-LA, is a long-acting formulation of the drug Edurant (ripilvirine) currently used in HIV therapy.

A number of Phase II clinical trials have shown the cabotegravir delivered intramuscularly is generally well tolerated with a mean half-life of between 21 to 50 days (compared to 40 hours following a single, oral dose). Similar studies demonstrated that the drug also ensured sustained drug concentration in rectal and vaginal tissues, suggesting that it could be administered as an effective, long-acting means of pre-exposure prophylaxis (PrEP).

By comparison, a Phase I study showed that TMC278-LA was able to maintain target plasma drug concentrations from 12-26 weeks. The drug also demonstrated promise as PrEP, with stronger concentrations seen in rectal tissues when compared to vaginal tissues.

On-going investigations are planned with the goal of expanding research to Phase II and III clinical trials.

Subdermal Antiretroviral Implants

Scientists at the Oak Crest Institute of Science in Pasadena, California reported developing a matchstick-sized implant that could deliver steady concentrations of antiretroviral medications when implanted beneath the skin.

Similar in design to long-acting contraceptive implants, the device was shown in early research to be able to deliver controlled, sustained release of the drug tenofovir alafenamide (TAF) for up to 40 days.

While research is currently focusing on the device for PrEP, it is suggested that other long-acting agents could eventually be used to provide combination antiretroviral therapy (cART) to people living with HIV.

Future research hopes to open the door to the development of implants that can last for up to a year or more.

Source: https://www.verywellhealth.com/once-monthly-hiv-drugs-on-the-horizon-49311

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