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

Plant compound 'much more effective' than traditional anti-HIV drug

Azidothymidine, the first drug that was approved in the fight against AIDS in the 1980s, is still a main component in the medication mix commonly prescribed to HIV patients today. But new research may have found a plant-derived chemical compound that is much more effective than azidothymidine.

In the United States, the Centers for Disease Control and Prevention (CDC) estimate that around 1.1 million people have HIV, and 1 in 7 of them are not aware that they have it.

Due to awareness campaigns and efforts to prevent HIV, the number of new infections dropped by 19 percent between 2005 and 2014. The number of HIV-related deaths has also been falling since the mid-1990s, largely due to advances in HIV treatment.

Although there is yet no cure for HIV, antiretroviral therapy significantly slows down the progression of the virus. The first drug to have been approved in the fight against AIDS is azidothymidine (AZT).

Since 1987, however - the year in which AZT was approved by the U.S. Food and Drug Administration (FDA) - the virus has adapted to the drug. Today, HIV patients are given a combination of various drugs, of which AZT is often still the main component.

AZT works by inhibiting an enzyme that the HIV virus needs to replicate inside a host cell. This enzyme is called reverse transcriptase.

New research, published in the Journal of Natural Products, has found a plant compound that may be more effective at inhibiting this enzyme than AZT.

The chemical compound is called "patentiflorin A" and is derived from a medicinal plant found in East Asia: Justicia gendarussa.

The discovery is the result of a research effort extending over several years, carried out by an international team of scientists from the University of Illinois at Chicago (UIC), the Hong Kong Baptist University in Kowloon Tong, and the Vietnam Academy of Science and Technology in Hanoi.

The team was led by Lijun Rong, a professor of microbiology and immunology at the UIC College of Medicine, who has special expertise in identifying antiviral agents.

Patentiflorin A inhibits HIV 'much more effectively' than AZT

Prof. Rong and colleagues selected Justicia from a pool of more than 4,500 plants.

After separating the extracts of the stems and roots of this plant using bioassay-guided isolation - which is the most common procedure for separating extracted compounds based on their biological activity - the researchers found the "anti-HIV arylnaphthalene lignan glycoside" that is patentiflorin A.

Then, Prof. Rong and team assessed the effect of the compound against the M-tropic and T-tropic HIV isolates. "Tropism" refers to the type of cells that the virus can invade. M-tropism refers to the virus' ability to invade macrophages, while T-tropism refers to its ability to invade T cells, which are both white blood cells with key roles in immunity.

The tropism tests showed that patentiflorin A had "a significantly higher inhibition effect than the clinically used anti-HIV drug AZT."

"Patentiflorin A was able to inhibit the action of reverse transcriptase much more effectively than AZT and was able to do this both in the earliest stages of HIV infection when the virus enters macrophage cells and alter infection when it is present in T cells of the immune system," Prof. Rong explains.

He also notes that his team managed to synthesize the compound de novo, or "from scratch." He says:

"If we can make the drug in the lab, we don't need to establish farms to grow and harvest the plant, which requires significant financial investment, not to mention it has an environmental impact."

He concludes, "Patentiflorin A represents a novel anti-HIV agent that can be added to the current anti-HIV drug cocktail regimens to increase suppression of the virus and prevention of AIDS."

Source: https://www.medicalnewstoday.com/articles/317966.php

Study shows how HIV is shielded from Immune Attack

Scientists from UNSW Sydney and the UK have discovered that the human immunodeficiency virus (HIV) hijacks a small molecule from the host cell to protect itself from being destroyed by the host's immune system.

The finding, as well as details of the new strategy that enabled it, are published as back-to-back papers in eLife. They identify a new target for antiviral therapy against HIV and provide a method for testing and measuring new drugs designed to target the capsid.

UNSW Ph.D. student Chantal Márquez is involved in both studies and is the first author of the paper describing the new method.

HIV forms a protein shell—called a capsid—that shields its genetic material from host defence mechanisms as it enters the cell and makes its way to the nucleus to establish infection.

Using a new single-molecule microscopy technique—developed at UNSW's Single Molecule Science in the Faculty of Medicine—the research teams found that HIV specifically incorporates a small molecule from the host cell—inositol hexakisphosphate—to strengthen its capsid. The host inadvertently provides the key for the virus infecting it to lock down the protective shell, keeping the genetic cargo safe until it is released into the nucleus.

"The HIV capsid falls apart within minutes once it's isolated from the virus," said Associate Professor Till Böcking, who led the UNSW team involved in both studies.

"Our strategy lets us study exactly how a native capsid breaks apart in real-time without taking it out of the viral membrane."

With the help of Associate Professor Stuart Turville of the Kirby Institute, the team engineered viruses with fluorescent tags to monitor the viral capsid using fluorescence microscopy.

"We can now see the effect of different molecules on the capsid, and pinpoint precisely when it cracks open and begins to collapse," says Associate Professor Böcking.

"Capsids need to be much more stable inside a cell because the infection process takes hours, not minutes—so we wanted to find out what keeps it stable inside a cell," says Dr. David Jacques of Single Molecule Science, who is an author of both studies.

The researchers found that inositol hexakisphosphate, which is abundantly present inside mammalian cells, makes the capsid much stronger, stabilizing it for 10-20 hours.

"It's like a switch. When you bind this molecule, you stabilize the capsid, and release the molecule to open it up," explains Associate Professor Böcking.

"The HIV capsid has been intensively studied, but the question of how it can simultaneously be both stable and poised to 'uncoat' has been one of the great unanswered questions in HIV biology," says Dr. Leo James, leader of the research team at the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK.

Most of the currently approved HIV therapies target enzymes needed at different stages of the virus' life cycle, but none of them are directed at the HIV capsid. New drug alternatives could improve the treatment of HIV with reduced toxic effects.

Source: https://medicalxpress.com/news/2018-07-hiv-shielded-immune.html

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A New Method for Removing Cells Infected with the AIDS Virus

With the successful suppression of the AIDS virus (HIV) through medication, the focus turns toward its eradication. Researchers from Kumamoto University in Japan have developed a new compound that is key to the destruction of HIV. When the compound is introduced into infected cells, viral budding (release) is suppressed thereby confining it within the host cells. The cells then die naturally through apoptosis (cell death). This treatment is believed to lead to the complete recovery from AIDS in the near future.

In recent years, multi-drug therapy has made it possible to suppress HIV multiplication in the body when taken properly. This method, however, cannot remove the virus particles of the latent HIV reservoir—non-replicating virus particles that remain dormant in the cells of the body. As soon as drug administration is stopped, the viral load will again increase in the body. Removal of the viral reservoir is currently the top goal in AIDS research.

The "kick and kill" approach, which was developed several years ago, is a strategy for killing reservoir cells. This technique uses a drug that targets the reservoir cells and activates the virus which then allows the immune system to find these cells using the activated virus as a landmark. Although this approach was clinically tested, there is still the problem of not being able to efficiently deactivate the virus after successful activation.

Researchers at Kumamoto University developed a new approach that they call "Lock-in and apoptosis." First, they synthesized the compound L-HIPPO, which binds strongly to the HIV protein Pr55Gag and suppresses viral budding. When L-HIPPO was added to virus-infected cells via a carrier called α-CDE, the virus became confined within the cell and the cell would die through natural apoptosis.

"Unfortunately, this approach is not immediately available for people infected with HIV," said Associate Professor Mikako Fujita of Kumamoto University, one of the leaders of the study. "First, we have to improve upon the drugs that activate the virus and combine them with L-HIPPO to efficiently target the viral reservoir. This would be a big step towards a complete recovery from HIV. We believe that our research will help to completely eradicate AIDS."

Source: https://medicalxpress.com/news/2017-10-method-cells-infected-aids-virus.html

Co-Infections of Sexually Transmitted Diseases

With early diagnosis, proper monitoring and care, most of the illnesses caused by HIV can be prevented. They are much less frequent than they were before effective anti-HIV drugs became available.

There are a number of infections and illnesses that can develop in people who are living with HIV, particularly those people who are not able to take anti-HIV drugs. Some of these life-threatening infections are called opportunistic infections. These only occur if your immune system is quite weakened (usually in the absence of anti-HIV drug therapy) and your body becomes vulnerable to infections that would not affect you otherwise.

Co-infections are illnesses that can occur in people with normal immune systems, but they can impact how you live with HIV.

Some types of cancers are thought to be more common in people with HIV.

Increasingly, the distinction between these different types of infections—life-threatening infections, co-infections and even some cancers—is blurred, as some infections can fit all three categories (for example, human papillomavirus is a co-infection which can lead to cervical and anal cancer).

Life-threatening infections

These infections occur only when a person’s immune system has been seriously weakened by HIV due to lack of diagnosis and/or anti-HIV treatment. HIV attacks immune cells called CD4+ cells, which are needed for fighting off infections and some cancers. A normal CD4+ cell count in an HIV-negative person is around 500 to 1,500 cells in each cubic millimetre (mm³) of blood. If your CD4+ cell count gets lower, your immune system becomes unable to fight off a number of common viruses, bacteria and parasites. These infections can then take hold. (They are sometimes called opportunistic infections because they take advantage of your weakened immune system.)

Life-threatening infections are uncommon now, since most people take anti-HIV drugs, which controls their viral load, raises their CD4+ levels and stabilizes and restores immune system function. This helps prevent life-threatening infections caused by HIV.

The main danger nowadays is in not finding out you are HIV-positive until your CD4+ cell counts are already so low that you are at risk or are already sick with a life-threatening infection.

The more common life-threatening infections are listed in the accompanying table. Some of these can still occur in people with relatively high CD4+ levels but are more serious when the immune system is weakened.

Life-threatening infections include a lung infection called Pneumocystis pneumonia (PCP), an eye infection caused by cytomegalovirus (CMV), a brain infection called toxoplasmosis, and a generalized infection called Mycobacterium avium complex (MAC). If it happens that you find out you have HIV when your CD4+ cell count is very low, there are drugs you can take to prevent these infections. This is called prophylaxis.

Co-infections

Hepatitis

These are infections that can occur even in people with HIV who have adequate CD4+ levels—just as they can occur in people who do not have HIV. They are called co-infections because you have them along with HIV. Co-infections can complicate your HIV treatment and make living with HIV more difficult. HIV can also complicate the treatment and diagnosis of a co-infection. Although they may occur at normal CD4+ levels, the lower your CD4+ cell count is, the more of a problem they can be.

Chronic hepatitis is an increasingly common co-infection for many people with HIV. Hepatitis is a liver condition usually caused by viruses called hepatitis A, hepatitis B or hepatitis C. These viruses infect the liver and can cause jaundice (yellow skin and eyes), dark urine, pale stool and severe fatigue. It is a good idea for your doctor to check regularly for these infections. Hepatitis B and C are transmitted by:

·         blood-to-blood contact through sharing drug-using equipment, or personal care items like razors;

·         transfusion of blood and blood products before 1992 when the Canadian system started screening;

·         unprotected sexual intercourse;

·         being passed from mother to child during childbirth.

Hepatitis A is another, usually less serious, viral infection of the liver. Hepatitis A is spread through feces (shit), and you can be infected by contaminated food (for instance, if someone handling your food has hepatitis A and did not wash his or her hands). If you are exposed to hepatitis A, it can make you quite sick for a few weeks, but your immune system usually clears it. Hepatitis A very rarely causes permanent damage unless you already have hepatitis B or C as well.

If infected with the hepatitis A or B virus, some people get over the initial liver infection and develop immunity. This is much less likely to happen in people with HIV who are co-infected with hepatitis C. Without treatment, people can develop chronic hepatitis, remain infectious to others and develop ongoing liver problems.

As described below, there are vaccinations that will prevent you from getting hepatitis A and B infection. There is no vaccination available for hepatitis C.

Effective antiviral treatments are available for both hepatitis B and C infection. Treatment can cure hepatitis C and keep hepatitis B under control. There are interactions between drugs to treat hepatitis and HIV, so make sure you see a doctor with expertise in both conditions.

Tuberculosis (TB)

TB is a concern for people with HIV because it is so easily spread, especially in places where people live close to each other, in poverty and without adequate medical care.

TB usually infects the lungs, but it can also affect the bones, brain and other organs in your body. TB is spread through the air when someone with active TB coughs or sneezes. Diagnosis of TB is done by skin tests, tests of your sputum (phlegm) and chest X-rays. There are effective treatments for TB, but they need to be taken every day for many months. Missing doses, or stopping before the full treatment period is over, can cause the TB infection to become drug-resistant and much more difficult to treat. People with HIV with a history of previously treated TB may have it reactivate (come back again) if their immune system weakens.

Herpes infections

Herpes is a family of viruses that includes:

·         Herpes simplex, which causes cold sores on the mouth or painful sores on the genitals.

·         Varicella-zoster, which initially causes chicken pox and when reactivated causes painful sores called shingles anywhere on the skin.

Herpes infections are common and are often transmitted by physical contact and sex. Usually, the immune system keeps herpes infection under control until something like stress or a high fever brings the sores out in an outbreak lasting seven to 10 days, or longer. The lower your CD4+ cell count, the more frequent outbreaks may be. They may also last longer.

People with HIV with extremely weak immune systems (CD4+ cell counts less than 100 cells/mm3) are at risk for herpes infections all over the body (disseminated herpes) or in the brain (herpes encephalitis). People with frequent herpes outbreaks (even with normal CD4+ levels), or people at risk for more serious herpes infections, can take antiviral drugs—usually valacyclovir or similar drugs—to keep the herpes virus suppressed.

Fungal infections

Fungal or yeast infections can happen whether you are HIV-positive or not. Women get vaginal yeast infections, and men and women can get athlete’s foot or fungal infections on the skin or nails. The more weakened your immune system is, the more this can be a problem.

Even people with moderate CD4+ cell counts can get a fungal infection in the mouth or vagina called candidiasis or thrush. Antifungal creams, pills and vaginal suppositories are available to treat these problems, and probiotic supplements or yoghurts with friendly bacteria may also help. Watch your diet because the more sugar you eat, the more susceptible you are to fungus, which loves sugar.

Sexually transmitted infections

Some of the infections discussed above can be passed on in many ways, including through sex. Some other infections, like chlamydia, gonorrhea and syphilis, and the virus HPV, are virtually always transmitted sexually. 

Cancers

Cancer is the abnormal and uncontrolled growth of cells in different parts of the body. These cancerous growths then destroy healthy cells and cause serious illness. A normally functioning immune system acts to suppress this abnormal growth of cells.

People with HIV can become more vulnerable to certain types of cancer. Some of these cancers occur only when the immune system is weakened. Other cancers seem to be more common in people with HIV even when their immune system is relatively healthy.

Kaposi’s sarcoma

Kaposi’s sarcoma (KS), a rare form of skin cancer, is caused by a member of the herpes virus family and can be life-threatening.  It causes purple lesions on the skin that looked like bruises. Although slow growing, if it spreads to internal organs it could lead to illness and death. In the early days of HIV, it was quite common in people living with HIV. When HAART was introduced, KS became uncommon and now only occurs in people with very weak immune systems.

Non-Hodgkin’s lymphoma

When the cells in the lymph nodes become cancerous, this is called lymphoma. The non-Hodgkin’s type of lymphoma (NHL) is more common in people with HIV. The symptoms of NHL may include persistently swollen lymph glands, fevers, chills and sweats and weight loss. In the case of central nervous system lymphoma, the symptoms are often headaches and seizures.

Diagnosis of lymphoma, like many cancers, is done by biopsy where a sample of tissue from a swollen lymph node is examined under the microscope for evidence of abnormal cells. In the event of central nervous system lymphoma, the diagnosis is made by examining cerebrospinal fluid tapped from the spine. Lymphoma is usually treated by chemotherapy, where powerful anti-cancer drugs are injected into the vein on a regular basis, and/or radiation therapy where high-powered X-rays are directed at the cancer cells.

Cervical cancer

The cervix is the opening of the uterus (womb) inside a woman’s vagina. Sometimes abnormal cells can start to grow on the cervix, usually as a result of HPV infection. Over time, these abnormal growths can become a pre-cancerous condition called cervical dysplasia. If dysplasia is not found and treated, it can become cancer.

To prevent this, all women should have annual Pap tests to look for dysplasia from a small scraping of cells from the cervix. Women with a history of genital warts or cigarette smoking should have Pap exams more frequently. If dysplasia is found, it is usually treated with a laser in a procedure called colposcopy.

The HPV vaccine will protect women from some, but not all, strains of HPV and so it is hoped it will prevent some cases of cervical cancer. However, this vaccine is effective only if it is given before women have been exposed to the HPV strains the vaccine targets.

Anal cancer

Cancer in the anal canal of men and women is similar to cervical cancer. It is also usually caused by infection with HPV and, like cervical cancer, develops over time from dysplasia to cancer. Risk factors include a history of anal sex and/or genital warts. Both men and women with HIV are thought to be more vulnerable to this form of cancer. 

Other cancers

There are many other forms of cancers that people with HIV are thought to be at slightly higher risk for, even without immune suppression. These include Hodgkin’s lymphoma, lung cancer, skin cancer, vaginal cancer in women and testicular and prostate cancer in men. Fortunately, these cancers are not common and can often be successfully treated if they do occur in people with HIV who maintain healthy immune systems with effective anti-HIV drugs.

Source: http://www.catie.ca/en/practical-guides/managing-your-health/12

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