Tag Archives: Immune system

Book Review: Chronic Pain & HIV: A Practical Approach

chronic_pain_book_2016

Recent studies suggest many individuals with HIV have chronic pain. Estimates range from 39 percent all the way to 85 percent. Chronic pain is an important co-morbid condition in individuals with HIV, as it is common and causes substantial disability.

In the current HIV treatment era, HIV is a chronic disease with a near-normal life expectancy. However, individuals with HIV can have higher rates of other health problems than the general population.

A new reference guide for HIV care providers, “Chronic Pain and HIV: a practical approach,” offers insight into the assessment, diagnosis, testing and management of various chronic pain problems in patients with HIV.

Lead editor Jessica Merlin, M.D., an assistant professor in the University of Alabama at Birmingham School of Medicine Division of Infectious Diseases and Division of Geriatrics, Gerontology and Palliative Care, says the guide addresses issues that HIV care providers have when trying to provide relief to HIV patients with chronic pain, including pharmacological and non-pharmacological therapies.

“Chronic pain is increasingly recognized as an important co-morbidity in HIV-infected patients, and may influence adherence to antivirals and retention in care,” Merlin said. “Individuals with HIV also have higher rates of mental illness and addiction than the general population. HIV, mental illness and addiction are all highly stigmatized health problems, further compounding patients’ suffering.”

HIV and the medications once used to treat the disease can lead to nerve pain in the hands and feet in as many as 40 percent of patients. Also, for reasons that are not well-understood, patients with HIV may have a high burden of musculoskeletal pain, like joint pain, back pain and more widespread pain.

Non-pharmacologic treatments are an important mainstay of therapy, including graded exercise, complementary and alternative therapies, and behavioral therapies. Importantly, behavioral therapies are among the safest and most effective treatments for chronic pain. In 2014, Merlin was awarded a K23 Career Development Award from the National Institute of Mental Health. She is working on developing and pilot-testing a behavioral intervention that is specifically tailored to improving chronic pain in individuals with HIV.

Ideally, when medications are used, they should be prescribed alongside non-pharmacologic therapies.

“A multimodal approach is the most effective approach,” Merlin said. “Our book helps front-line HIV primary care providers use this approach with their patients.”

Medications such as opioids may not be as effective, and carry significant risks.

“Chronic pain can be challenging to manage to begin with, and even more challenging to manage in the setting of mental health and addiction problems found in individuals with HIV,” Merlin said. “Long-term treatment with opioids, such as morphine, oxycodone and others, has been commonly used to treat chronic pain in general and in individuals with HIV. Opioid therapy carries risks such as worsening of mood, development of addiction and overdose, and these risks can be heightened in the presence of pre-existing mental illness and addiction.”

Studies suggest that HIV care providers may feel unprepared to treat chronic pain.

“Managing chronic pain is rewarding; but it can be challenging, and is often not taught in HIV providers’ medical training,” Merlin said. “This book is the first practical guide on the topic for HIV care providers, and fills an important need.”

Chronic Pain & HIV: A Practical Approach is available from 22nd April 2016, available at Amazon.

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Stem cells edited to produce an HIV-resistant immune system

Bloods

A team of haematologists has engineered a particular white blood cell to be HIV resistant after hacking the genome of induced pluripotent stem cells (iPSCs).

The technique has been published in the Proceedings of the National Academy of Sciences and was devised by Yuet Wai Kan of the University of California, former President of the American Society of Haematology, and his peers.

The white blood cell the team had ideally wanted to engineer was CD+4 T, a cell that is responsible for sending signals to other cells in the immune system, and one that is heavily targeted by the HIV virus. When testing for the progress of HIV in a patient, doctors will take a CD4 cell count in a cubic millimetre of blood, with between 500 and 1,500 cells/mm3 being within the normal range. If it drops below around 250, it means HIV has taken hold — the virus ravages these cells and uses them as an entry point.

HIV gains entry by attaching itself to a receptor protein on the CD+4 T cell surface known as CCR5. If this protein could be altered, it could potentially stop HIV entering the immune system, however. A very small number of the population have this alteration naturally and are partially resistant to HIV as a result — they have two copies of a mutation that prevents HIV from hooking on to CCR5 and thus the T cell.

In the past, researchers attempted to replicate the resistance by simply transplanting stem cells from those with the mutation to an individual suffering from HIV. The rarity of this working has been demonstrated by the fact that just one individual, Timothy Ray Brown (AKA the Berlin patient), has been publicly linked to the treatment and known to be HIV free today. The Californian team hoped to go right to the core of the problem instead, and artificially replicate the protective CCR5 mutation.

Kan has been working for years on a precise process for cutting and sewing back together genetic information. His focus throughout much of his career has been sickle cell anaemia, and in recent years this has translated to researching mutations and how these can be removed at the iPSC stage, as they are differentiated into hematopoietic cells. He writes on his university web page: “The future goal to treatment is to take skin cells from patients, differentiate them into iPS cells, correct the mutations by homologous recombination, and differentiate into the hematopoietic cells and re-infuse them into the patients. Since the cells originate from the patients, there would not be immuno-rejection.” No biggie.

This concept has now effectively been translated to the study of HIV and the CD+4 T cell.

Kan and his team used a system known as CRISPR-Cas9 to edit the genes of the iPSCs. It uses Cas9, a protein derived from bacteria, to introduce a double strand break somewhere at the genome, where part of the virus is then incorporated into the genome to act as a warning signal to other cells. An MIT team has already used the technique to correct a human disease-related mutation in mice.

When Kan and his team used the technique they ended up creating HIV resistant white blood cells, but they were not CD+4 T-cells. They are now speculating that rather than aiming to generate this particular white blood cell with inbuilt resistance, future research instead look at creating HIV resistant stem cells that will become all types of white blood cells in the body.

Of course, with this kind of therapy the risk is different and unexpected mutations could occur. In an ideal world, doctors will not want to be giving constant cell transplants, but generating an entirely new type of HIV resistant cells throughout the body carries its own risks and will need stringent evaluation if it comes at all close to being proven.

Speaking to Wired.co.uk, Louis Picker of the Vaccine and Gene Therapy Institute at Oregon Health and Science University seemed cautiously hopeful: “This is an old idea, with an extensive literature, that is being updated in this paper with the use of the new CRISPR technology, which makes it much much easier to modify human genes.

“Given that the so-called Berlin patient was apparently functionally cured by getting a bone marrow transplant from a (rare) CCR5-null mutant donor, the approach would indeed be promising from a scientific standpoint. Keeping in mind that bone marrow transplant is not likely to be an option for treating the vast majority of HIV positive subjects on effective anti-retroviral therapy. CRISPR technology is no question a break-through, but whether this application will have wide impact is difficult to predict at this time.”

The California also used another technique to make the alterations to the genes. This resulted in resistance in CD+4 T-cells, with levels of the virus being reduced. However, further T-cell transplants were shown to be needed to maintain this. This result in itself is quite astounding, but not the cure Kan is working for.

Story via Wired

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Discovery of HIV ‘invisibility cloak’ reveals new treatment opportunities

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“Glass Microbiology” by Luke Jerram. (See: https://blog.lass.org.uk/2013/01/23/2393/) for artwork details. (Image unrelated to story).

Scientists have discovered a molecular invisibility cloak that enables HIV, the virus that causes AIDS, to hide inside cells of the body without triggering the body’s natural defence systems.

Their study shows how ‘uncloaking’ the virus using an experimental drug triggers an immune response that stops the virus from replicating in cells grown in the laboratory. The findings could lead to new treatments and help to improve existing therapies for HIV infection.

The innate immune system is the body’s first line of defence against infection and incorporates an alarm system present in all cells of the body that detects the presence of ‘foreign’ material from invading bacteria and viruses. When the alarm is tripped, the infected cell begins an antiviral programme and sends out warning signals to alert other cells that a virus is around.

HIV infects vital cells of the immune system, so its ability to replicate undetected without triggering this alarm system has puzzled scientists since the discovery of the virus.

The team identified two molecules inside host cells that are recruited by HIV after infection that stop the virus from reproducing its genetic material too early. The effect is to shield the virus from the alarm system and stop the innate immune system from kicking into action.

In the absence of these molecules, whether caused by depletion from infected cells or by blocking their recruitment using an experimental drug, HIV is exposed to the alarm system and an antivirus immune response is triggered. Targeting the cloaking molecules and not the virus itself makes it much more difficult for the virus to mutate and become resistant to this treatment approach, a significant problem with standard HIV therapies.

Professor Greg Towers, a Wellcome Trust Senior Research Fellow at UCL and lead author of the study, said: “HIV is extremely adept at hiding from our body’s natural defences, which is part of the reason the virus is so dangerous. Now we’ve identified the virus’ invisibility cloak, and how to expose it, we’ve uncovered a weakness that could be exploited for new HIV treatments.

“There’s a great deal more research needed, but the potential for this approach is huge – as a possible treatment in itself, but also as a complement to existing therapies. We’re also interested to see whether blocking these cloaking molecules can help to boost immune responses to experimental vaccines against HIV or be used to protect against HIV transmission.

“The hope is that one day we may be able develop a treatment that helps the body to clear the virus before the infection is able to take hold.”

The experimental drug used in the study is based on cyclosporine, a drug that is widely used to prevent organ rejection in transplant patients because of its ability to dampen the immune response. Cyclosporines have been shown to block the replication of HIV and other viruses but are not suitable for treating infected patients because of their negative effects on the immune system.

The team used a modified version of the drug, which blocks the effects of the two cloaking molecules without suppressing immune activity.

Dr Kevin Moses, Director of Science Funding at the Wellcome Trust, said: “In 2012, 2.3 million people were newly infected with HIV. While existing treatments are helping people with HIV to live longer and healthier lives, the challenge of adherence to treatment programmes means that drug resistance remains a threat and the virus continues to burden the world’s poorest communities. Understanding how HIV interacts with the body’s own defences might just be crucial for developing the best approaches to therapy.”

The study is published today in the journal ‘Nature’ and was funded by the Wellcome Trust, the Medical Research Council and the National Institute for Health Research University College London Hospitals Biomedical Research Centre.

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