Archive for Hanna

Study shows how HIV breaches macrophage defences, could be step towards cure

25 January 2017

A team led by UCL researchers has identified how HIV is able to infect macrophages, a type of white blood cell integral to the immune system, despite the presence of a protective protein. They discovered a treatment that can maintain macrophage defences which could be a key part of the puzzle of reaching a complete cure for HIV/AIDS.

Macrophages make an antiviral protein called SAMHD1, which prevents HIV from replicating in these cells – except for when the protein is switched off, as part of a natural process discovered by the UCL-led team.

“We knew that SAMHD1 is switched off when cells multiply, but macrophages do not multiply so it seemed unlikely that SAMHD1 would be switched off in these cells,” said Professor Ravindra Gupta (UCL Infection & Immunity), the senior author of the paper. “And yet we found there’s a window of opportunity when SAMHD1 is disabled as part of a regularly-occurring process in macrophages.”

Lead author of the EMBO Journal study, Dr Petra Mlcochova (UCL Infection & Immunity) said: “Other viruses can disable SAMHD1, but HIV cannot. Our work explains how HIV can still infect macrophages, which are disabling SAMHD1 by themselves.”

The reason why SAMHD1 gets switched off remains to be determined, but the authors suggest it might be done in order to repair damaged DNA, part of the normal functioning of the macrophage.

In a further part of the study, the researchers discovered how to close this window of opportunity by treating the cells with HDAC inhibitors, which are sometimes used in cancer treatments.

“Our findings could help explain why some people undergoing anti-retroviral therapy for HIV continue to have HIV replication in the brain, as the infected cells in the brain are typically macrophages. While this is a barrier to achieving control of HIV in just a minority of patients, it may more importantly be a barrier to a cure,” Gupta added.

The researchers say that macrophages can be an important reservoir of HIV infection that lingers away from the reach of existing treatments. Once a macrophage is infected, it will continually produce the HIV virus, so cutting off that point of infection within the body could be an important step towards safeguarding the entire immune system. HDAC inhibitors may be particularly helpful as they’re already known to reactivate latent HIV cells, thus making the virus vulnerable to the body’s defences, especially if supported by anti-retroviral therapy.

The series of tests involved cultures of macrophages derived from human cells in vitro, which responded well to HDAC inhibitor treatment, as well as macrophages residing in mouse brain tissues.

Study co-authors included researchers from the University of Oxford, King’s College London, and Emory University. The research was funded by Wellcome, the NIHR UCLH Biomedical Research Centre, the European Research Council, the Medical Research Council and the National Institutes of Health.

Original article

 

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European HIV testing week starts tomorrow! 18-25 November, 2016

European Testing Week 2016

The ultimate goal of European HIV Testing Week is to make more people aware of their HIV status and reduce late diagnosis by communicating the benefits of testing.

More information:

testingweek.edu

HIVheptestweek twitter

#EuroTestWeek

Sign up to the testing week

 

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aidsmap report on the RIVER study

Media reports of a British HIV cure ‘breakthrough’ are premature

By Keith Alcorn, www.aidsmap.com

First published: http://www.aidsmap.com/Media-reports-of-a-British-HIV-cure-breakthrough-are-premature/page/3087965/

October 3 2016

The Sunday Times yesterday reported that HIV had become undetectable in the blood of one man taking part in the RIVER study, a trial of an intensive treatment regimen designed to test whether it is possible to reduce levels of HIV-infected cells in the bodies of people recently infected with HIV. The researchers hope that the treatment may eradicate HIV infection altogether.

The Sunday Times reported that British scientists are on the “brink of an HIV cure”. In fact, the study is still in its early stages and will not be able to describe participants as “cured” until extensive follow-up has taken place. Investigator Professor Sarah Fidler of Imperial College, London, told The Sunday Times that participants in the study will be followed for five years.

About the RIVER study

The RIVER study stands for ‘Research in Viral Eradication of HIV Reservoirs’. The trial is being conducted by the CHERUB Collaboration, a consortium of research teams at Imperial College and King’s College, London, Oxford University and Cambridge University, funded by the NHS National Institute for Health Research.

The study is recruiting people who were infected with HIV within the previous six months – so-called ‘primary infection’. HIV may have infected fewer cells in the body at this time, so in theory it might be easier to eradicate HIV in this group of people, or to stop antiretroviral therapy without causing a rebound in HIV levels.

Antiretroviral treatment reduces levels of HIV in the blood to undetectable levels but has little or no effect on levels of HIV DNA in cells. HIV DNA can remain silent or `latent`, in cells of the immune system and brain as long as they live. These cells will produce HIV if they are activated to do their job as immune cells. The immune system can then identify HIV-infected cells and kill them. HIV can only be cured if HIV DNA is eradicated altogether – or if HIV-infected cells remain in a state of permanent `sleep`, unable to produce new viruses.

Participants in the study receive a four-drug combination of antiretrovirals that includes raltegravir, which is included because it can reduce HIV levels in the blood more quickly than other antiretrovirals. Aggressive antiretroviral treatment started during primary infection has been shown to permit treatment to be stopped altogether, without viral rebound, in around 15% of people in a French cohort study called VISCONTI.

After 22 weeks of antiretroviral treatment, participants in the study are randomly assigned to continue receiving the four-drug antiretroviral regimen alone, or to receive the antiretroviral regimen plus a vaccination designed to improve immune responses to HIV-infected cells. Participants in this study arm also receive ten doses of vorinostat, a drug which activates cells infected with HIV.

If the experimental regimen is effective, vorinostat should ‘kick’ cells latently infected with HIV to produce HIV. The surge in virus production as a result of activation will be suppressed by the highly effective antiretroviral drug combination. The infected cells should be spotted by the immune system and the vaccination should improve the ability of the immune system to seek out and kill the infected cells. This “kick and kill” strategy – ten rounds of vorinostat over 28 days – is designed to flush out the infected cells and kill them, leaving little or no HIV DNA left in the body’s cells.

The study is designed to test whether the approach does indeed reduce levels of HIV DNA in cells, or even eradicates the infection altogether. The study is measuring HIV DNA levels 40 and 42 weeks after treatment begins, but is not testing whether treatment can be stopped altogether after 42 weeks.

The RIVER study aims to recruit 52 people diagnosed with primary HIV infection. Recruitment is taking place at clinics in London and Brighton.

What has the study reported?

The Sunday Times reported that one participant in the study has no detectable HIV after completing the study regimen. This participant continues to take antiretroviral therapy (ART). This participant has not been cured of HIV infection at this point: prolonged follow-up will be needed to determine whether the virus has been eradicated entirely by the experimental treatment.

Professor Sarah Fidler of Imperial College, London, told The Sunday Times: “We will continue with medical tests for the next five years and at the moment we are not recommending stopping ART but in the future depending on the test results we may explore this.”

The RIVER study is not due to complete tests on all participants until December 2017, so the earliest that any results from the study will be available is likely to be the first half of 2018. At that stage the researchers will be able to say whether or not the experimental regimen eliminated all traces of HIV DNA in study participants. But the real test of an eradication regimen will be to see what happens when treatment is stopped.

To date, the only person who appears to have been cured of HIV infection is Timothy Ray Brown, the so-called ‘Berlin patient’ who lost all evidence of HIV infection after a bone marrow transplant. A more recent study of similar bone marrow transplant recipients with HIV identified people who had undetectable viral load, and no detectable HIV DNA in their cells, who have nevertheless experienced viral rebound after treatment was stopped – sometimes after a long interval. Long-term follow-up will be essential for anyone who stops treatment, in order to determine whether HIV has been truly eradicated from the body.

Whether participants stop treatment after the end of the study, assuming that the regimen is successful in making HIV DNA undetectable, will be a matter for discussion between investigators and study participants, and will depend on the best available information at the time about the consequences of stopping treatment. In other words, it is very premature to report a cure breakthrough.

Update: 4 October

The CHERUB Collaboration has issued a statement confirming that the RIVER study will report its findings in 2018. Until then the researchers emphasise that “we cannot yet state whether any individual has responded to the intervention or been cured.”

The researchers point out “An important clarification is that all participants involved in the study will be expected to have no HIV in their blood because they are receiving antiretroviral therapy – these are the standard drugs we use to treat HIV. This does not mean they have been cured as some headlines have suggested. This does mean that their immune systems will recover and that they will not transmit the virus.”

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New animation explaining the RIVER study

Watch the animation to find out more about the RIVER study design. The study will report in 2018.

 

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Why talk of a cure for HIV is premature’ – BBC News

Beware of headlines which suggest scientists are “on the brink of HIV cure”, or “HIV cure close”.

They grab the attention – which is of course the aim of a headline – but talk of a breakthrough is premature.

The Sunday Times reported that a British man with HIV was receiving a prototype therapy designed to eradicate the virus from his body.

Early tests from the clinical trial have apparently shown no signs of the virus in his blood.

That may sound astonishing unless you know that conventional antiretroviral therapy (ART) – which the patient was also taking – already reduces HIV to undetectable levels.

Viral load

Sarah Fidler, Prof of HIV Medicine at Imperial College London, who is leading the trial, told me: “All the participants are taking antiretrovirals and so will have an undetectable viral load, which shows the great success of current treatment.”

It does indeed. HIV medication has turned the infection from a death sentence to a chronic, manageable condition, which is remarkable.

The limitation of ART is that it cannot eliminate HIV.

The virus remains dormant in some immune cells and will start replicating if patients stop taking their medication.

That’s why antiretrovirals must be taken for life.

The RIVERS trial (sic) – which stands for Research in Viral Eradication of HIV Reservoirs – is trying to rid the virus completely from the body.

‘Kick and kill’

So far, 39 out of a total of 50 patients have been recruited to the trial. All will receive ART but half will also be given a drug which forces the virus to emerge from hiding places in the body. These chosen patients will also receive two vaccines which aim to boost the immune system so that it can attack HIV-infected cells.

The strategy is called “kick and kill”.

The anonymous patient quoted in the newspaper article is simply the first of the participants to have completed the kick and kill treatment.

No results are expected until 2018.

The trial is being conducted by a consortium of research teams at Imperial and King’s College, London, Oxford and Cambridge Universities and University College London.

The partnership began six years ago, and set out to search for a cure for HIV.

Mark Samuels, managing director of the National Institute for Health Research Office for Clinical Research Infra­structure, which set up the medical consortium, told me: “This is an unprecedented collaboration and to get to clinical trials in six years shows remarkable progress.”

So how will the researchers know whether their trial has been a success?

This will take some time and involve detailed analysis of blood samples from volunteers.

Viral reservoir

John Frater, Prof of Infectious Disease at Oxford University, told me: “We will carry out a very targeted genetic test to look for HIV lying dormant within immune cells.”

All the trial volunteers are newly infected HIV patients which means they will have a small viral reservoir and their immune system will not have been repeatedly damaged by the virus.

If it is possible to cure HIV, these patients represent the easiest target.

But even if the trial is a complete success, caution will be required in interpreting the results because it may not work in long-standing HIV patients.

Dr Michael Brady, medical director Terrence Higgins Trust told me: “In test tubes it has been shown that you can drive the virus out of dormant cells, but we will have to wait and see whether it works in patients.

“Even if it works we can’t talk about a cure for everyone and there would need to be bigger trials.”

To date, only one person appears to have been cured of HIV infection.

Timothy Ray Brown, the so-called Berlin patient, received a bone marrow transplant from a donor with natural immunity to the virus.

However, bone marrow transplants are potentially dangerous and so not an approach that is recommended.

Earlier this year I reported on a gene editing trial in California involving 80 HIV patients.

They had immune cells in their blood removed and editing to try to mimic the gene mutation which gives some people a natural immunity to HIV.

One of the volunteers, Matt Chappell, has been off all antiretroviral medication for two years since having his immune cells gene edited.

These were small trials so caution is needed before reading too much into the results, but they are nonetheless promising.

The British trial is taking a different approach but with the same aim – trying to free patients from the need to take daily medication.

But talk of cures is premature.

3 October, 2016

Original article

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