̽��ֱ�� of Cambridge - HIV and AIDS

Genetic variant linked to lower levels of HIV virus in people of African ancestry

cjb250 — Wed, 02 Aug 2023 15:00:57 +0000

Reported today in Nature, this is the first new genetic variant related to HIV infection discovered in over 25 years of research. It could, in the future, help direct the development of new treatment approaches for those living with HIV.

HIV remains a major threat to global health. According to UNAIDS, there were 38.4 million people living with HIV globally in 2021. A combination of pre-exposure drugs and medicines that dramatically reduce viral loads has had a major impact on transmission, yet 1.5 million people were newly infected in 2021. And while treatments have improved dramatically since the virus was first identified, 650,000 people still died from AIDS-related illnesses in that year.

Viral load is the amount of a virus in a patient’s system. Higher levels are known to correlate with faster disease progression and increased risk of transmission. But viral load varies widely among infected individuals, influenced by a number of factors including an individual’s genetic makeup.

Most of what we know about the relationship between our DNA and HIV comes from studies among European populations. But given that HIV disproportionately affects people on the African continent – more than 25 million people who are HIV-positive live on the continent – it’s important to better understand the role of genetics in HIV infection in African populations.

To investigate this question, researchers analysed the DNA of almost 4,000 people of African ancestry living with HIV-1, the most common type of the virus. They identified a variant within a region on chromosome 1 containing the gene CHD1L which was associated with reduced viral load in carriers of the variant. Between 4% and 13 % of people of African origin are thought to carry this particular variant.

Paul McLaren from the Public Health Agency of Canada’s National Microbiology Laboratory, joint first author, said: “African populations are still drastically underrepresented in human DNA studies, despite experiencing the highest burden of HIV infection. By studying a large sample of people of African ancestry, we’ve been able to identify a new genetic variant that only exists in this population and which is linked to lower HIV viral loads.”

CHD1L is known to play a role in repairing damaged DNA, though it is not clear why the variant should be important in reducing viral load. However, as HIV attacks immune cells, researchers at the ̽��ֱ�� of Cambridge’s Department of Medicine, led by Dr Harriet Groom and Professor Andrew Lever, used stem cells to generate variants of cells that HIV can infect in which CHD1L had either been switched off or its activity turned down.

HIV turned out to replicate better in a type of immune cell known as a macrophage when CHD1L was switched off. In another cell type, the T cell, there was no effect – perhaps surprising since most HIV replication occurs in the latter cell type.

Dr Groom said: “This gene seems to be important to controlling viral load in people of African ancestry. Although we don’t yet know how it’s doing this, every time we discover something new about HIV control, we learn something new about the virus and something new about the cell. ̽��ֱ��link between HIV replication in macrophages and viral load is particularly interesting and unexpected.”

Co-author Professor Manjinder Sandhu from the Faculty of Medicine at Imperial College London said: “With more than a million new HIV infections a year, it’s clear that we still have a long way to go in the fight against HIV – we are yet to have a vaccine to prevent infection, have yet to find a cure and still see drug resistance emerging in some individuals. ̽��ֱ��next step is to fully understand exactly how this genetic variant controls HIV replication.”

̽��ֱ��research in Cambridge was largely funded by the Medical Research Council. A full list of funders can be found in the research paper.

Dr Groom is a Research Fellow at Sidney Sussex College and Professor Andrew Lever is a Professorial Fellow Peterhouse, Cambridge.

Reference
McLaren, PJ; Porreca, I; Iaconis, G; Mok, HP, Mukhopadhyay, Sl; Karakoc, E et al. Africa-specific human genetic variation near CHD1L associates with HIV-1 load. Nature; 2 Aug 2023; DOI: 10.1038/s41586-023-06370-4

An international team of researchers has found a genetic variant that may explain why some people of African ancestry have naturally lower viral loads of HIV, reducing their risk of transmitting the virus and slowing progress of their own illness.

Every time we discover something new about HIV control, we learn something new about the virus and something new about the cell

Harriet Groom

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Fewer than one in 20 people living with HIV in England expected to be unaware of status by 2025

cjb250 — Fri, 24 Sep 2021 07:49:11 +0000

In 2014, UNAIDS set an ambitious target of 90-90-90 by 2020 – that is, 90% of all people living with HIV will know their HIV status; 90% of all people with diagnosed HIV infection will receive sustained antiretroviral therapy; and 90% of all people receiving antiretroviral therapy will have viral suppression.

According to the Cambridge and PHE team, in 2019 there were an estimated 105,200 people living with HIV in the UK, of whom 94% were aware of their HIV status. In addition, 98% of those living with diagnosed HIV were on treatment, and 97% of these were virally suppressed. In other words, England had already reached the UNAIDS goals.

In a publication today in ̽��ֱ��Lancet Public Health, the researchers extended their analysis of evidence from multiple surveillance, demographic, and survey datasets relevant to HIV in England from estimating HIV prevalence in a single year to estimating the trends over time in HIV prevalence. Trends in the number of people living with HIV, the proportion of people unaware of their HIV infection, and the corresponding prevalence of undiagnosed HIV are reported.

According to their analysis, the estimated number of people in England living with HIV aged 15-74 years who were unaware of their infection halved from 11,600 in 2013 to 5,900 in 2019, with a corresponding fall in prevalence from 0.29 to 0.14 per 1,000 people.

At the same time, the increase in the number of people living with diagnosed HIV resulted in the total number of people living with HIV rising from 83,500 to 92,800 over the same period. ̽��ֱ��percentage of people living with HIV whose infection was diagnosed therefore steadily increased from 86% in 2013 to 94% in 2019, reaching the UNAIDS target in 2016 – and even earlier, in 2013, for Black African heterosexuals.

Professor Daniela De Angelis from the MRC Biostatistics Unit, the study’s senior author, said: “Overall, we see a positive picture for the HIV epidemic in England, with a dramatic fall in the number of people living with undiagnosed HIV. We estimate we are already several years ahead of the UNAIDS 2020 goals and are on target to reach 95% diagnosed by 2025 and to eliminate HIV infections by 2030.

Dr Anne Presanis from the MRC Biostatistics Unit added: “Examined more closely, the situation is not as positive for everyone. We estimate that areas of England outside London have not seen as steep a decrease in undiagnosed HIV prevalence as in London, and there is evidence of missed opportunities to diagnose HIV infections among some population subgroups.”

In England, gay, bisexual, and other men who have sex with men, and Black African heterosexuals remain disproportionately affected by HIV, with considerably higher undiagnosed HIV prevalence per population in 2019 than heterosexuals in other ethnic groups. However, undiagnosed HIV prevalence rates within these communities have seen dramatic falls: for gay, bisexual, and other men who have sex with men, prevalence fell from 13.9 to 5.4 per 1,000, and for Black African heterosexuals prevalence fell from 3.3 to 1.7 per 1,000 population.

London saw more dramatic falls in the prevalence of undiagnosed HIV during the study period than other regions of England, down from 0.74 to 0.31 per 1,000, compared to a decrease from 0.20 to 0.11 per 1,000 outside London.

Although sexual health clinics provide free and confidential HIV testing to all clinic attendees, the researchers estimated that among heterosexuals in an ethnic group other than Black African, undiagnosed prevalence in clinic attendees in 2019 was more than 30 times greater than in those who had not attended in the past year. This implies that sexual health clinics are missing opportunities for testing attendees. This is in line with findings from Public Health England that among individuals outside those subgroups at greatest risk of HIV infection, the proportion declining a HIV test had increased to more than one in four (27%) in 2016.

̽��ֱ��researchers say their estimates have important implications for efforts to eliminate HIV transmission in England and the UK.

Dr Valerie Delpech, head of the HIV Team at Public Health England said: “This research is good news and shows that combination prevention, and in particular HIV testing and early treatment, is working in England. ̽��ֱ��increasing use of pre-exposure prophylaxis among persons at higher risk of HIV has further amplified our response to end HIV transmission. Nevertheless, further reducing the number of people who remain undiagnosed with HIV infection will become very challenging in the coming years. This is particularly the case for heterosexuals who may not consider themselves at risk of HIV.

“ ̽��ֱ��priority must be to ensure that all sexual health clinic attendees are offered and encouraged to accept a HIV test, regardless of ethnicity, rather than the 73% that currently do test. If we can increase the number of clinic attendees unaware of their HIV status who get tested and diagnosed, as well as improve partner notification, the prospect of eliminating HIV transmission becomes increasingly likely.”

̽��ֱ��research was funded by the Medical Research Council and Public Health England.

Reference
Presanis AM, et al. Trends in undiagnosed HIV prevalence in England and implications for eliminating HIV transmission by 2030: an evidence synthesis model. Lancet Public Health; 23 Sept 2021; DOI: 10.1016/S2468-2667(21)0042-0

England is on track to have diagnosed 95% of people living with HIV by 2025, putting it in a strong position to eliminate HIV transmission by 2030, say researchers at the MRC Biostatistics Unit, ̽��ֱ�� of Cambridge, and Public Health England (PHE).

Overall, we see a positive picture for the HIV epidemic in England, with a dramatic fall in the number of people living with undiagnosed HIV

Daniela De Angelis

Andy McCarthy

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England on track to achieve elimination of HIV transmission by 2030 as model shows sharp decrease in HIV incidence

Anonymous — Thu, 10 Jun 2021 08:20:10 +0000

To manage the HIV epidemic among men who have sex with men (MSM) in England, enhanced testing and earlier treatment strategies were scaled-up between 2011 and 2015 and supplemented from 2015 by pre-exposure prophylaxis (PrEP). ̽��ֱ��researchers examined the effect of these interventions on the number of new infections and investigated whether the United Nations (UN) targets for HIV control and elimination of HIV transmission by 2030 might be within reach among MSM in England.

A complexity in this assessment is that HIV infections are not observed. Routine surveillance collects data on new HIV diagnoses, but trends in new diagnoses alone can be misleading as they can represent infections that occurred many years previously and depend on the testing behaviour of infected individuals.

To estimate new HIV infections among adult MSM (age 15 years and above) over a 10-year period between 2009 and 2018, the researchers used a novel statistical model that used data on HIV and AIDS diagnoses routinely collected via the national HIV and AIDS Reporting System in England, and knowledge on the progression of HIV. Estimated trends in new infections were then extrapolated to understand the likelihood of achieving the UN elimination target defined as less than one newly acquired infection per 10,000 MSM per year, by 2030.

̽��ֱ��peak in the number of new HIV infections in MSM in England is estimated to have occurred between 2012 and 2013, followed by a steep decrease from 2,770 new infections in 2013 to 1,740 in 2015, and a further steadier decrease from 2016, down to 854. ̽��ֱ��decline was consistent across all age groups but was particularly marked in MSM aged 25–34 years, and slowest in those aged 45 years or older. Importantly, this decrease began before the widespread roll-out of PrEP in 2016, indicating the success of testing and treatment as infection prevention measures among MSM in England.

Through extrapolation, the researchers calculated a 40% likelihood of England reaching the UN elimination target by 2030 and identified relevant age-specific targeting of further prevention efforts (i.e., to MSM aged ≥45 years) to increase this likelihood.

Senior author, Professor Daniela De Angelis, Deputy Director of the MRC Biostatistics Unit, ̽��ֱ�� of Cambridge, said: “This is very good news and suggests that prevention measures adopted in England from 2011 have been effective. With the rollout of PrEP, England looks on course to meet the goal of zero transmissions by 2030. Our study also shows the value of regular estimation of HIV incidence to recognise and respond appropriately to changes in the current downward trend. ̽��ֱ��challenge now is to achieve these reductions in all groups at risk for HIV acquisition.”

Valerie Delpech, Head of National HIV Surveillance at Public Health England, said: “We have made good progress towards ending HIV transmission by 2030 in England. Frequent HIV testing and the use of PrEP amongst people most at risk of HIV, together with prompt treatment among those diagnosed, are key to ending HIV transmission by 2030.

“You can benefit from life-saving HIV treatments if you are diagnosed with HIV and it also means you cannot pass the virus on.

“HIV and STI tests are still available through sexual health clinics during the COVID pandemic. Many clinics offer online testing throughout the year – people can order tests on clinic websites, take them in the privacy of their own home, return by post and receive results via text, phone call or post.”

This research is funded by the UK Medical Research Council, UK National Institute of Health Research Health Protection Unit in Behavioural Science and Evaluation, and Public Health England.

Reference
Brizzi, F et al. Tracking elimination of HIV transmission in men who have sex with men in England: a modelling study. Lancet HIV, 10 June 2021; DOI: 10.1016/ S2352-3018(21)00044-8

̽��ֱ��annual number of new HIV infections among men who have sex with men in England is likely to have fallen dramatically, from 2,770 in 2013 to 854 in 2018, showing elimination of HIV transmission by 2030 to be within reach – suggests work by researchers from the MRC Biostatistics Unit at the ̽��ֱ�� of Cambridge and Public Health England, published in ̽��ֱ��Lancet HIV.

This is very good news and suggests that prevention measures adopted in England from 2011 have been effective

Daniela De Angelis

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Cambridge researcher named to Time 100 list of world's most influential people

sc604 — Wed, 23 Sep 2020 06:13:13 +0000

In 2019, the case of ‘ ̽��ֱ��London Patient’ made global headlines, as 40-year-old Adam Castillejo underwent a bone marrow transplant which both cured him of Hodgkins lymphoma, and eradicated the HIV virus from his system.

In his piece about Gupta for Time, Castillejo said, "Through the years, our partnership has developed and strengthened as Gupta has shared his knowledge and his enthusiasm to find a feasible cure for everyone. He has championed me and empowered me to become an ambassador of hope to millions of people living with HIV around the world...I’m so fortunate and humbled to know him, and to see how his dedication can conquer this disease."

As Professor of Clinical Microbiology and Wellcome Trust Senior Fellow in Clinical Science at Cambridge, Ravi’s primary research focus is on the increasing problem of drug-resistant HIV, and the potential development of alternative treatments. He is also a Professorial Fellow at Homerton College.

Since March this year, however, his attention has been on COVID-19, and increasing our understanding of the virus which has brought the world to a standstill. Early on, his work to develop rapid testing transformed the ability of hospitals to isolate infected patients. He is now in regular demand as a commentator on our evolving knowledge about how COVID-19 works and what the next stage of its impact might be.

"In the future I want to keep doing COVID-19 research alongside the HIV research," he said in June 2020. "This is partly because there’ll be plenty to do, and partly because I think there’s lots to learn that could translate to other viruses. ̽��ֱ��next pandemic may be a related virus, so we really do need to keep plugging away."

Professor Ravi Gupta has been named today as one of Time Magazine’s 100 Most Influential People of the Year, in recognition of his work to bring about the second-ever cure of a patient with HIV.

People who change the world - Professor Ravi Gupta

Ravi Gupta

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Antiretroviral therapy fails to treat one-third of HIV patients in Malawi hospital

Anonymous — Thu, 03 Sep 2020 11:37:55 +0000

̽��ֱ��observational study involving more than 1,300 people was led by the London School of Hygiene & Tropical Medicine (LSHTM), ̽��ֱ�� of Malawi College of Medicine and ̽��ֱ�� of Cambridge.

It found most patients admitted to hospital knew their HIV status, and that 90% were taking antiretroviral therapy. However, approximately one-third of patients established on HIV treatment had significant levels of HIV in their blood, and more than 80% of these patients had resistance to two or more of their HIV antiretroviral drugs.

Patients with multidrug resistant HIV were 70% more likely to die within two months of being admitted to hospital than those without drug resistance.

This is the first study reporting such data in hospitalised patients, as access to HIV drug resistance testing is not widely available in high-HIV-burden African settings.

Dr Ankur Gupta-Wright from LSHTM and project lead said: “There has been an unprecedented scale-up of antiretroviral therapy in high-HIV prevalence settings in sub-Saharan Africa. However, HIV remains a common cause of admission to hospital, with a high risk of death. Our results show drug resistance is an important cause.”

Distinguishing HIV drug resistance from alternative explanations for progressive illness whilst taking antiretroviral (HIV) treatment, such as patients not sticking to required dosage or stopping treatment altogether, is not usually possible. Patients who develop advanced HIV while established on ART often go undetected.

Most available data on HIV drug resistance come from outpatient clinics, where failing HIV treatment is much less common. However, hospitalised patients represent a key target group for intensified interventions, given their relatively high risks of treatment failure, advanced immunosuppression, and high short-term mortality.

This study was based on patients living with HIV who were admitted to hospital in Zomba, southern Malawi. Samples were collected at the time of hospital admission to test for the amount of HIV virus in the blood, to see if patients were responding to their HIV antiretroviral medication.

By sequencing the virus and looking for mutations, patients with high levels of HIV in their blood were tested for resistance to HIV drugs. After two months, the team compared whether patients failing ART and/or with HIV drug resistance were more likely to die.

Of 237 patients with HIV drug resistance results available, 195 (82%) had resistance to lamivudine, 128 (54%) to tenofovir, and 219 (92%) to efavirenz (all first-line drugs used to treat HIV at the time of the study).

Dr Gupta-Wright said: “These are worrying results. ART changes and saves lives, but drug resistance is threatening this progress. Timely diagnosis and management of ART failure and drug resistance in this patient population could improve individual patient outcomes and contribute to the UNAIDS 95-95-95 targets set for 2030. Rapid HIV-1 viral load tests for hospital inpatients need to be implemented, so results are available quickly and patients can be switched to alterative antiretroviral therapy.

“This could potentially save the lives of many patients living with HIV on treatment who are admitted to hospital.”

Professor Ravi Gupta, from Cambridge ̽��ֱ�� and senior author on the study said: ‘’These important findings highlight the threat posed by drug resistant HIV and call for rapid tests for drug resistant virus that could aid in determining treatments and interventions for patients in hospital.’’

̽��ֱ��authors acknowledge limitations of this study including the introduction of a new antiretroviral drug in Malawi last year called Dolutegravir, which may overcome some of the resistance found in this study.

̽��ֱ��study was funded by the Joint Global Health Trials Scheme of the Medical Research Council, UK Department for International Development, and Wellcome.

Reference
Gupta-Wright, A, et al. Virological failure, HIV-1 drug resistance, and early mortality in adults admitted to hospital in Malawi: an observational cohort study. Lancet HIV; 1 Sept 2020; DOI: 10.1016/S2352-3018(20)30172-7

Adapted from a press release from the London School of Hygiene & Tropical Medicine

Antiretroviral therapy (ART) failure and drug resistance are extremely common in patients living with HIV who are admitted to hospital in Malawi, according to new research published in Lancet HIV.

These important findings highlight the threat posed by drug resistant HIV and call for rapid tests for drug resistant virus that could aid in determining treatments and interventions for patients in hospital

Ravi Gupta

Andrew Moore

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HIV remission achieved in second patient

cjb250 — Tue, 05 Mar 2019 09:07:48 +0000

̽��ֱ��case report, carried out by researchers at UCL and Imperial College London, together with teams at the ̽��ֱ�� of Cambridge and the ̽��ֱ�� of Oxford, comes ten years after the first such case, known as the ‘Berlin Patient.’

Both patients were treated with stem cell transplants from donors carrying a genetic mutation that prevents expression of an HIV receptor CCR5.

̽��ֱ��subject of the new study has been in remission for 18 months after his antiretroviral therapy (ARV) was discontinued. ̽��ֱ��authors say it is too early to say with certainty that he has been cured of HIV, and that they will continue to monitor his condition.

“At the moment the only way to treat HIV is with medications that suppress the virus, which people need to take for their entire lives, posing a particular challenge in developing countries,” said the study’s lead author, Professor Ravindra Gupta from the ̽��ֱ�� of Cambridge, who led the study while at UCL.

“Finding a way to eliminate the virus entirely is an urgent global priority, but is particularly difficult because the virus integrates into the white blood cells of its host.”

According to the World Health Organization, there were approximately 36.9 million people worldwide living with HIV/AIDS in 2017 and only 59% of these are receiving ARV. Drug-resistant HIV is a growing concern. Almost one million people die annually from HIV-related causes.

̽��ֱ��report describes a male patient in the UK, who prefers to remain anonymous, and was diagnosed with HIV infection in 2003 and on antiretroviral therapy since 2012.

Later in 2012, he was diagnosed with advanced Hodgkin’s Lymphoma. In addition to chemotherapy, in 2016 he underwent a haematopoietic stem cell transplant from a donor with two copies of the genetic mutation (or ‘allele’) that prevents expression of CCR5.

CCR5 is the most commonly used receptor by HIV-1, the most common and most harmful type of HIV. People who have two mutated copies of the CCR5 allele are resistant to the HIV-1 virus strain that uses this receptor, as the virus cannot enter host cells.

Chemotherapy can be effective against HIV as it kills cells that are dividing. Replacing immune cells with those that don’t have the CCR5 receptor appears to be key in preventing HIV from rebounding after the treatment.

̽��ֱ��transplant was relatively uncomplicated, but with some side effects including mild graft-versus-host disease, a complication of transplants wherein the donor immune cells attack the recipient’s immune cells.

̽��ֱ��patient remained on ARV for 16 months after the transplant, at which point the clinical team and the patient decided to interrupt ARV therapy to test if the patient was truly in HIV-1 remission.

Regular testing confirmed that the patient’s viral load remained undetectable, and he has been in remission for 18 months since ceasing ARV therapy (35 months post-transplant). ̽��ֱ��patient’s immune cells remain unable to express the CCR5 receptor.

Dr Hoi Ping Mok, and Dr Fanny Salasc from the Department of Medicine at the ̽��ֱ�� of Cambridge tested for virus that is ‘latent’ and may not be found by conventional lab assays. ̽��ֱ��researchers are part of Professor Andrew Lever’s lab, which has developed a highly sensitive assay for latent virus.

“This is the most reliable assay there is to demonstrate that there really are no hidden reservoirs of HIV that might be temporarily ‘sleeping’ and might reactivate at a later date,” said Professor Lever. “Our Cambridge lab is unique in the UK in being able to carry out this assay.”

̽��ֱ��patient is only the second person documented to be in sustained remission without ARV. ̽��ֱ��first, the Berlin Patient, also received a stem cell transplant from a donor with two of the CCR5 alleles, but to treat leukaemia. Notable differences were that the Berlin Patient was given two transplants and underwent total body irradiation, while the UK patient received just one transplant and less intensive chemotherapy.

Both patients experienced mild graft-versus-host disease, which may also have played a role in the loss of HIV-infected cells.

“By achieving remission in a second patient using a similar approach, we have shown that the Berlin Patient was not an anomaly, and that it really was the treatment approaches that eliminated HIV in these two people,” said Professor Gupta.

̽��ֱ��researchers caution that the approach is not appropriate as a standard HIV treatment due to the toxicity of chemotherapy, but it offers hope for new treatment strategies that might eliminate HIV altogether.

“We need to understand if we could knock out this receptor in people with HIV, which may be possible with gene therapy,” said Professor Gupta.

“While it is too early to say with certainty that our patient is now cured of HIV, and doctors will continue to monitor his condition, the apparent success of haematopoietic stem cell transplantation offers hope in the search for a long-awaited cure for HIV/AIDS,” said Professor Eduardo Olavarria from Imperial College Healthcare NHS Trust and Imperial College London.

̽��ֱ��research was funded by Wellcome, the Medical Research Council, the Foundation for AIDS Research, and National Institute for Health Research (NIHR) Biomedical Research Centres at ̽��ֱ�� College London Hospitals, Oxford, Cambridge and Imperial.

̽��ֱ��research team is presenting the findings today at the annual Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

Reference
Gupta, R et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem cell transplantation. Nature; 5 March 2019; DOI: 10.1038/s41586-019-1027-4

Adapted from a press release from UCL

A second person has experienced sustained remission from HIV-1 after ceasing treatment, according to a study published today in Nature.

At the moment the only way to treat HIV is with medications that suppress the virus, which people need to take for their entire lives, posing a particular challenge in developing countries

Ravindra Gupta

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Study clears important hurdle towards developing an HIV vaccine

cjb250 — Wed, 13 Sep 2017 07:03:22 +0000

In a study published in 2009, results from a clinical trial carried out in Thailand found that an experimental vaccine against HIV lowered the rate of human infection by 31%. This gave cautious optimism that a vaccine against the virus might be a feasible prospect. A vaccine has obvious advantages over treatment with anti-retroviral drugs in that prevention could lead to eradication.

However, one of the major problems that prevented the vaccine from generating long-lasting protection was that the key immune response it needed to generate was very short-lived. ̽��ֱ��reason has now become clear and researchers have found a potential solution.

When a virus enters the body, its aim is to get into our cells and replicate itself again and again, spreading throughout the body. HIV is especially notorious because a protein on its outer coat specifically targets CD4 T-helper cells, the master regulators of the immune system. These cells produce important signals for other types of immune cell: B-cells, which make antibodies; and T-killer cells, which kill virus-infected cells.

By specifically targeting the CD4 T-helper cells, HIV cripples the command and control centre of the immune system and prevents immune defences from working effectively. HIV does not even need to enter and kill the CD4 T-cells – it can cause a functional paralysis of these cells simply by binding its gp140 with the CD4 receptor, an important molecule on the surface of T-helper cells.

HIV’s envelope proteins are a key component of vaccines to protect against HIV infection. ̽��ֱ��body’s immune system targets this protein and generates antibodies directed at HIV’s outer coat to prevent the virus from entering the cells. If the effects of the vaccine last long enough, then with the assistance of robust helper T-cells, the human body should be able to develop antibodies that neutralise a large variety of HIV strains and protect people from infection.

Previous studies showed that vaccinating using a form of the outer coat protein called gp140 leads to the triggering of B-cells which produce antibodies to the virus, but only for a brief period and insufficient to generate sufficient antibodies that are protective from HIV infection over a long period.

Working with scientists in the UK, France, the USA, and the Netherlands, Professor Jonathan Heeney from the Laboratory of Viral Zoonotics at the ̽��ֱ�� of Cambridge recognised that the binding of gp140 to the CD4 receptor on T-helper cells was probably causing this block, and that by preventing gp140 attaching to the CD4 receptor, the short-term block in antibody producing B-cells could be overcome.

In two back-to-back studies published in the print edition of Journal of Virology, the research team has demonstrated for the first time that this approach works, providing the desired responses that were capable of lasting over a year.

“For a vaccine to work, its effects need to be long lasting,” says Professor Heeney. “It isn’t practical to require people to come back every 6-12 months to be vaccinated. We wanted to develop a vaccine to overcome this block and generate these long-lived antibody producing cells. We have now found a way to do this.”

̽��ֱ��study showed that the addition of a tiny specific protein patch to the gp140 protein dramatically improved B-cell responses by blocking binding to the CD4 receptor and hence preventing the paralysis of T-helper cells early in the key stages of the immune response – like preventing a key from getting stuck in a lock. This small patch was one of several strategies to improve gp140 for an HIV vaccine by a team led by Susan Barnett (now at the Bill and Melinda Gates Foundation).

This modified vaccine approach now better stimulates long-lasting B-cell responses, boosting the ability of B-cells to recognise different contours of the virus coat and to make better antibodies against it. This new finding will allow HIV vaccines to be developed that give the immune system enough time to develop the essential B-cell responses to make protective antibodies.

“B-cells need time to make highly effective neutralising antibodies, but in previous studies B-cell responses were so short lived they disappeared before they have the time to make all the changes necessary to create the ‘silver bullets’ to stop HIV,” adds Professor Heeney.

“What we have found is a way to greatly improve B-cell responses to an HIV vaccine. We hope our discovery will unlock the paralysis in the field of HIV vaccine research and enable us to move forward.”

̽��ֱ��team now hopes to secure funding to test their vaccine candidate in humans in the near future.

̽��ֱ��studies were funded by the National Institutes of Health, USA, and the Isaac Newton Trust Cambridge.

Reference

Bogers, WMJM, et al. Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site. Journal of Virology; DOI: 10.1128/JVI.00811-17.

Shen, X et al. Cross-Linking of a CD4-Mimetic Miniprotein with HIV-1 Env gp140 Alters Kinetics and Specificities of Antibody Responses against HIV-1 Env in Macaques. Journal of Virology; DOI: 10.1128/JVI.00401-17.

An international team of researchers has demonstrated a way of overcoming one of the major stumbling blocks that has prevented the development of a vaccine against HIV: the ability to generate immune cells that stay in circulation long enough to respond to and stop virus infection.

For a vaccine to work, its effects need to be long lasting. It isn’t practical to require people to come back every 6-12 months to be vaccinated

Jonathan Heeney

NIAID

3D print of HIV (edited)

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Meeting local needs: how the Fens can learn from research in Africa

cjb250 — Fri, 03 Mar 2017 09:59:00 +0000

When Dr Rosalind Parkes-Ratanshi first arrived in Africa in 2003, the situation regarding HIV – her specialism – was “just awful”, she says. We’re all familiar with the devastating images of emaciated and very sick African patients dying in hospital wards, but to see this first hand, she says, was truly shocking.

At the time, antiretroviral therapy (ART), which in developed countries were helping patients manage their condition and limit the spread of the disease, were not widely available in Africa. People were dying from opportunistic infections which most of us were not at risk of or could fend off with adequate treatment.

She had been practising as a doctor in London and had seen HIV treatment transformed. No longer did it carry a death sentence; for the majority of people, if diagnosed early enough, it could now be managed as a chronic condition, like for example diabetes.

Seeing and hearing about the situation in sub-Saharan Africa, which carries by far the greatest global burden of the disease, Parkes-Ratanshi headed to Uganda to carry out a PhD at the UK Medical Research Council/Uganda Virus Research Institute. She was looking at the treatment of cryptococcal meningitis, a potentially life-threatening fungal infection of the brain and spinal cord in Masaka in the rural South West of the country.

Turning the tide

Parkes-Ratanshi saw the tide begin to turn on HIV. Masaka Regional Referral Hospital and ̽��ֱ��AIDS Support Organisation (an NGO) where she worked were among the first to trial the rollout of ART. ̽��ֱ��government and the president had recognised the severity of the problem very quickly and sought help from the international community. It also promoted public health messages around ‘ABC’ – abstinence, be faithful, wear a condom. At its peak, around 15% of Ugandans were HIV-positive – this figure has now fallen to just over 7%.

Nowadays, a person living with HIV in Uganda should be able to manage their HIV as in the West. In fact, the national and international efforts to control the epidemic have been so effective that a cohort of infected individuals has been recruited to help researchers study how people live with their chronic infection.

“We used to look at cohorts to try to understand what patients were dying from,” says Parkes-Ratanshi, “but now we have patients who have been on ART for over ten years. They’re no longer dying from infections related to a poor immune system, but face other issues such as treatment fatigue, stigma and non-communicable diseases like cardiovascular disease and cancers.”

Parkes-Ratanshi is working with the cohort as part of her involvement with the Ugandan Academy for Health Innovation and Impact, of which she is Director. ̽��ֱ��Academy is a joint initiative between Janssen, the pharmaceutical companies of Johnson & Johnson, the Ugandan Ministry of Health, the Infectious Diseases Institute in Uganda and the Johnson & Johnson Corporate Citizenship Trust to address unmet needs in HIV and TB. It is there, she says, to ensure that the outcomes of clinical research are embedded in health policies that benefit the population. “It’s more translational than translational! It’s not lab to clinic, it’s clinic to population.”

One of its flagship programmes is Call for Life™, a randomised controlled trial which aims to promote healthy behaviours and adherence to drug regimens amongst the HIV cohort through the use of mobile phone technology. Participants receive a call at certain times of the day and are offered advice on adherence, health tips and reminders to attend clinic. This simple, cost-effective intervention could help patients manage their infection without over-reliance on the country’s limited resources.

“ ̽��ֱ��thing I’m particularly interested in is this concept of ‘differentiated care’,” she adds. “How can we offer a light touch for those that are doing well and are taking their drugs well and responding well to treatment, and save the resources for those that really need extra help – they’ve only just been diagnosed, or they’re adolescents or pregnant or kids, for example.”

̽��ֱ��Academy is about more than just conducting research, however. It is about providing much needed skills and training to researchers across Africa. It works with the Infectious Diseases Institute,which has provided training through short courses to some 16,000 clinicians and scientists across Africa, and is developing a series of online courses using a smartphone and desktop platform so that scientists/ clinicians who are unable to attend in person can still benefit.

Learning from each other

In 2015, Parkes-Ratanshi returned to the UK and took up a position as a lecturer at the Cambridge Institute of Public Health. She has not given up her ties to Uganda – she is still Director of the Academy – but felt this was the right time to increase links with the UK. There were, she says, two main reasons that influenced her decision.

In Uganda, HIV is treated using a standardised approach using national pathways and limited, but effective, treatments. If you’re a patient with HIV, you get the first line treatment recommended by the Ministry of Health and WHO; if and when that fails, you receive the second line treatment, and so on. In the UK, however, treatment is individualised to a patient so that they receive maximum benefit with minimum side effects. “In order to know what the options are, I need to be clinically ‘on the ball’,” she says. “I need to be up to date with clinical skills from an international perspective to know what the opportunities are for research and clinical care in Uganda.”

But it is the strengths of Cambridge’s research networks – Cambridge Institute of Public Health, Cambridge-Africa and Cambridge Infectious Diseases to name but a few – that hold real appeal.

“When you’re working in a resource-poor setting like Uganda, you are thinking about the immediate problems facing you and there aren’t huge amounts of basic science and translational medical research. There are initiatives like the Ugandan Academy and Cambridge-Africa that are looking to change this, trying to bring up a generation of basic scientists, but at the moment, that capacity isn’t there.

“If we’re going to think of ways to benefit the widest possible group, we’re going to need to make collaborations with other researchers in other areas. For somebody like me, those cross-university networks are vitally important. That’s the only way we’re going to be able to solve problems for our resource-limited environments.”

Parkes-Ratanshi is now working with Professor Carol Brayne, Director of the Cambridge Institute of Public Health, to look at how evidence generated in a well-resourced part of the world might be linked with that from lower-resource settings. In the spirit of initiatives such as Cambridge-Africa, this isn’t about making assumptions about research priorities and carrying them out on particular populations. “It’s very much about community participation,” she explains, “It’s about going to the communities and asking them ‘What are your priorities around ageing? What are you interested in? What’s concerning you on a daily basis?’ and then co-developing research that’s relevant to them.”

One might assume that when she refers to “lower-resource settings”, she means Africa. Not necessarily. “There’s great inequality even within the UK,” she says. And so, while they have identified sites in Uganda and South Africa, as well as in Bali, they are also looking at areas in the Fenlands around Cambridge, where deprivation levels are high.

And in a sense, this is one of the real benefits of encouraging collaborations between geographically and economically diverse areas of the world: everyone has something to give, everyone has something to learn. “When you’re in a poorly-resourced setting, you generate ideas and innovations that might help in a resource-rich setting as well as your own. And who knows, some of the ideas that come out of this might be helpful in the future as the UK itself becomes more resource-limited.”

Dr Rosalind Parkes-Ratanshi is used to working in resource-poor settings. She spent over a decade on the frontline fighting HIV and AIDS in Uganda. Now in Cambridge, she plans to focus on working in areas of deprivation – in Africa and south east Asia, but also much closer to home.

We used to look at cohorts to try to understand what patients were dying from, but now... they’re no longer dying from infections, but face other issues such as treatment fatigue and stigma

Rosalind Parkes-Ratanshi

Robert F D Gilchrist (Bobbygee1952)

Safe sex billboard, Kabale, Uganda

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