HIV in the US

HIV Infections in the US Could be Reduced By Up to 67 Percent by 2030, Study Finds

HIV Infections in US Could be Reduced By Up to 67 Percent by 2030, Study Finds

New HIV infections in the United States could be substantially reduced by up to 67 percent by 2030 if ambitious goals for HIV care and treatment are met and targeted prevention interventions for people at risk for HIV are rapidly scaled up, according to a study by Georgia State University and the University at Albany-SUNY.

The federal administration recently announced a goal to reduce new HIV infections by 90 percent in the next 10 years during the 2019 State of the Union address. This study shows the goal is unlikely to be achieved, but that it is possible to substantially reduce new HIV infections in the next decade with innovative models for delivering HIV care and prevention interventions and sufficient investments to bring them to scale.

The researchers analyzed the latest HIV surveillance data from the Centers for Disease Control and Prevention (CDC) and estimated how many new HIV infections could be averted through ambitious, but attainable, national HIV prevention goals.

They predict that meeting internationally accepted targets for HIV diagnosis and care by 2025 and preventing an additional 20 percent of transmissions through targeted interventions such as pre-exposure prophylaxis (PrEP) for people with HIV risk would enable the U.S. to reduce new HIV infections by 67 percent in the next decade.

Achieving this goal would require the percentage of people diagnosed with HIV who are receiving care to increase from under 70 percent to 95 percent in six years and 40 percent PrEP coverage among people at risk for HIV, levels that are unprecedented in the U.S. epidemic. The results are published in the journal AIDS and Behavior.

“It is important to set HIV prevention goals that are ambitious, but realistic,” said Dr. Heather Bradley, lead author of the study and assistant professor in the School of Public Health at Georgia State. “We know that treating people living with HIV greatly improves health and also prevents transmission of HIV infection to others. However, treating enough people to meaningfully reduce new HIV infections will require us to confront issues like poverty, unstable housing and mental health conditions that keep people living with HIV from accessing care.”

Progress to reduce HIV infections in the U.S., particularly among key minority and risk groups, has been relatively stagnant, and a new national HIV strategy with achievable targets is critically needed.

“Greatly increasing the number of people living with HIV who are receiving care and treatment combined with targeted prevention strategies for people at risk for HIV infection could result in substantial reductions in new HIV infections in the next decade. Our study estimates how much improvement is possible and can help quantify what it would take to get there,” Bradley said.

 

Source: DDDmag

custom-margin-blog

How immune cells can recognize – and control – HIV when therapy is interrupted

How immune cells can recognise - and control - HIV when therapy is interrupted

New findings reveal how HIV-1-specific immune cells can recognize viral particles that have the capacity to rebound following interruptions to antiretroviral therapy, with implications for new treatment strategies.

Immune cells that can recognise residual HIV-infected cells in people living with HIV (PLWH) who take antiretroviral therapy (ART) remain active for years, says a new study published today in eLife.

The findings also suggest the majority of these immune cells, called CD8+ T cells, should have the capacity to detect the HIV-infected cells that drive HIV-1 rebound following interruptions to treatment. This insight could contribute to the development of new curative strategies against HIV infection.

ART has transformed HIV-1 from a fatal disease to a chronic condition in PLWH. However, it must be taken by those with the infection for the rest of their lives, as interrupting treatment often allows the virus to rebound within weeks. This rebound results from cells harbouring HIV-1 DNA that is integrated into the human genome.

“While more than 95% of proviral DNA is unable to replicate and reactivate HIV-1, the remaining fraction that we define in our study as the ‘HIV-1 reservoir’ maintains its ability to produce infectious virus particles and cause viral rebound,” explains lead author Joanna Warren, Postdoctoral Investigator at the Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, US. “The largest and most well-characterised HIV-1 reservoir resides in ‘resting’ CD4+ T cells, which circulate in the blood and are long-lived.”

There are a couple of strategies to allow people with HIV-1 to stop ART without viral rebound. Both approaches may harness HIV-1-specific CD8+ T cells to achieve the reduction or elimination of the HIV-1 reservoir. However, variations (or mutations) in viral particles that exist in the HIV-1 reservoir may limit the capacity of these T cells to recognise and clear virus-infected cells, meaning the cells can escape detection and go on to cause viral rebound. “In our study, we wanted to determine the frequency and patterns of T-cell escape mutations in the HIV-1 reservoir of people who are on ART,” Warren says.

To do this, the team measured HIV-1-specific T-cell responses and isolated reservoir virus in 25 PLWH who are on ART. Of these participants, four started on ART during acute HIV-1 infection, which means virus levels were controlled early, while the other 21 started on ART during chronic HIV-1 infection, which means considerable virus mutation occurred before virus levels were controlled.

In the HIV-1 proteome (the entire set of proteins expressed by the virus) for each participant, the team identified T-cell epitopes (regions of proteins that trigger an immune response). They sequenced HIV-1 ‘outgrowth’ viruses from resting CD4+ T cells and tested mutations in T-cell epitopes for their effect on the size of the T-cell response. These strategies revealed that the majority (68%) of T-cell epitopes did not harbour any detectable escape mutations, meaning they could be recognised by circulating T cells.

“Our findings show that the majority of HIV-1-specific T cells in people on ART can detect HIV viruses that have the capacity to rebound following treatment interruption,” concludes senior author Nilu Goonetilleke, a faculty member at the Department of Microbiology and Immunology, University of North Carolina at Chapel Hill. “This suggests that T cells likely help to control viral rebound and could be leveraged in future treatment strategies against HIV.”

 

Source:  Eurekalert.org

HIV Positive

Being HIV positive and staying on antiretroviral therapy in Africa: A qualitative systematic review and theoretical model

Being HIV positive and staying on antiretroviral therapy in Africa: A qualitative systematic review and theoretical model

Abstract

Background

Adherence to antiretroviral therapy (ART) and long-term uninterrupted engagement in HIV care is difficult for HIV-positive people, and randomized trials of specific techniques to promote adherence often show small or negligible effects. Understanding what influences decision-making in HIV-positive people in Africa may help researchers and policy makers in the development of broader, more effective interventions and policies.

Methods

We used thematic synthesis and a grounded theory approach to generate a detailed narrative and theoretical model reflecting life with HIV in Africa, and how this influences ART adherence and engagement decisions. We included qualitative primary studies that explored perspectives, perceptions and experiences of HIV-positive people, caregivers and healthcare service providers. We searched databases from 1 January 2013 to 9 December 2016, screened all studies, and selected those for inclusion using purposeful sampling methods. Included studies were coded with Atlas.ti, and we assessed methodological quality across five domains.

Results

We included 59 studies from Africa in the synthesis. Nine themes emerged which we grouped under three main headings. First, people who are HIV-positive live in a complicated world where they must navigate the challenges presented by poverty, competing priorities, unpredictable life events, social identity, gender norms, stigma, and medical pluralism—these influences can make initiating and maintaining ART difficult. Second, the health system is generally seen as punishing and uninviting and this can drive HIV-positive people out of care. Third, long-term engagement and adherence requires adaptation and incorporation of ART into daily life, a process which is facilitated by: inherent self-efficacy, social responsibilities, previous HIV-related illnesses and emotional, practical or financial support. These factors together can lead to a “tipping point”, a point in time when patients choose to either engage or disengage from care. HIV-positive people may cycle in and out of these care states in response to fluctuations in influences over time.

Conclusion

This analysis provides a practical theory, arising from thematic synthesis of research, to help understand the dynamics of adherence to ART and engagement in HIV care. This can contribute to the design of service delivery approaches, and informed thinking and action on the part of policy makers, providers, and society: to understand what it is to be HIV-positive in Africa and how attitudes and the health service need to shift to help those with HIV lead ‘normal’ lives

HIV-Antibiotic

Antibiotic molecule enables the immune system to kill HIV infected cells

Antibiotic molecule enables immune system to kill HIV infected cells

Researchers have discovered an unexpected potential weapon against HIV protein

Ever since the first cases of a mysterious disease in the early 1980s exploded into the HIV/AIDS pandemic, researchers have been searching for ways to outsmart the deadly virus. Now thanks to anti-retroviral therapy, people living with HIV can live relatively normal lifespans–as long as they take their medications every day.

“If they ever stop, in short order the virus rebounds and resets at the high levels seen before starting– and that seems to be the case even after decades of therapy,” says Mark Painter, Ph.D., a graduate student in the University of Michigan Medical School’s department of microbiology and immunology.

The reason is that HIV can hide inside the human genome, lying dormant and ready to emerge at any time. Because of this, a true cure for HIV relies on waking the latent virus and eliminating it before it has a chance to again take hold of the body’s cells, an approach known as shock and kill.

Working with a team under the direction of Kathleen Collins, M.D., Ph.D., they set out to find a weapon to kill HIV by targeting a protein called Nef. In 1998, Collins, who is a professor of internal medicine and microbiology and immunology, discovered that HIV uses Nef to evade the body’s immune system by overriding the functioning of a protein on a cell’s surface that lets immune cells know that the cell is infected and in need of elimination. By disabling this protein, called MHC-I, infected cells are able to proliferate.

The research tried determine if there was an FDA-approved drug or molecule already on the market that could override Nef, restore the functioning of MHC-I and allow the body’s own immune system, specifically cells known as cytotoxic T lymphocytes, to recognize the HIV-infected cells and destroy them.

“We started out screening a library of 200,000 small molecules and found none inhibited Nef,” says Painter. Undeterred, they approached David Sherman, Ph.D. of the U-M Life Sciences Institute, whose lab studies the biosynthesis of natural products from microbes, such as cyanobacteria.

“Often synthetic molecules have quite a low molecular weight, meaning they are fairly small. And if you need to disrupt a large protein surface or interface, such as with Nef, a small molecule won’t work well or at all,” explains Sherman. “A natural products library like the one at the LSI, on the other hand, is going to have molecules with a large range of weights and sizes.”

After screening approximately 30,000 molecules, they discovered that a class of antibiotic molecules called pleicomacrolides inhibited Nef.

“Pleicomacrolides are widely used in lab experiments when you want to shut down the lysosome. Because of this, they are considered toxic and risky to use as drugs,” says Painter. The lysosome is an essential cell organelle used to break down worn out cell parts, viruses and bacteria.

However, the team determined that a pleicomacrolide called concanamycin A inhibits Nef at much lower concentrations than those needed to inhibit the lysosome. “As a lead compound for drug development, it’s fairly exciting because we can use a very low dose, and inhibit Nef without short-term toxicity to the cells,” said Painter.

In a proof of concept experiment, they treated HIV-infected, Nef expressing cells with concanamycin A and found that cytotoxic T cells were able to clear the infected T cells.

“It’s been extremely gratifying for this project, which began in my lab over a decade ago to finally come to fruition. I had hoped we would find something that worked as well as this compound does but it was never a guarantee that we would actually be successful. This type of research is risky but extremely important because of the potential reward,” says Collins. But, she adds, the molecule is not yet ready to be used as a drug for treatment of HIV infected people. “More research will be needed to optimize the compound. We will need to further separate the potent Nef inhibitory activity from the more toxic effect on lysosomal function to make it a viable therapy.”

Collins, Painter and their colleagues are continuing work on refining the chemistry of concanamycin A to make it even more viable as a potential therapy. When combined with ART and future treatments that shock latent HIV awake, Painter notes the therapy could be used to clear any remaining virus, essentially curing HIV.

 

Source: Eurekalert.org

Merck

Merck inks $2.8B VelosBio buyout to snag anti-ROR1 ADC

Merck inks $2.8B VelosBio buyout to snag anti-ROR1 ADC

Merck has struck a deal to buy VelosBio for $2.75 billion. The takeover will give Merck control of an antibody-drug conjugate (ADC) that caused complete responses in 80% of previously treated diffuse large B-cell lymphoma (DLBCL) patients in a small clinical trial.

 

VelosBio’s ADC, VLS-101, targets ROR1, a tyrosine-protein kinase transmembrane receptor thought to be overexpressed in multiple cancers. The target has attracted a small clutch of companies, including Bristol Myers Squibb’s Juno Therapeutics, but there are limited clinical data to show it works as hoped.

Merck has swooped in to buy VelosBio in the run up to the presentation of data that will start the process of validating the target. At the American Society of Hematology’s annual meeting next month, VelosBio will share data from a phase 1 trial that gave VLS-101 to previously treated hematological cancer patients. 

Seven of the 15 mantle cell lymphoma patients had complete responses after treatment with the ADC. Four of the five patients in the DLBCL cohort had complete responses. Complete response rates of 47% and 80% in the two patient populations were good enough to persuade Merck to write a check for VelosBio.

The deal cements ADC’s status as a hot modality. This year, AstraZeneca and Merck have entered into deals worth $1 billion or more upfront to access ADCs in development at Daiichi Sankyo and Seagen, respectively. Gilead blew those figures away by striking a $21 billion deal to buy Immunomedics for its anti-Trop-2 ADC Trodelvy.

Merck and its peers have bought into the space after a series of clinical trial readouts and approvals have suggested the problems that made ADCs a minor modality have been overcome. While the FDA approved the first ADC in 2000, it is only in recent years that the modality has consistently delivered eye-catching data.

VelosBio became the latest biotech to deliver eye-catching data by targeting ROR1. Other groups are going after the same target. Juno has a ROR1-directed CAR-T therapy in phase 1 development. NBE Therapeutics recently began a first-in-human trial of its anti-ROR1 ADC. Oncternal Therapeutics has an anti-ROR1 monoclonal antibody in the clinic. Kancera is developing a small molecule inhibitor of ROR1 in the belief it can reprogram cancer cells to destroy themselves.

The Merck deal raises the profile of the target. VelosBio has tied its future to ROR1, advancing the ADC at the head of a pipeline of other drugs against the target including bispecific antibodies. The next step is to test VLS-101 in patients with solid tumors including triple-negative breast cancer and non-small cell lung cancer in a phase 2 trial that began last month.

VelosBio began the phase 2 using the proceeds of a $137 million series B round it closed in July. The round attracted an investor syndicate that appeared to tee VelosBio up for a future on Nasdaq, but then Merck intervened. 

 

Source: fiercebiotech

1_pea

Wrinkled ‘super pea’ could be added to foods to reduce diabetes risk

Wrinkled 'super pea' could be added to foods to reduce diabetes risk

A type of wrinkled ‘super pea’ may help control blood sugar levels and could reduce the risk of type 2 diabetes, suggests a new study.

The research, from scientists at Imperial College London, the John Innes Centre, Quadram Institute Bioscience and University of Glasgow, suggests incorporating the peas into foods, in the form of whole pea seeds or flour, may help tackle the global type 2 diabetes epidemic.

The work, published in the journal Nature Food and funded by the BBSRC, focused on a naturally occurring type of pea. Unlike regular (smooth) peas, they contain higher amounts of ‘resistant starch’, which takes longer for the body to break down.

The study reveals that compared to eating smooth peas, wrinkled peas prevented ‘sugar spikes’—where blood sugar levels rise sharply after a meal. The same effect was seen when consuming flour made from wrinkled peas incorporated in a mixed meal.

According to the researchers, this could be important as frequent, large sugar spikes are thought to increase the risk of diabetes. They add that flour from their ‘super peas’ could potentially be used in commonly consumed processed foods which, if eaten over the long term, could prevent these sugar spikes.

Dr. Katerina Petropoulou, first author of the research from the Centre for Translational and Nutrition Food Research at Imperial College London, said: “Despite national campaigns to promote healthy eating, type 2 diabetes diagnosis rates continue to rise. An alternative dietary strategy to maintain normal blood glucose rates among the population is to improve the composition of commonly consumed foods. There is much evidence that diets rich in a type of carbohydrate called resistant starch have a positive impact on controlling blood glucose levels, and hence reduce susceptibility to type 2 diabetes.”

The peas used in the research are similar to the frozen peas you can buy in the supermarket. They are also the same as those used by the famous scientist Gregor Mendel in the 1800s, to show how dominant and recessive genetic traits can be passed on through selective breeding.

However, in these latest experiments, researchers used larger, mature versions of those typically found in the freezer aisle. This is because larger, mature peas contain more so-called ‘resistant starch’. The high amount of resistant starch is due to the way the starch is made in the cell, and the fact that the cells themselves are more resistant to digestion.

 

Starch is a compound that the body breaks down to release sugar, but resistant starch is broken down more slowly, so that sugar is released more slowly into the blood stream, resulting in a more stable increase rather than in a spike.

In the latest study, the researchers used a type of ‘super pea’ – wrinkled peas with a naturally occurring genetic mutation, or variant, that produces a greater amount of resistant starch, but a lower overall carbohydrate content.

Over a series of experiments, the team gave healthy volunteers a mixed meal including 50 grams of wrinkled peas, and in a series of control experiments gave them regular ‘smooth’ peas. Working with the University of Glasgow, researchers also added a tracer molecule to the peas, so that they could trace how they were absorbed and digested by the human gastrointestinal tract.

They repeated the experiments using flour made from wrinkled peas or control peas. To further investigate the impact of long-term consumption they recruited 25 volunteers and asked them to consume pea hummus and mushy peas (made from wrinkled or control peas) for a period of 4 weeks.

Professor Gary Frost, lead author of the study and head of Imperial’s Centre for Translational and Nutrition Food Research, said: “The ‘super pea’ contains a naturally-occurring variant gene that means they are high in resistant starches. These starches are not completely digested in the upper parts of the digestive tract and are available for fermentation by bacteria in the colon.”

Previous research from the same group has suggested that, as these bacteria ferment the starch, they produce compounds called short chain fatty acids. These compounds in turn help boost the function of cells that produce insulin, which helps control blood sugar.

Further tests using a mimic of the human gut, carried out by researchers at Quadram Institute Bioscience, showed that the way that the peas were prepared and cooked affected how quickly they were digested. Researchers also showed that there were significant benefits to our gut microbiota because of the fermentation process taking place there.

Professor Pete Wilde of the Quadram Institute said: “This study has shown us that by preparing these peas in certain ways we can further reduce blood sugar spikes, opening up new possibilities for making healthier foods using controlled food processing techniques.”

The researchers are now planning further trials involving volunteers with early stage type 2 diabetes. This will also involve a major pea breeding programme with help from industry partners to develop more ‘super peas’ with the resistant starch. They will also explore the genetic background of commonly consumed pulses (beans) to see if similar genetic variation in other crops shows the same positive effects on health.

Professor Claire Domoney of the John Innes Centre in Norfolk said: “This research has emphasized the value of developing the pea lines used in this study, which could be compared meaningfully and involved many years of breeding. It also demonstrates how plant genetics can be used effectively across many disciplines to study the impact of food on human health.”

The study authors point out that it is not only peas which have the resistant starch mutation. Other research is focusing on breeding the mutation into staple crops, such as rice and wheat. With modern genomic tools there is the potential for discovery or generation of the mutation across a range of seed and grain crops—which make up many of the carbohydrate-rich foods we consume.

Professor Domoney added: “Longer term it could become policy to include resistant starch in food. We have precedents for this kind of intervention, such as iron being added to bread to tackle anemia. It could potentially be a policy that food should contain a certain amount of resistant starch to tackle type 2 diabetes and other metabolic illnesses.”

Professor Melanie Welham, BBSRC’s Executive Chair, said “By investing in plant research, such as this collaboration between Imperial College, the Quadram Institute and the John Innes Centre, new solutions that help address the health problems affecting many people across the country are being developed. Long term benefits come from long term investments that equip our research base to tackle new and emerging challenges.”

 

Source:Phys.org

stem-cells

Exposure to small molecule cocktails allows induction of neural crest lineage cells from human adipose-derived mesenchymal stem cells

Exposure to small molecule cocktails allows induction of neural crest lineage cells from human adipose-derived mesenchymal stem cells

Abstract 

Neural crest cells (NCCs) are a promising source for cell therapy and regenerative medicine owing to their multipotency, self-renewability, and capability to secrete various trophic factors. However, isolating NCCs from adult organs is challenging, because NCCs are broadly distributed throughout the body. Hence, we attempted to directly induce NCCs from human adipose-derived mesenchymal stem cells (ADSCs), which can be isolated easily, using small molecule cocktails. We established a controlled induction protocol with two-step application of small molecule cocktails for 6 days. The induction efficiency was evaluated based on mRNA and protein expression of neural crest markers, such as nerve growth factor receptor (NGFR) and sex-determining region Y-box 10 (SOX10). We also found that various trophic factors were significantly upregulated following treatment with the small molecule cocktails. Therefore, we performed global profiling of cell surface makers and identified distinctly upregulated markers, including the neural crest-specific cell surface markers CD271 and CD57. These results indicate that our chemical treatment can direct human ADSCs to developing into the neural crest lineage. This offers a promising experimental platform to study human NCCs for applications in cell therapy and regenerative medicine.

Source: Journal Plos

diabetes

November is Diabetes Awareness Month!

November is Diabetes Awareness Month!

Diabetes is a condition that affects how the body uses blood sugar (glucose). About 34 million Americans suffer from diabetes, and roughly 7 million of those cases go undiagnosed. There are two types of diabetes: Type 1 and Type 2. 

Type 1 diabetes can develop at any age, and a combination of genes and environmental factors are thought to be the cause. Meanwhile, Type 2 diabetes occurs at a later stage in life and generally appears after prediabetes. In Type 2 diabetes, genes and environmental factors play a role, but being overweight can also present an issue. November is Diabetes Awareness Month, and it provides an opportunity to spread more information on this condition: 

  • 1 in 5 Americans do not know they have diabetes 
  • Diabetes is the 7th leading cause of death in the US 
  • Type 2 diabetes accounts for approximately 90% to 95% of all diagnosed cases 
  • Exercise and weight loss reduces the risk of prediabetes becoming Type 2 diabetes 

  • 25% of adults over 65 have diabetes 
 
Source:  nih.gov

Interaction between central obesity and frailty on the clinical outcome of peritoneal dialysis patients

Interaction between central obesity and frailty on the clinical outcome of peritoneal dialysis patients

Background

Frailty is described by Fried et al. [1] as a clinical syndrome involving at least three of the following features: unintentional weight loss (10 lbs in one year), self-reported exhaustion, weakness (as determined by grip strength), slow walking speed, and low physical activity. It is highly prevalent among patients on dialysis, with a prevalence of up to 67.7% in previous report [2].

Physical frailty has important health consequences. Frail patients are more susceptible to the development of adverse outcomes when faced with a stressor. It also leads to a decline in physical function, gait disability, increase in the risks of fall. As a result, frail peritoneal dialysis (PD) patients have a higher hospitalization risk and their hospital stay tends to be prolonged [3]. Physical frailty is also a well-established independent predictor of adverse outcomes including mortality in pre-dialysis end stage renal disease patients [4], hemodialysis (HD) patients and PD patients [35].

Physical frailty causes alteration in body composition. Frail patients tend to suffer from obesity [69]. On the other hand, PD patients are more susceptible to central obesity [10] due to exposure to glucose-containing dialysate fluid. In contrast to general obesity, central obesity confers a worse survival in dialysis patients [11]. Previous study has shown synergistic effect on mortality between physical frailty and central obesity in HD patients. However, the interaction between physical frailty and body composition has not been explored.

 

Source: Journal Plos

Breast Cancer

Breast Cancer Awareness Month 

This month we are focusing on Breast Cancer Awareness Month and giving a voice to survivors and advocates. This October we are featuring breast cancer advocates on The Monthly Dose to learn more about their experiences and their road to advocacy. We want to give a voice to survivors and raise awareness of this condition that affects more than 200,000 women per year in the US. Here are some facts on breast cancer:

  • 1 in 8 women in the United States will develop breast cancer in her lifetime
  • 64% of breast cancer cases are diagnosed at a localized stage
  • Men can also develop breast cancer although it is extremely rare about 15% of US cases
  • For women in the U.S., breast cancer death rates are higher than those for any other cancer, besides lung cancer
  • A woman’s risk of breast cancer nearly doubles if she has a first-degree relative (mother, sister, daughter) who has been diagnosed with breast cancer. Less than 15% of women who get breast cancer have a family member diagnosed with it

Source: Cancer Org