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Smoking HIV out of dormancy

Little bits of virus can lie dormant in immune cells for years, so that if patients stop taking the drugs, the dormant virus can come out of hiding and re-infect the patient.

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Ever since antiretroviral treatments against HIV infection were introduced in 1996, scientists have eagerly been hunting for a cure for the disease.

Although drugs can allow people infected with HIV to live normal, healthy lives, people infected by HIV have to take antiretroviral treatments for as long as they live. Little bits of virus can lie dormant in immune cells for years, so that if patients stop taking the drugs, the dormant virus can come out of hiding and re-infect the patient.

And now, as the first people to start taking this treatment are entering middle or old age, doctors are seeing side effects from inflammation that are caused by having even tiny amounts of HIV in your blood. That’s yet another reason for developing a cure for the disease.

Now, researchers from the Norwegian University of Science and Technology’s (NTNU) Centre of Molecular Inflammation Research (CEMIR) have uncovered a previously unknown way in which the body’s immune system can detect and respond to HIV infection — which could help improve the chances of developing a cure.

Their results have been published in Nature Communications.

To understand exactly what the researchers did requires a refresher course in how HIV actually works inside the body and how the body responds.

When the virus gets into the body, it infects the very cells that the body would use to combat it — these are called CD4 T helper cells, or CD4 T cells.

Once the T cells are infected, they can’t do their part in helping protect the body from other diseases or infections. That’s why the illness that people get from HIV infection is called Acquired Immune Deficiency Syndrome, or AIDS.

Someone with full-blown AIDS would have almost no T cells, and they could die of any number of different infections or diseases that wouldn’t normally afflict someone with a healthy immune system.

“Today we have treatments that can stop HIV from replicating itself, and the T helper cells can come back,” said Hany Zakaria Meås, a postdoc at CEMIR and a co-first author of the article. “You can live a perfectly healthy life, but you have to take medicine your whole life, because the day you stop treating it, the virus will come back.”

The virus comes back if antiretroviral therapy is stopped because HIV hides its genetic material inside T cells that are dormant. That means there’s always the potential for more virus to appear and wreak havoc.

These reservoirs of virus have spurred a worldwide hunt for ways to shock, or kick the virus out of the cells where it lies dormant.

If the virus that lies dormant in cells could be smoked out into the open, the formally dormant virus could then be killed by the body’s immune system or drugs, and that would leave the patient HIV free, and cured, Meås said.

“We need to activate the virus so it can start replicating, and that will make the cell visible to the immune system,” he said. “That is the current idea for a cure. We just need to activate cells that are hiding away so we can kill them, while we give medicine that protects cells from infection, because there will be more virus produced.”

One such clinical trial in the UK, called the RIVER study, tried this approach but reported last year that the trial did not succeed, he said.

HIV comes in different varieties, and not all varieties are equally able to infect all T helper cells. To infect a cell, the virus has to have to have a specific ligand, which functions like a key, that has to match up on the target cell with the right kind of receptor, or keyhole.

When a T helper cell doesn’t have the receptor that matches the ligand on the HIV virus trying to infect the cell, that means the virus can’t actively infect that T cell. Instead, the virus can get trapped in a vesicle in the cell called an endosome.

The CEMIR researchers decided to look at what happened with uninfected T helper cells that had trapped HIV in endosomes. The uninfected cell responds to the HIV in the endosome by destroying the contents of the endosome, Meås said.

In the past, researchers have believed that this particular pathway — HIV being trapped in an endosome of a T helper cell, and the T helper cell destroying the contents of the endosome — was a kind of dead end for HIV infection. After all, the T helper cell hadn’t actually been infected, and the endosome destroyed the virus.

But now CEMIR researchers have found a previously undescribed immune response that results from HIV destruction in the endosome. This response may hold the key to allowing the shock-and-kill approach to work.

What the researchers found was when the endosome destroys the HIV, some of the genetic material is exposed to the T cell, which in turn activates a type of molecule called TLR8. This in turn results in the production of substances called cytokines, which cause inflammation in the body.

One reason this is surprising is that T cells are part of our immune system called the “adaptive” immune system, which responds to specific infectious substances over time.

Our immune system also has an “innate” part, which we are born with, and which provides more general immune protection by recognizing and responding to bits of viruses or bacteria that are common across many different viruses or bacteria.

TLR8 is a part of the body’s innate immune system. T cells are part of the adaptive immune system. Generally, it has been thought that these two systems were separate, independent branches.

“In this study we show that a receptor associated with the innate system actually exists and functions in the adaptive immune system,” Meås said.

The inflammation caused by the cytokines helps to wake up T cells that had formally been dormant and that contain HIV genetic material, said Markus Haug, a staff scientist at CEMIR and co-first author of the study.

“The T cell detects the virus and produces cytokines, and these cytokines act on cells that are properly infected with HIV and makes them produce more virus. The dormant T helper cells produce virus, and the T cells that were actively producing virus will produce more of it,” Haug said.

In other words, the TLR8 signal and cytokine-induced inflammation shock the HIV out of the dormant cells — where it can be destroyed.

The destruction of HIV by endosomes and the associated inflammation may also be one reason why patients who have been on antiretroviral treatments for decades are now beginning to develop inflammatory diseases more commonly associated with people decades older.

These include dementia, cardiovascular diseases, metabolic syndrome and cancers that aren’t related to HIV.

Meås said that the mechanism where endosomes destroy HIV might release enough genetic material to trigger the T cell’s innate immune receptors to cause inflammation.

Beyond that, however, the findings do offer hope, said Jan Kristian Damås, a chief attending physician at the Department of Infectious Diseases, St. Olav’s Hospital, Trondheim University Hospital and an NTNU professor associated with CEMIR. Damås works with HIV patients and recruited the nine patients whose cells were used as part of the research. He is also an author on the paper.

“Today we have very efficient drugs for suppressing HIV. However, we are not able to eradicate the virus and just weeks after patients stop medication the virus will reappear from virus reservoirs. Researchers and scientists believe that we can find a cure for HIV if we are able to eradicate these reservoirs,” Damås said.

“The breakthrough paper by Meås and Haug brings novel insight in mechanisms for reversal of HIV latency, and their findings of TLR8 as an important receptor for HIV in T cells, clearly represent a potential novel therapeutic target for treating HIV. Moreover, their findings may also represent major step forward in vaccine development as TLR8 ligands could be used as vaccine adjuvants that shape the type of T cell responses that is induced by the vaccine.”

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New cause of inflammation in people with HIV identified

While current antiretroviral treatments for HIV are highly effective, data has shown that people living with HIV appear to experience accelerated aging and have shorter lifespans – by up to five to 10 years – compared to people without HIV. These outcomes have been associated with chronic inflammation, which could lead to the earlier onset of age-associated diseases.

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While current antiretroviral treatments for HIV are highly effective, data has shown that people living with HIV appear to experience accelerated aging and have shorter lifespans – by up to five to 10 years – compared to people without HIV. These outcomes have been associated with chronic inflammation, which could lead to the earlier onset of age-associated diseases, such as atherosclerosis, cancers, or neurocognitive decline.

A new study led by researchers at Boston Medical Center examined what factors could be contributing to this inflammation, and they identified the inability to control HIV RNA production from existing HIV DNA as a potential key driver of inflammation. Published in The Journal of Infectious Diseases, the results underscore the need to develop new treatments targeting the persistent inflammation in people living with HIV in order to improve outcomes.

After infection, HIV becomes a part of an infected person’s DNA forever, and in most cases, infected cells are silent and do not replicate the virus. Occasionally, however, RNA is produced from this HIV DNA, which is a first step towards virus replication. Antiretroviral treatments help prevent HIV and AIDS-related complications, but they do not prevent the chronic inflammation that is common among people with HIV and is associated with mortality.

“Our study set out to identify a possible association between HIV latently infected cells with chronic inflammation in people with HIV who have suppressed viral loads,” said Nina Lin, MD, a physician scientist at Boston Medical Center (BMC) and Boston University School of Medicine (BUSM).

For this study, researchers had a cohort of 57 individuals with HIV who were treated with antiretroviral therapy. They compared inflammation in the blood and various virus measurements among younger (age less than 35 years) and older (age greater than 50 years) people living with HIV.

They also compared the ability of the inflammation present in the blood to activate HIV production from the silent cells with the HIV genome. Their results suggest that an inability to control HIV RNA production even with antiretroviral drugs correlates with inflammation.

Antiretroviral treatments help prevent HIV and AIDS-related complications, but they do not prevent the chronic inflammation that is common among people with HIV and is associated with mortality.

“Our findings suggest that novel treatments are needed to target the inflammation persistent in people living with HIV,” said Manish Sagar, MD, an infectious diseases physician and researcher at BMC and the study’s corresponding author. “Current antiretroviral drugs prevent new infection, but they do not prevent HIV RNA production, which our results point as a potential key factor driving inflammation in people living with HIV.”

According to the Centers for Disease Control and Prevention, it is estimated that 1.2 million Americans are living with HIV; however, approximately 14 percent of these individuals are not aware that they are infected.

Another CDC reporter found that of those diagnosed and undiagnosed with HIV in 2018, 76 percent had received some form of HIV care; 58 percent were retained in care; and 65 percent had undetectable or suppressed HIV viral loads. Antiretroviral therapy prevents HIV progression and puts the risk of transmission almost to zero.

The authors note that these results need to be replicated in larger cohorts. “We hope that our study results will serve as a springboard for examining drugs that stop HIV RNA production as a way to reduce inflammation,” added Sagar, also an associate professor of medicine and microbiology at BUSM.

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Global HIV response is neglecting gay and bi men, and trans women – study

To date, gay and bisexual men account for about one in five new HIV infections. However, they were only allocated approximately 2% of the $57 billion in global donor funding to treat the virus and combat its spread between 2016 and 2018.

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Funding to fight HIV among gay and bisexual men, as well as transgender women is just a fraction of what it should be. This is according to researchers from Dutch HIV charity Aidsfonds.

To date, gay and bisexual men account for about one in five new HIV infections. However, they were only allocated approximately 2% of the $57 billion in global donor funding to treat the virus and combat its spread between 2016 and 2018.

Meanwhile, while trans people represented about 1% of new global HIV infections in 2018, programs targeting them received only 0.06% of the total funding.

The Aidsfonds report stated that globally, the total number of new HIV infections hasn’t declined for several years, stagnating at 1.7 million in 2018. This is above the global target of 500,000 per year by 2020, and can even be a reflection of a worsening picture for key populations.

Between 2016 and 2018, the total combined resources for the HIV response was approximately $57.3 billion. In the same period, the total funding of HIV programs for key populations is estimated at around US$1.3 billion.

This means that “programs targeting key populations received only 2% of all HIV funding, even though key populations accounted for over half of all new infections in 2018.”

In 2016, UNAIDS estimated that $6.3 billion was needed for the delivery of comprehensive service packages for key populations between 2016 and 2018. Another $551 million was required for the distribution of pre-exposure prophylaxis (PrEP) to these communities, making a total of $6.8 billion needed.

And so “there was a staggering gap of 80% between the budget required for HIV programs targeting key populations ($6.8 billion) and the amount made available ($1.3 billion),” Aidsfonds stated.

To end the AIDS epidemic by 2030, Aidsfonds’ recommendations included:

  1. Increase of funders’ investments towards the $36.49 billion
    needed for HIV programming for key populations, over the next decade.
  2. Scale up the proportion of funding focused on community-led and community-based interventions.
  3. Increase the proportion of funding for advocacy and support to key populations to create enabling environments.
  4. Undertake concerted and coordinated efforts to systematically disaggregate, track and make public, funding allocation and spending for key population HIV programming.
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Stereotypes and discrimination contribute to HIV-related stigma among nursing staff

Faculty attitudes about caring for PLHIV can impact student attitudes and the care they provide.

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In December 2012, Xander (not his real name) was tested HIV-positive. And he recalled that during one of his visits to his treatment hub in Metro Manila, “there was this one nurse who told me: ‘Now you’re HIV-positive; stop having sex and stop increasing your numbers’,” he said, adding that it was never clear to him “how to react when healthcare providers themselves stigmatize and discriminate.”

But HIV-related stigma and discrimination among healthcare providers – e.g. nurses – has been studied before, even if, according to Dr. Juan Leyva (Universitat Autonoma de Barcelona), Dr. Patrick Palmieri (Universidad Norbert Wiener and A.T. Still University), and Dr. Joan Edwards (Texas Woman’s University), this issue has not been frequently re-visited.

This is why they looked at this issue again; though this time, focusing on nursing faculty and students, believing that teaching about HIV-related stigma and discrimination may actually start in nursing schools. Particularly, they did a cross-sectional study of nursing faculty in six countries that appeared in The Open AIDS Journal.

According to them, “since the earliest study about nursing faculty and students attitudes and beliefs about caring for people living with HIV/AIDS (PLHIV) in the early 1990’s, there have only been 17 additional studies.” And so “knowledge in this area of study is still lacking to fill some gaps in understanding attitudes towards people living with the disease.”

The researchers sought to understand HIV-related attitudes of nursing faculty in three continents from six countries (Canada, Colombia, England, Peru, Spain, and the US) and how it correlates to three dimensions of prejudice, stereotypes and discrimination.

The researchers found that HIV-related stigma about caring for PLHIV are slightly positive with notable differences between countries. Apart from Peru, and to a lesser extent neighboring Colombia, the results are consistent with other findings from a few smaller studies. The results can be explained, among other reasons, by the high HIV-related stigma in South America and the pervasive discrimination experienced by the LGBTQ community. Although myths and knowledge deficits about HIV/AIDS remain problematic, the results appear to be influenced by nationality in terms of prejudices, stereotypes, and discrimination.

Faculty attitudes about caring for PLHIV can impact student attitudes and the care they provide. According to Dr. Palmieri, “nursing faculty attitudes can become part of an informal curriculum where implicit learning is impregnated with personal values.”

The researchers note that in terms of HIV/AIDS education, faculty might not be comfortable teaching what they do not understand. The researchers conclude that theory-derived, evidence-informed interventions need to be developed to advance the knowledge and attitudes of nursing faculty about caring for people living with HIV. The researchers plan to attempt to address negative attitudes with a stigma-reduction intervention based on the information from similar studies.

For the likes of Xander, “healthcare providers need to be more sensitive to the plight of PLHIV. Otherwise, they become part of the problem, not the solution.”

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HIV-1-specific immune cells can recognize viral particles with capacity to rebound following ART interruptions

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.

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Immune cells that can recognize residual HIV-infected cells in people living with HIV (PLWH) who take antiretroviral therapy (ART) remain active for years, says a study published 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-characterized HIV-1 reservoir resides in ‘resting’ CD4+ T cells, which circulate in the blood and are long-lived.”

T cells likely help to control viral rebound and could be leveraged in future treatment strategies against HIV.

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 harbor any detectable escape mutations, meaning they could be recognized 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.”

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Study links low immunity to poor outcomes in patients with HIV who contract COVID-19

“When we have vaccines, our goal is to identify the most vulnerable populations. Patients with HIV should be a priority target when we are looking at any measure that could improve outcomes for patients at high risk for complications with COVID-19.”

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Clinical trials are testing whether medications that treat human immunodeficiency virus (HIV) can also treat COVID-19, leading some patients with HIV to believe they might be protected against the coronavirus. But a researcher from the MU School of Medicine not only found patients with HIV are susceptible to the virus, she also discovered which factors increased the risk of hospitalization and death.

Principal investigator Dima Dandachi, MD, assistant professor of clinical medicine, examined data that included 286 adult patients with HIV who were diagnosed with COVID-19 across 36 institutions in 21 states. Within 30 days of COVID-19 diagnosis, 57% of the patients required hospitalization, 16% required ICU admission and 9% did not survive. In the study, more than 94% of patients were actively taking HIV medication.

“We were able to show that patients with HIV who are actively taking their medication are just as susceptible to COVID-19 as the general public,” Dandachi said. “And those with low immunity uncontrolled HIV or newly diagnosed HIV are at a higher risk of hospitalization or death. The key message for these patients is to take precautions against contracting the virus while ensuring they are compliant with their HIV medications to raise their immune cell count as high as possible.”

Dandachi and her team of researchers found people with HIV older than 60 and those with chronic health issues also had a much higher risk of being hospitalized or dying from COVID-19.

“The medications that prolong the lives of patients with HIV have improved life expectancy, but now we are seeing these patients develop other chronic conditions such as obesity, diabetes and heart disease that we didn’t see 15 years ago,” Dandachi said. “And when we looked at the data from this study, we found that lung disease, kidney disease, hypertension and older age were associated with higher hospitalization rates, higher ICU admissions and increased mortality from COVID-19.”

As a researcher-clinician who treats patients with HIV, Dandachi will use this study to counsel her patients to best protect themselves against COVID-19 while also using it as proof that this patient population should be among the first considered for protection once a vaccine is developed.

“When we have vaccines, our goal is to identify the most vulnerable populations,” Dandachi said. “Patients with HIV should be a priority target when we are looking at any measure that could improve outcomes for patients at high risk for complications with COVID-19.”

Dandachi’s study, “Characteristics, Comorbidities, and Outcomes in a Multicenter Registry of Patients with HIV and Coronavirus Disease-19,” also featured contributions from Mojgan Golzy, PhD, an assistant research professor in the Department of Health Management and Informatics; and MU School of Medicine students Grant Geiger and Maraya Camazine. It was published by the journal Clinical Infectious Diseases.

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Study supports WHO recommendation to use dolutegravir as first-line HIV treatment; efavirenz an alternative option

A study supports the current recommendation from the World Health Organization to use dolutegravir as first-line treatment for HIV, with efavirenz as an alternative option. However, the study also suggests that dolutegravir should be combined with TDF/FTC, which is associated with suppression of weight gain.

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A study supports the current recommendation from the World Health Organization to use dolutegravir as first-line treatment for HIV, with efavirenz as an alternative option. However, the study also suggests that dolutegravir should be combined with TDF/FTC, which is associated with suppression of weight gain, and not with the newer combination of TAF/FTC, which is associated with excess weight gain and clinical obesity, especially in women.

For the ADVANCE research study, conducted in central Johannesburg in South Africa, over 1,000 participants were recruited from routine HIV services in and around the inner city area of Hillbrow. Data was cross-analyzed with two of the current Department of Health antiretroviral regimens, recommended in the 2019 ART guidelines, and a third regimen favored by higher-income countries. The newer regimens appeared to have side effect and resistance benefits over older regimens, and potential cost benefits, but little research had been done on non-Western populations with them.

All three regimens were very potent and well tolerated by patients; however, the newer regimens containing dolutegravir (DTG) and tenofovir alafenamide (TAF) demonstrated a large increase in weight, especially in women.

After 96 weeks of treatment, the percentage of people with viral suppression was 79% in the TAF/emtricitabine (FTC)+DTG arm, 78% in the TDF (tenofovir disoproxil fumarate)/FTC+DTG arm and 74% in the TDF/FTC/EFV (efavirenz) arm.

There were no significant differences in overall efficacy between the three treatments tested.

In terms of weight gain, after 96 weeks of treatment, men gained 5.4 kg in the TAF/FTC+DTG arm, 3.6 kg in the TDF/FTC+DTG arm, and 1.1 kg in the TDF/FTC/EFV arm.

For women, at the same time point, the weight gain was 8.1 kg in the TAF/FTC+DTG arm, 4.8 kg in the TDF/FTC+DTG arm, and 3.2 kg in the TDF/FTC/EFV arm.

The treatment emergent obesity for women at week 96 was 28% for those on TAF/FTC+DTG (5% for men), 18% for those on TDF/FTC+DTG (4% for men), and 12% for those on TDF/FTC/EFV (3% for men).

Dr Simiso Sokhela, lead clinician on the study, commented: “We are concerned about the weight gain and body composition changes which are more severe in women, and we have predicted new risk of associated diabetes and other complications, especially when taking both TAF and DTG together. The 96 week results supports the WHO treatment guidelines which reserve TAF only for patients with osteoporosis or impaired renal function.”

The study team suggest that service providers should consider the best options for patients to reduce their risk of long-term co-morbidities, and should consult with patient groups, researchers and other expert groups for guidance.

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