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Gladstone scientists identify a new potential reservoir of latent HIV

New study identifies a type of T cells in tissues that preferentially supports latent infection by HIV.

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Scientists have long known that even in the face of antiretroviral therapy, some HIV virus remains in infected individuals forever, hiding in small reservoirs of cells of the immune system. When these individuals discontinue the therapy, the virus almost always rebounds rapidly from the reservoirs, causing deadly symptoms to re-emerge.

These reservoirs remain the main obstacle to curing HIV/AIDS. But there is at present no easy way of targeting reservoir cells for elimination. Nor can scientists efficiently extract reservoir cells from patients to study them, and, ultimately, find ways to control them.

The reason is that the virus in these cells is silent. As a result, the cells do not carry on their surfaces the viral proteins that would make them easy to find.

Scientists have therefore been looking for other means to pinpoint reservoir cells.

In a paper in PLOS Pathogens, Gladstone Visiting Scientist Nadia Roan, PhD, and her team describe a class of cells that preferentially support latent infection by HIV. These cells are characterized by a surface protein called CD127 and are found in tissues such as lymph nodes, which are thought to harbor a larger share of the HIV reservoir than blood does.

“Our findings suggest that CD127 cells from tissues may be an important population to target for an HIV cure,” says Roan, who is also an associate professor of urology at UC San Francisco.

In addition, scientists can potentially use the CD127 protein as a handle to isolate reservoir cells from patients, and study what makes them able to silence the virus, and occasionally reactivate it.

A New Reservoir?

HIV targets immune cells, known as T cells, that reside primarily in lymphoid tissues, such as lymph nodes and tonsils. Yet HIV infection studies have largely focused on T cells circulating in the blood, which are relatively easy to gain access to–volunteers are more likely to submit to a blood draw than a tissue biopsy.

But focusing on T cells present in the blood is probably giving scientists a skewed view of the reservoir composition.

“We have long suspected that reservoir cells come in different flavors, and that different tissues harbor different types of reservoir cells. But that has been difficult to show because reservoir cells in infected individuals are rare. The vast majority of in vitro models of latency use cell lines or cells circulating in the blood,” says Roan.

Roan and her team, by contrast, have been studying HIV infection using tissue specimens. In previous work, her team exposed tonsil cells to HIV in the lab to see which ones were most susceptible to infection. Using a variety of experimental approaches, the team found that tonsil cells with the surface protein CD127 efficiently took up the HIV virus but only rarely let it replicate. By contrast, another type of tonsil cells, carrying CD57 on their surface, readily supported a productive infection.

That was intriguing, but that did not necessarily mean that CD127 were reservoir cells.

“After HIV enters a cell, the cell still has ways to escape infection,” says Feng Hsiao, a former research associate in Roan’s lab and co-first author of the present study.

One way is to prevent the virus from copying its genome. Unlike the genome of human cells, the HIV genome is made of RNA. One of the virus’s first tasks upon entering a cell is to make DNA copies of its RNA genome, using a viral enzyme called reverse transcriptase.

Cells can hamper this step by activating an enzyme called SAMHD1 that depletes the stores of building blocks the virus needs to copy its genome. There was some evidence that this mechanism might be at play in blood cells.

However, in their present work, Roan and her team found that eliminating SAMHD1 by genetic manipulation did not allow CD127 cells to churn out virus, even though it boosted viral production by CD57 cells.

“This suggested to us that CD127 cells blocked the virus at a later step in its life cycle,” says Julie Frouard, PhD, a postdoctoral scholar in Roan’s lab and the other first-author of the study.

A Preference for Latent Infection

The next step for the virus is to integrate a copy of its genome into the host cell’s DNA. Once there, the viral genes can take advantage of the cell machinery to produce their own proteins, which assemble new viral particles that can go infect other cells.

Reservoir cells harbor HIV’s genetic material integrated in their own genomes, though they somehow silence it. The occasional mobilization of this material permits the release of infectious virus. Did CD127 tonsil cells allow HIV genome integration?

To answer this question, the scientists extracted the genome of CD127 and CD57 cells that had been exposed to virus in the lab. Using genetic tools that can specifically detect integrated viral DNA sequences, they found that both cell types harbored copies of the virus’s genome, even though CD127 cells produced far less virus than CD57 cells did. The CD127 cells appeared to favor a latent infection.

And yet, the virus integrated in CD127 cells is not silenced forever. Roan and her team found that by treating latently infected CD127 cells with agents known to stimulate T cells, they could coax the cells to reactivate the virus.

Hence, CD127 tissue cells could very well serve as reservoir cells in the body, keeping the virus dormant most of the time, yet able to occasionally activate it and release the seeds of a new round of infection.

“The ability of a specific type of tissue T cell to preferentially support latent infection is very intriguing, and can teach us much about how the tissue reservoir becomes established initially,” says Roan.

Controlling the Reservoir

To what extent CD127 cells are a major component of the reservoir in people living with HIV awaits follow-up studies analyzing these cells from multiple tissue sites. Preliminary studies from Roan’s team are encouraging, as they show that the CD127 marker on the cells’ surface can indeed be used to purify enough infected tissue cells from infected individuals to allow further analyses.

Meanwhile, “CD127 tonsil cells exposed to HIV in vitro provide a novel model to study viral latency in tissues,” says Roan.

Roan and her team have already started analyzing what makes CD127 cells uniquely prone to silent infections. By comparing all the genes expressed in CD127 and CD57 tonsil cells, they found evidence that CD127 cells are in a quiescent state that may prevent the expression of the virus’s genes. Moreover, they also found that the virus’s gene products, or RNAs, failed to undergo the necessary processing that would allow them to make viral proteins.

“Ultimately, our hope is that the mechanisms we uncover can be harnessed to control the latent reservoir and move us closer to achieving a cure for HIV,” says Roan.

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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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