“I don’t know how I was able to accept I have HIV,” said Louie, 34, in Filipino. In actuality, it was – perhaps – harder for him to accept that some things in life do not last forever, “such as losing loved ones” because a former partner eventually died from AIDS-related complications.

Louie can still remember the exact date when he was diagnosed to be HIV-positive (on July 3, 2013; he was 28 then).

“I didn’t know anything about HIV then,” he said, adding that the only thing he knew was “if you have HIV, you’d already die.”

He actually didn’t have any medical condition that merited him to get tested; but his former partner had AIDS diagnosis, so he also had to get tested.

When Louie’s HIV test came out, he said he felt two things.

First, he felt happy because – following his former logic that if one has HIV, then he/she will already die – he and his former partner can then die together and “stay happy wherever we may go after death.”

But there was also sadness because if he died, then he’d leave behind his family.

At that time, Louie also had opportunistic infections – e.g. TB (which he got from his former partner). The bad thing for him at that time was his body’s non-acceptance of widely used TB meds; so he had to be issued a different med that had to be injected every now and then. This meant he had to be at his treatment hub more frequently.

It was this – the need to be at his treatment hub more often that he needed to be if only his situation wasn’t dire – that led to his resignation from work, since “I didn’t know how to inform (my boss) anymore about the frequent absence.”

It was his sister who knew first of his status; but then one morning, before he was to go to his treatment hub again, his mom confronted him. “She asked me how I was. I got nervous. Then she said she already knew; my sister told her,” Louie said.

Though her mom cried then, Louie was able to pacify her by telling her he’d be okay; and that he’s already taking his meds (LTE).

The relationship is okay now; and there are times when she’d tell him she wishes there’s a cure for HIV. But Louie said he’d kid her: “Even if there’s a cure, I doubt we’d be able to afford it; it will be extremely expensive.”

Louie said he keeps telling his mom to just “accept… and love.”

Louie is in a relationship with an HIV-negative person now (Matt). And he said that may PLHIVs think that because of their HIV status, no one will love them anymore. “That someone will only love you because if he/she doesn’t, you’d get depressed and you’d kill yourself.”

But Louie doesn’t believe this.

“This never entered my mind,” he said, suggesting for PLHIVs “just to be honest. If he/she accepts you, then that’s love. If he/she doesn’t that’s not really love; so just look for another. If he/she really loves you, whatever your HIV status may be, he/she will love you.”

Premature aging in people with HIV is now recognized as a new, significant public health challenge. Accumulating evidence shows that people with HIV who are between 45 to 60 years old develop characteristics typically observed in people without HIV that are more than 70 years of age. For instance, declining gait speed, physical function and cognition, mitochondrial aging, elevated inflammation, immune dysfunction, frailty and other health conditions are significantly higher in people with HIV when compared to age- and sex-matched uninfected people.

This is what endocrinologist Dr. Rajagopal Sekhar, associate professor of medicine-endocrinology at Baylor College of Medicine, and his team eyed in a study published in the journal Biomedicines. Specifically, they wanted to “build a bridge between laboratory bench and bedside by showing proof-of-concept that supplementing people with HIV specifically with a combination of glycine and N-acetylcysteine, which we call GlyNAC, as precursors of glutathione, a major antioxidant produced by the body, improves multiple deficits associated with premature aging,” said Sekhar.

Why we age?

For several decades, experimental evidence has supported two theories for aging. The free radical theory and the mitochondrial theory propose that elevated free radicals (oxidative stress) and mitochondrial dysfunction, respectively, are at the core of geriatric aging. Both, elevated oxidative stress and mitochondrial dysfunction, are present in people with HIV.

Free radicals, such as reactive oxygen species, and the mitochondria are physiologically connected. The mitochondria are like the batteries of the cell, they produce the energy needed for conducting cellular functions. The body transforms the food we eat into sugar and fat, which the mitochondria burns as fuel to produce energy.

However, one of the waste products of cellular energy generation is free radicals, which are highly reactive molecules that can damage cells, membranes, lipids, proteins and DNA. Cells depend on antioxidants, such as glutathione, to neutralize these toxic free radicals. When cells fail to neutralize free radicals, there is an imbalance between the radicals and the antioxidant responses, leading to harmful and damaging oxidative stress.

“The free radicals produced during fuel burning in the mitochondria can be compared to some of the waste products produced by a car’s combustion engine, some of which are removed by the oil filter,” Sekhar said. “If we don’t change the oil filter periodically, the car’s engine will diminish its performance and give less mileage.”

Similarly, if the balance between free radical production and antioxidant response in cells consistently favors the former, in time cellular function could be disrupted. Glutathione helps cells keep oxidative stress in balance, it keeps the oil filter clean. GlyNAC helps the cell make glutathione.

Sekhar and his colleagues have been studying mitochondrial function and glutathione for more than 20 years. Their findings, and those of other researchers, have shown that glutathione is the ultimate natural antioxidant.

Interestingly, compared to those in younger people, glutathione levels in older people are much lower, and the levels of oxidative stress are much higher. Glutathione levels also are lower and oxidative stress is higher in conditions associated with mitochondrial dysfunction, including ageing, HIV infection, diabetes, neurodegenerative disorders, cardiovascular disorders, neurometabolic diseases, cancer, obesity and other conditions.

“When the mitochondrial batteries are running low on power, as a medical and scientific community, we do not know how to recharge these batteries,” Sekhar said. “Which raised the question, if the levels of glutathione were restored in cells, would the mitochondria be recharged and able to provide power to the cell? Would restoring mitochondrial functioning improve conditions associated with mitochondrial dysfunction?”

Restoring glutathione

Restoring glutathione in cells was not straightforward because glutathione cannot work if taken orally for the same reasons that diabetic patients cannot eat insulin. It would be digested before it reached the cells. Also, providing glutathione in the blood cannot correct glutathione deficiency because every cell makes its own.

“Glutathione is a small protein made of three building blocks: amino acids cysteine, glycine and glutamic acid. We found that people with glutathione deficiency also were deficient in cysteine and glycine, but not glutamic acid,” Sekhar said. “We then tested whether restoring deficient glutathione precursors would help cells replenish their glutathione. But there’s another catch, because cysteine cannot be given as such, we had to supplement it in another form called N-acetylcysteine.”

In past studies, Sekhar and his colleagues determined that supplementing GlyNAC, a combination of glycine and N-acetylcysteine, corrected glutathione deficiency inside the cells of naturally aged mice to the levels found in younger mice. Interestingly, the levels of glutathione and mitochondrial function, which were lower in older mice before taking GlyNAC, and oxidative stress, which was higher before GlyNAC, also were comparable to those found in younger mice after taking GlyNAC for six weeks.

The same results were observed in a small study in older humans who had high oxidative stress and glutathione deficiency inside cells. In this case, taking GlyNAC by mouth for 2-weeks corrected the glutathione deficiency and lowered both oxidative stress and insulin resistance (a pre-diabetic risk factor).

In past clinical trials, Sekhar provided GlyNAC to small groups of people to correct a nutritional deficiency, and produced encouraging evidence supporting further studies of the value of this approach to restoring mitochondrial function in clinical trials.

Improving premature aging in people with HIV

In the current study, Sekhar and his colleagues conducted an open-label clinical trial that included six men and two women with HIV, and eight age-, gender- and body mass index-matched uninfected controls, all between 45 and 60 years old. The people with HIV were on stable antiretroviral therapy and had not been hospitalized for six months prior to the study.

Before taking GlyNAC, the group with HIV, compared with the controls, was deficient in glutathione and had multiple conditions associated with premature aging, including higher oxidative stress; mitochondrial dysfunction; higher inflammation, endothelial dysfunction and insulin resistance; more damage to genes; lower muscle strength; increased belly fat and impaired cognition and memory.

The results are encouraging. GlyNAC supplementation for 12 weeks improved all the deficiencies indicated above. Some of the improvements declined eight weeks after stopping GlyNAC.

“It was encouraging to see that GlyNAC can reverse many of these hallmark defects in people with HIV as there is no current treatment known to reverse these abnormalities. Our findings could have implications beyond HIV and need further investigation,” Sekhar said.

Overall, these findings in HIV patients provide proof-of-concept that dietary supplementation of GlyNAC improves multiple hallmarks of aging and that glutathione deficiency and oxidative stress could contribute to them.

Encouraged by these results, Sekhar has continued his investigations by testing the value of GlyNAC supplementation for improving the health of the growing older population, and has completed an open label trial, and another NIH-funded, double-blind, placebo-controlled trial in older adults.

“The results from these recently completed trials support the findings of the HIV study,” said Sekhar, who is currently the Principal Investigator of two NIH-funded randomized clinical trials studying the effect of GlyNAC in older humans with mild cognitive impairment, and with Alzheimer’s disease.

Other contributors to this work include Premranjan Kumar, Chun Liu, James W. Suliburk, Charles G. Minard, Raja Muthupillai, Shaji Chacko, Jean W. Hsu and Farook Jahoor. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Baylor-St. Luke’s Medical Center- Houston and the Thomas Street HIV-Health Center.

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.

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.

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.”

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.”