Though many negative repercussions of human immunodeficiency virus infection can be mitigated with the use of antiretroviral therapy (ART), one area where medical advances haven’t made as much progress is in the reduction of cognitive impacts. Half of HIV patients have HIV-associated neurocognitive disorders (HAND), which can manifest in a variety of ways, from forgetfulness and confusion to behavior changes and motor deficiencies.

To better understand the mechanisms underlying HAND, researchers from Penn’s School of Dental Medicine and Perelman School of Medicine and from the Children’s Hospital of Philadelphia (CHOP) brought together their complementary expertise to create a laboratory model system using three of the types of brain cells thought to be involved. Led by doctoral student Sean Ryan, who was co-mentored by Kelly Jordan-Sciutto of Penn Dental Medicine and Stewart Anderson of CHOP and Penn Medicine, the model recapitulates important features of how HIV infection and ART affect the brain.

“Frankly the models we generally use in the HIV field have a lot of weaknesses,” says Jordan-Sciutto, co-corresponding author on the paper, which appears in the journal Stem Cell Reports. “The power of this system is it allows us to look at the interaction between different cell types of human origin in a way that is more relevant to patients than other models.”

In addition to studying HIV, members of the team plan to use the same model to shed light on the neurological mechanisms that underlie other conditions, such as schizophrenia, Alzheimer’s, and even normal aging.

“We’re collaborating with a variety of colleagues to use this system to study Alzheimer’s disease as well as schizophrenia,” says Anderson, co-corresponding author on the paper. “We have the components in a dish that we know are interacting in these diseases, and this gives us a new mix-and-match way to understand how certain cells are contributing to neuronal damage.”

Indeed, the impetus to create the model grew not out of HIV research but work that Ryan was pursuing in Anderson’s lab on schizophrenia.

“We had been looking at the role of microglia, the resident immune cells of the central nervous system,” says Ryan, first author on the work. “We wanted to see if we could see the mechanistic changes that occur with microglia in schizophrenia.”

To do so, Ryan and Anderson were interested in using human-induced pluripotent stem cells–adult cells that are reprogrammed to resemble embryonic stem cells–which can be coaxed into differentiating into a variety of different cell types.

But schizophrenia is a complicated disease with a variety of contributing genetic and environmental factors and a broad spectrum of presentations. Rather than looking at something complex, they sought to apply their new system to a disease that likewise causes neurological damage but does so in a more dramatic way and in which microglia are also implicated: HIV/AIDS infection.

They reached out to Jordan-Sciutto, who has deep experience investigating the mechanisms of HAND and was eager for the opportunity to develop a model superior to those currently available. Together, the scientists identified the three cell types they were most interested in studying: neurons, astrocytes, and microglia.

Neurons aren’t directly infected by HIV but are known to be damaged during infection. Meanwhile astrocytes are believed to interact with neurons, causing damage by sending pro-inflammatory factors into the spaces between cells, called synapses. And microglia, which are responsible for maintaining a healthy environment in the absence of disease, are seen to expand and contribute to inflammation during HIV infection.

After nailing the technical challenge of creating this tractable model in which each cell type is generated independently and then mixed together, the team used it to probe how HIV infection and ART impact the cells, both alone and in combination.

“A lot of people are taking PreEP [pre-exposure prophylaxis] if they’re in a situation where their risk of contracting HIV is heightened,” says Ryan. “Just as we want to understand the cognitive impacts of HIV, we also want to see whether these drugs alone are impacting the brain health of otherwise healthy people.”

The researchers looked at RNA expression in their cultures to get a sense of what proteins and signaling pathways were becoming activated in each scenario. During infection, they saw inflammatory pathways that had previously been implicated in HIV in earlier research. When they introduced the antiretroviral drug EFZ, which is not in common use in the United States but remains a frontline therapy in many other areas of the world, with an infection, the activity of most of these pathways was reduced.

“But this scenario involved its own unique response,” says Ryan. Certain pathways associated with inflammation and damage remained despite the introduction of EFZ.

“EFZ treatment of the tri-cultures that included HIV-infected microglia reduces inflammation by around 70%,” Ryan says. Interestingly, EFZ by itself also triggered inflammation, though to a lesser extent than infection.

“It seems a combination of infection and ART is creating its own unique response that is different from the sum of its parts,” Ryan says. “Knowing what pathways are still active due to ART could help us appropriately target additional therapies so patients don’t develop HAND.”

Many features of infection seen in the three-cell culture mirror what is known from HIV infection and ART treatment in people, giving the researchers confidence in the reliability of their model.

“Just looking at the microglia,” says Anderson, “we see in our system that they are taking on both of their normal roles in keeping key signaling systems balanced during their normal state and activating and causing damage when they’re fighting infection. We’re able to model normality and abnormality in a way we haven’t been able to before.”

For Jordan-Sciutto, the new system “is really going to change the way my lab operates going into the future.” She’s hopeful many other HIV scientists will take it up to further their studies as she also explores more aspects of HIV’s impact on the brain, such as how it navigates through the blood-brain barrier that normally protects the central nervous system from inflammation and infection.

The study authors give credit to the collaborative environment at Penn for this cross-disciplinary project. “Tentacles of this project extend from CHOP to the dental school to the vet school to the medical school,” says Anderson. “Penn is a very special place where people seem to be more likely to share their technologies around and let other people work with and develop them. This project is a great example of that.”

Kelly L. Jordan-Sciutto is vice chair and professor in the Department of Basic and Translational Sciences in Penn’s School of Dental Medicine, associate dean of graduate education, and director of biomedical graduate studies at the Perelman School of Medicine.

Designated treatment hubs and primary HIV care facilities are advised to “observe client-centered approach in the provision of antiretroviral (ARV) drugs to PLHIVs amid the imposition of Enhanced Community Quarantine and declaration of the entire Philippines under a state of calamity over Covid-19.”

DOH recognizes that “this current situation poses challenges in accessing life-saving medications… which may result in treatment interruption”, so it is mandating treatment facilities to “exhaust all possible methods to ensure reliable access to PLHIVs to treatment without having to risk increased exposure to Covid-19 when accessing their medicines.”

For the DOH, various methods recommended are:

1. Use of available courier service for pick-up and delivery of ARVs. Cost of service may be shouldered by the treatment facility, the client, community-based organizations (CBOs), or PhilHealth’s OHAT package
2. Hub-designated ARV access points (e.g. local government units or CBOs)
3. Use of LGU vehicles for delivery of ARVs at agreed meeting points
4. Use of electronic or SMS appointment information as proof of entry of PLHIVs in areas under community quarantine during extreme instances where visit to the primary treatment facility is inevitable

The DOH also emphasized the provisions of the Guidelines on Service Delivery of PLHIV Affected by the Community Quarantine, including the catering of affected PLHIVs by other treatment facilities for their ARV refills and for other services.

There is still confusion re access to treatment, however.

For instance, some facilities are reportedly requiring PLHIVs not under their care to bring their HIV confirmatory test results and their ARV booklets (that list down their ARV intake); but these requirements are with the primary hubs, not with the PLHIVs.

In the end, the DOH is giving hubs leeway on implementation, stating that “treatment facilities shall ensure mechanisms are in place for the close coordination and communication between treatment facilities, partner organizations/support groups, and PLHIVs.”

Meaning: PLHIVs ought to still coordinate with their respective hubs if these have efforts at all re access to treatment, care and support during the quarantine period.

Some hubs reiterate the policy on co-sharing of responsibility – e.g. In a Facebook post, Dr. Jeffrey Garcia stated: “To all the patients from DOH-RITM ARG and other treatment hubs/primary HIV Clinics: You may temporarily have your ARV refill and medical consultations at a hub nearest to you.”

However, Garcia himself eventually noted that “there were incidents where PLHIVs/patients were not allowed to pass through the borders to have their ARV refill despite showing their IDs and cards” while “some cannot go the nearest hubs due to public transportation suspension.”

“I hope the DOH will address this soon”, just as he is asking other government agencies (e.g. Department of Social Welfare and Development, Armed Forces of the Philippines and local government units) to “please help our patients.”

Garcia added: “For now, you may seek assistance from your local government units/barangay officials.”

This, obviously, introduces other issues to PLHIVs – e.g. the need to unnecessarily disclose their HIV status so that other agencies will help them.

There are hubs that have been stepping up – e.g. Ospital ng Biñan – HIV/AIDS Core Team is conducting emergency ARV refill stations.

CBO The Red Whistle, meanwhile, partnered with MapBeks to create the Oplan #ARVayanihan map so those who want – or are able – to access other treatment hubs while the quarantine is in effect.

In a Facebook post, Benedict Bernabe – who helms the group – stated that “because of road closures at borders between towns, cities, and municipalities, the paralyzation of the public transport system, the unreliability of courier services, the lack of viable documents that can be accepted at checkpoints, some PLHIVs are worrying about their supply of ARVs.” So the group created a map containing “ALL the DOH-designated treatment hubs across the country. This will give you the nearest treatment hub where you are located.”

The map also contains 1-km and 2-km area markers for PLHIV to check if the treatment hubs are within walking distance if there’s no transportation available.

HIV hides in reservoirs during antiretroviral therapy (ART). These viral sanctuaries are the reason why ART is not a cure. And research teams have striven for years to determine how the HIV reservoirs are established and maintained during ART. Thanks to an unprecedented access to blood, and biopsies of rectums and lymph nodes of people at the earliest stages of HIV infection, an international team of researchers at the University of Montreal Hospital Research Centre (CRCHUM), the US Military HIV Research Program and the Thai Red Cross AIDS Research Centre has shown that the first established reservoirs are still “sensitive” during these early stages and could be downsized about 100 times upon immediate ART initiation.

In this study published in Science Translational Medicine, the researchers provide insight into the events unfolding during the crucial stages of early HIV infection. Through the U.S. Military HIV Research Program’s acute infection cohort, RV254/SEARCH010, which started 10 years ago in collaboration with the Thai Red Cross AIDS Research Centre, they identified acutely infected individuals in the first two weeks of infection (Fiebig I-II stages) and placed them onto ART immediately.

“The initiation of ART at this very early stage leads to a drastic decrease in the size of viral reservoirs by clearing large pools of infected cells harboured in gut-associated lymphoid tissues and lymph nodes, which are known to be preferential sites for HIV persistence during ART,” said Dr. Nicolas Chomont, a CRCHUM researcher and a professor at Université de Montréal.

“Although the viral reservoirs from these early treated people are extremely small, the virus is still there and one might say there is no immediate clinical benefit for now. Nonetheless, since these early treated individuals have viral reservoirs 100 times smaller compared to our control group, we could reasonably think that it will be easier to eradicate these mini-reservoirs than the large reservoirs in people who started ART later.”

Louise Leyre, the study’s first author and a master student in Chomont’s lab at the time of the research, analyzed blood and tissues collected from individuals at the earliest stages of HIV infection to identify the locations in which HIV reservoirs are seeded and persist during ART. Previous studies in nonhuman primates had shown that the viral reservoirs can be found preferentially in lymphoid tissues.

“It was the first time researchers had access to blood, rectal and lymph node biopsies from the same people at this very early stage of infection,” said Dr. Chomont. “We owe these volunteers a lot.”

For this study, the researchers used samples from 170 acutely infected individuals in Thailand with a median age of 27, who initiated ART within a median time of 2 days after diagnosis. Ninety-six per cent (164) of the participants were male.

The researchers showed that participants starting ART at the earliest infection stages, known as Fiebig I to III, demonstrated a drastic decrease in the frequency of infected cells to nearly undetectable levels throughout the body. The rare infected cells that persisted were mostly found in their lymphoid tissues. Initiation of ART in infected individuals at later stages, i.e. Fiebig IV-V or chronic infection, induced only a slight reduction in the frequency of infected cells.

According to the World Health Organization, approximately 37.9 million people were living with HIV at the end of 2018. The majority of what is known about HIV comes from research done in high-income countries, where HIV subtype B predominates. However, subtype B only accounts for 12 per cent of global HIV infections. Nearly 50 per cent of all people living with HIV have subtype C. In this study, HIV subtype AE, prevalent in the Southeastern Asia region, was investigated.

This research was supported by the U.S. Military HIV Research Program, Walter Reed Army Institute of Research; the Foundation for AIDS Research (amfAR Research Consortium on HIV Eradication); the Canadian Institutes of Health Research and the Fonds de Recherche du Québec-Santé.

“Abundant HIV-infected cells in blood and tissues are rapidly cleared upon ART initiation during acute HIV infection” by Louise Leyre et al. appeared in Science Translational Medicine.

By AIDS Society of the Philippines

How can Persons Living with HIV protect themselves from COVID-19?

Recently, persons living with HIV have been voicing their concerns regarding COVID-19, especially if their immunocompromised status makes them more vulnerable to the coronavirus. The AIDS Society of the Philippines acknowledges and empathizes with the key affected population, and provides the following advice for prevention.

Adhere to ARV regimen

Continue to faithfully take your anti-retrovirals (ARVs) and ensure you have enough supply of ARVs. Reach out to your treatment hub, primary care facility, or community-based organization so they can help expedite your ARV refill despite the community quarantine in NCR. Call them to set an appointment before you visit.

Maintain a strong immune system

Continue to maintain a strong immune system with proper diet and enough sleep. Currently, there is no COVID-19 data specifically about persons who are immunocompromised. However, Dr. John Brooks from the HIV/AIDS Division of the CDC said publicly that, most likely, the risk for severe illness will be greater for persons at lower CD4 cell counts and those who aren’t virally suppressed.

Follow general precautions vs. COVID-19

Continue to follow DOH and WHO advice in COVID-19 prevention. This includes frequent handwashing, practicing cough hygiene, avoid touching the mouth, eyes, and nose, social distancing (maintain 3 feet distance), working from home, going out as little as possible, and seeking medical care when you have fever, cough, or difficulty breathing.

If you have been exposed to a Person Under Investigation or Person Under Monitoring (PUI and PUM) for COVID-19, contact your treatment hub or primary care facility to request for advice. Home quarantine will likely be required, even without symptoms. If symptoms appear, visit your nearest government hospital for triaging and indicate the presence of co-morbidities.

Keep in touch with friends and family

Continue to take care of your mental health by reaching out and staying in touch with friends, family members, and support groups remotely or through the Internet. Social distancing doesn’t mean social isolation. But advise family and friends that due to your status, you have to limit your exposure to others. Finally, encourage other PLHIV and fellow Filipinos.

We stand with you in this difficult time. Stay strong—we will get through this together.

A man from London is now considered as the second person ever cured of HIV.

The man’s case was first announced a year ago; and he has now been HIV-free for 30 months, not needing antiretoviral medications (ARVs), according to a report published in The Lancet HIV.

The man was previously known only as the “London patient”; but his identity was revealed just as this development came into view.

Adam Castillejo is a 40-year-old who grew up in Venezuela. He was first diagnosed with HIV in 2003 after moving to London a year earlier, and developed advanced Hodgkin lymphoma in 2012. In 2016, to fight the rare cancer, he received bone marrow stem cells from a donor with a rare genetic mutation that resists HIV infection.

Last year, he experienced “long-term remission” from the virus after undergoing a special bone-marrow transplant. At that time, he was already HIV-free for 18 months. Now, 12 months later, his doctors are “more sure” that his case does indeed represent a cure.

In a statement, Ravindra Kumar Gupta, a professor of clinical microbiology the University of Cambridge and the lead author of the report published in The Lancet HIV, said: “We propose that these results represent the second ever case of a patient to be cured of HIV.”

The first patient to be cured of HIV is Timothy Brown, who was earlier known as the “Berlin patient”. He also received a similar bone-marrow transplant in 2007 and has been HIV-free for more than a decade.

In the two cases, stem cells used for their transplants came from a donor who had a relatively rare genetic mutation that confers resistance to HIV.

The researchers, nonetheless, stressed that such a bone-marrow transplant would not work as a standard therapy for all patients with HIV because: 1. such transplants are risky, and 2. both Castillejo and Brown needed the transplants to treat cancer rather than HIV.

In the new report, doctors found no active viral infection in Castillejo’s body. But they found “remnants” of HIV’s DNA in some cells (traces of DNA that can be considered as “fossils” because they are unlikely to allow the virus to replicate). Such remnants were also found in Brown’s case.

The second cure is now taken to mean that the first one (in the Berlin patient) wasn’t an anomaly or a fluke.

For people living with HIV, any level of alcohol consumption is associated with lower levels of a protein involved in bone formation, raising the risk of osteoporosis, according to a study by researchers from the Boston University School of Public Health (BUSPH) and School of Medicine (BUSM) and published in the journal Alcoholism: Clinical and Experimental Research.

“We did not find an amount of alcohol consumption that appeared ‘safe’ for bone metabolism,” says study lead author Dr. Theresa W. Kim, an assistant professor at BUSM and a faculty member of the Clinical Addiction Research Education (CARE) program at Boston Medical Center.

“As you get older, your ability to maintain adequate bone formation declines,” Kim says. “These findings suggest that for people with HIV, alcohol may make this more difficult.”

Low bone density is common among people living with HIV, even those who have successfully suppressed their viral loads with antiretroviral therapy.

“Our finding highlights an under-recognized circumstance in which people with HIV infection often find themselves: Their viral load can be well controlled by efficacious, now easier-to-take medications, while other health conditions and risks that commonly co-occur–like substance use and other medical conditions–are less well-addressed,” says Dr. Richard Saitz, professor of community health sciences at BUSPH and the study’s senior author.

The researchers used data from 198 participants in the Boston ARCH cohort, a long-running study led by Saitz and funded by the National Institute on Alcohol Abuse and Alcoholism that includes people living with HIV and current or past alcohol or drug use disorder. For the current study, the researchers analyzed participants’ blood samples, looking at biomarkers associated with bone metabolism (a life-long process of absorbing old bone tissue and creating new bone tissue) and a biomarker associated with recent alcohol consumption. They also used data from interviews in their analyses, and controlled for other factors such as age, sex, race/ethnicity, other substance use, medications, vitamin D levels, and HIV viral suppression.

The researchers found a significant association between a participant’s drinking and their levels of serum procollagen type 1 N-terminal propeptide (P1NP), a marker of bone formation. For every additional drink per day on average, a participant’s P1NP levels dropped by 1.09ng/mL (the range for healthy P1NP levels is 13.7 to 42.4?ng/mL). Participants who drank more than 20 days out of each month also had lower P1NP levels than those who drank fewer than 20 days per month, and participants with high levels of the alcohol-associated biomarker also had lower P1NP levels.

“If I were counseling a patient who was concerned about their bone health, besides checking vitamin D and recommending exercise, I would caution them about alcohol use, given that alcohol intake is a modifiable risk factor and osteoporosis can lead to fracture and functional decline,” says Kim, who is also a primary care physician at the Boston Health Care for the Homeless Program.