Nav: Home

Surprise finding about HIV reservoir could lead to better therapies

October 09, 2019

CHAPEL HILL, NC - Antiretroviral therapy (ART) can suppress HIV to the point where the virus is nearly undetectable, and people on medication can live many years. But therapy cannot completely eradicate the virus; it persists in reservoirs inside immune cells, a phenomenon called "latency." This latent reservoir forms even when a person begins therapy very early after infection, but the dynamics of the reservoir's formation have been largely unknown. Now scientists have discovered evidence that the initial use of ART alters the host environment to allow the formation or stabilization of most of the long-lived HIV reservoir that is then present for many years.

This research was published in Science Translational Medicine and led by scientists at the University of North Carolina School of Medicine, the University of Cape Town, and the CAPRISA research team in South Africa.

Their research shows that the long-lived reservoir of HIV in blood mostly reflects viral strains that were present at the time treatment was initiated, with these latent viruses persisting after years of treatment. The implication is that treatment itself indirectly contributes to the formation of most of the latent HIV reservoir - or alternatively that the viral reservoir population is unstable prior to treatment but stabilizes when treatment starts.

"This comes as a big surprise," said co-senior author Ronald Swanstrom, PhD, professor of biochemistry and biophysics at the UNC School of Medicine. "Our work suggests that if we could understand the reservoir-forming process better, we might be able to intervene at the start of treatment to reduce the majority of the reservoir that forms at this time."

More than 1 million people in the United States are living with HIV, according to the U.S. Centers for Disease Control & Prevention (CDC). The World Health Organization estimates that globally about 38 million people are living with the virus. Antiretroviral treatments are widely available and in most cases will prevent people with HIV from developing the fatal immune deficiency syndrome AIDS. However, these treatments must be taken indefinitely. HIV encodes itself in the DNA of millions of CD4 immune cells, and this latent viral reservoir not only survives treatment but also will seed a new, actively replicating virus population in the blood if antiretroviral treatment ever stops.

Swanstrom and collaborator Carolyn Williamson, PhD, of the University of Cape Town, set up the study to try to understand more about the origins of the HIV reservoir. They analyzed the genetic sequences of HIV in blood samples that had been taken from nine South African women in the CAPRISA 002 cohort over a period of several years before they began treatment; since the virus rapidly evolves they could use the differences in viral sequence at each time point as a clock for the different time points. The researchers also examined blood samples taken from these women years after treatment had started so that the researchers could analyze the sequences of the latent HIV reservoir strains that grew from their CD4 T cells in the lab.

The researchers hoped that a comparison of the pre-treatment strains and the reservoir strains would provide clues to when and how the reservoir formed. The comparison revealed something unexpected. For the nine women, most of their HIV reservoirs - about 71 percent on average - consisted of viral strains that were closely related to the strains circulating just before they started treatment.

"This is a much higher proportion than you'd see if the reservoir formed continuously before treatment and was always long-lived," said Swanstrom, Director of the UNC Center for AIDS Research and member of the UNC Institute for Global Health and Infectious Diseases. "So either the therapy indirectly induced the formation of much of the reservoir, or it stabilized a reservoir that until then had been turning over rapidly."

Swanstrom and Williamson found support for their conclusion in an earlier 2016 study published in eLife that had examined the evolution of HIV during treatment by analyzing HIV DNA in the blood cells of treated patients. Most such DNA cannot form replicating viruses, but the investigators in that study observed that the sequences of DNA in the latent reservoir closely resembled the sequences of HIV strains that had been replicating in patients' blood just before treatment started.

Swanstrom, Williamson, and their colleagues are now following up to determine in more detail how the HIV reservoir forms and how that formation relates to antiretroviral treatment. They hypothesize that the initiation of treatment quiets the immune system by reducing the presence of actively replicating HIV. This makes CD4 T cells more likely to turn into long-lived "memory cells." And if they were already infected by HIV, the memory cells that form when therapy is initiated will constitute much of the long-term viral reservoir.

Thus, combining HIV antiretroviral treatment with a drug that inhibits the transition of CD4 T cells to the memory cell state might prevent much of the viral reservoir from ever forming.

"A major goal of current HIV research is to allow people to stop therapy without having the virus come back," Swanstrom said. "One strategy to achieve this is to eradicate the latent reservoir. Starting with a smaller reservoir could help make that an attainable goal."
The research was supported by the National Institutes of Health (R01 AI115981, UM1 AI126619).

The other authors were Melissa-Rose Abrahams, Lynn Tyers, David Matten, Deelan Doolabh, and Colin Anthony of the University of Cape Town; Nigel Garrett and Salim Abdool Karim of the University of KwaZulu- Natal/CAPRISA; Sergei Kosakovsky Pond of Temple University; and Sarah Joseph, Matthew Moeser, Nancie Archin, Olivia Council, Shuntai Zhou, Nilu Goonetilleke, and David Margolis of UNC-Chapel Hill.

University of North Carolina Health Care

Related Hiv Articles:

The Lancet HIV: Study suggests a second patient has been cured of HIV
A study of the second HIV patient to undergo successful stem cell transplantation from donors with a HIV-resistant gene, finds that there was no active viral infection in the patient's blood 30 months after they stopped anti-retroviral therapy, according to a case report published in The Lancet HIV journal and presented at CROI (Conference on Retroviruses and Opportunistic Infections).
Children with HIV score below HIV-negative peers in cognitive, motor function tests
Children who acquired HIV in utero or during birth or breastfeeding did not perform as well as their peers who do not have HIV on tests measuring cognitive ability, motor function and attention, according to a report published online today in Clinical Infectious Diseases.
Efforts to end the HIV epidemic must not ignore people already living with HIV
Efforts to prevent new HIV transmissions in the US must be accompanied by addressing HIV-associated comorbidities to improve the health of people already living with HIV, NIH experts assert in the third of a series of JAMA commentaries.
The Lancet HIV: Severe anti-LGBT legislations associated with lower testing and awareness of HIV in African countries
This first systematic review to investigate HIV testing, treatment and viral suppression in men who have sex with men in Africa finds that among the most recent studies (conducted after 2011) only half of men have been tested for HIV in the past 12 months.
The Lancet HIV: Tenfold increase in number of adolescents on HIV treatment in South Africa since 2010, but many still untreated
A new study of more than 700,000 one to 19-year olds being treated for HIV infection suggests a ten-fold increase in the number of adolescents aged 15 to 19 receiving HIV treatment in South Africa, according to results published in The Lancet HIV journal.
Starting HIV treatment in ERs may be key to ending HIV spread worldwide
In a follow-up study conducted in South Africa, Johns Hopkins Medicine researchers say they have evidence that hospital emergency departments (EDs) worldwide may be key strategic settings for curbing the spread of HIV infections in hard-to-reach populations if the EDs jump-start treatment and case management as well as diagnosis of the disease.
NIH HIV experts prioritize research to achieve sustained ART-free HIV remission
Achieving sustained remission of HIV without life-long antiretroviral therapy (ART) is a top HIV research priority, according to a new commentary in JAMA by experts at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
First ever living donor HIV-to-HIV kidney transplant
For the first time, a person living with HIV has donated a kidney to a transplant recipient also living with HIV.
The Lancet HIV: PrEP implementation is associated with a rapid decline in new HIV infections
Study from Australia is the first to evaluate a population-level roll-out of pre-exposure prophylaxis (PrEP) in men who have sex with men.
Researchers date 'hibernating' HIV strains, advancing BC's leadership in HIV cure research
Researchers have developed a novel way for dating 'hibernating' HIV strains, in an advancement for HIV cure research.
More HIV News and HIV Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Climate Mindset
In the past few months, human beings have come together to fight a global threat. This hour, TED speakers explore how our response can be the catalyst to fight another global crisis: climate change. Guests include political strategist Tom Rivett-Carnac, diplomat Christiana Figueres, climate justice activist Xiye Bastida, and writer, illustrator, and artist Oliver Jeffers.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Speedy Beet
There are few musical moments more well-worn than the first four notes of Beethoven's Fifth Symphony. But in this short, we find out that Beethoven might have made a last-ditch effort to keep his music from ever feeling familiar, to keep pushing his listeners to a kind of psychological limit. Big thanks to our Brooklyn Philharmonic musicians: Deborah Buck and Suzy Perelman on violin, Arash Amini on cello, and Ah Ling Neu on viola. And check out The First Four Notes, Matthew Guerrieri's book on Beethoven's Fifth. Support Radiolab today at