California woman, 66, could become the first person to be cured of HIV without drugs or surgery: Study
A 66-year-old woman, who was diagnosed with HIV in 1992, could be the first person to be cured of the virus without taking any drugs or having undergone a bone marrow transplant. Additionally, 63 other people living with HIV – who researchers are referring to as “elite controllers” – and can suppress the virus naturally and prevent replication without the need for medication.
Unlike people on antiretroviral drugs, elite controllers’ viral reservoirs appear to be incapable of being reactivated. This likely helps the elite controllers maintain spontaneous, drug-free control of HIV and may represent a distinguishing feature for a “functional cure of HIV infection,” say authors in the study published in Nature. The team includes experts from Ragon Institute of Massachusetts General Hospital, (MGH), MIT and Harvard, Brigham and Women’s Hospital, the University of California at San Francisco, and Johns Hopkins University School of Medicine, among others. “In elite controllers, HIV is hidden in parts of the cell’s DNA where it cannot be used to create new copies of the virus. If researchers can better understand how elite controllers’ immune systems prevent HIV from replicating, they may be able to create a functional cure,” they explain.
The woman is Loreen Willenberg from California. Two other people – Timothy Ray Brown from California, and Adam Castillejo of London – have earlier been declared cured of HIV, but both underwent risky bone marrow transplants, as well as antiretroviral therapy (ART). Standard ART consists of the combination of at least three antiretroviral drugs to maximally suppress the HIV virus and stop the progression of the disease. Castillejo, who is also referred to as the “London patient,” had a successful stem cell transplantation from donors with an HIV-resistant gene. A recently-published study said that there was no active viral infection in the patient’s blood 30 months after they stopped antiretroviral therapy. Brown, referred to as the “Berlin patient,” was the first HIV patient to be reported cured of the virus three-and-a-half-years after undergoing similar treatment.
Willenberg, who also belongs to the group of elite controllers, is the third patient who may have been cured of HIV but without any medical treatment. She is well-known among scientists for having suppressed the virus for decades. In the current study, scientists examined 1.5 billion blood cells from Willenberg, as well as cells from her gut, rectum and intestine, and did not find any trace of the virus. “One of the elite controller participants had no intact HIV found in over 1.5 billion cells analyzed. This raises the possibility that a “sterilizing cure” of HIV -- in which the participant’s immune system has removed all intact HIV genomes from the body -- may be achieved naturally in extremely rare instances,” emphasizes the team.
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In a review of the paper, Nicolas Chomont, an associate research professor in the Department of Microbiology, Infectiology and Immunology at the Université de Montréal, says that whether HIV has been completely eradicated from this individual’s body will be hard to demonstrate, but “their case is certainly reminiscent of previous reports of HIV cure.”
HIV affects more than 35 million people worldwide and can be effectively controlled, but not cured, with a daily regimen of ART. According to the authors, upon infection, retroviruses like HIV place copies of their viral genetic material into cells’ genomes, “creating viral reservoirs,” sanctuaries where HIV persists despite ART, throughout the body. When a complete copy of the virus, or intact viral genome, is incorporated into a cell’s genome, it can be used to create new copies of HIV. For people living with HIV, this means that if they stop taking ART, the intact viral genomes previously integrated into the cells' genomes start making new copies of the virus, leading to rapid viral rebound and disease progression. The HIV viral reservoir has remained a major obstacle to an HIV cure.
In the current study, researchers sequenced billions of cells from 64 elite controllers, and 41 individuals on antiretroviral drugs. “Elite controllers’ immune systems use a T-cell mediated immune response to control the virus without medication, to the point that the virus is completely undetectable by standard assays. Understanding the interplay between their immune system and HIV may hold the key to helping the immune systems of people living with HIV to suppress the virus without daily treatment,” the findings state.
The experts studied the viral reservoir in elite controllers, using next-generation sequencing techniques to precisely map the locations of intact HIV genomes in the human genome. They found that in elite controllers, HIV was often found in locations of the genome that researchers call “gene deserts.” The analysis says that in these inactive parts of the human genome, human DNA is never turned on, and HIV cannot be effectively expressed but remains in a “blocked and locked state.” This implies that HIV is locked in the cell’s genome, and the viral genome is blocked from being used to create more viruses and is, therefore, incapable of causing disease. “This positioning of viral genomes in elite controllers is highly atypical, as, in the vast majority of people living with HIV-1, HIV is located in the active human genes where viruses can be readily produced,” writes Dr Xu Yu, Ragon group leader.
When the authors collected cells from elite controllers and infected them with HIV in the lab, they found the virus integrated into active sites in the cell genomes, not in the inactive gene deserts. “This suggests that the elite controllers’ unique viral reservoirs may be a result of their HIV-suppressing T-cell response eliminating intact viral genomes from active sites,” explains the team.
According to the authors, if researchers can identify which viral reservoirs can make new copies of the virus after treatment stops, it may help them to target a treatment against the active, or rebound-competent, reservoirs. “This study suggests that if researchers can activate the kind of T-cell immunity that is present in elite controllers, they may be able to eliminate rebound-competent viral reservoirs in people living with HIV, achieving a functional cure. The remaining viral DNA, located in non-active parts of the human genome, could be allowed to exist without causing disease,” they conclude.
Dr Keith Hoots, director of the Division of Blood Diseases and Resources at the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, and a veteran HIV researcher himself, says that the National Heart, Lung, and Blood Institute NHLBI is interested in understanding how the immune systems of some people living with HIV naturally control their infection without medication. “What happens with these individuals, whom we call elite controllers, may shed light on an HIV-1 cure and also help us understand how a person with HIV might control the virus and avoid HIV-associated comorbidities,” explains Dr Hoots.