CNS Cells Can Be Reservoirs for Long-term HIV-1 Persistence Despite Antiretroviral Therapy
Key findings
- HIV-1 reservoir cells are well known to circulate in peripheral blood during suppressive antiretroviral therapy, but little is known about their dissemination into other anatomical tissues
- In this study, single-genome proviral sequencing was used to analyze HIV-1 proviral sequences in autopsy samples from multiple organ systems of three individuals who were treated with antiretroviral therapy while living
- Large clones of virally infected cells were broadly disseminated across multiple tissues, including the central nervous system, in two individuals
- In multiple instances in one of the two individuals, clones of HIV-1–infected cells were distributed across different autologous CNS tissues
- These observations emphasize the difficulties in eliminating HIV-1 from the body but may also provide clues to the strategies needed
Even during suppressive antiretroviral therapy (ART), a long-lived reservoir of HIV-1-infected cells persist and circulates in the peripheral blood. These cells consist mostly of memory T cells and harbor HIV-1 viral DNA, also called a provirus.
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The vast majority of HIV-1 DNA species in ART-treated individuals are defective, but recent studies have determined proviral gene expression can be ongoing in some HIV–1–infected cells in peripheral blood during ART.
Published in eLife, researchers at Massachusetts General Hospital have detected the persistence of HIV provirus in other organ systems, notably the central nervous system (CNS). The authors are Weiwei Sun, PhD, a research fellow in medicine at the Ragon Institute of Mass General, MIT and Harvard, Shibani Mukerji, MD, PhD, associate professor in the Department of Neurology at Massachusetts General Hospital, Xu G. Yu, MD, an associate professor in medicine at the Ragon Institute, Mathias Lichterfeld, MD, PhD, professor in the Infectious Diseases Division at Brigham and Woman's Hospital and Mass General, and colleagues.
Methods
Using fresh autopsy specimens, the researchers performed single-genome, nearly full-length HIV-1 next-generation sequencing to evaluate the proviral landscape in distinct anatomical compartments of three individuals. Two participants began ART shortly after HIV-1 diagnosis; the other was diagnosed 25 years before starting ART and died 10 months after ART commencement.
13 CNS tissue samples were analyzed, including specimens from the basal ganglia, thalamus, occipital lobe, frontal lobe, and periventricular white matter.
Results
The principal findings of interest to neurologists were:
- HIV-1 reservoir cells harboring genome-intact proviruses were found in lymphoid, gastrointestinal, genitourinary, and CNS tissues
- Proviral sequences were detected in basal ganglia in two subjects and periventricular white matter in one of those two
- In one of the two subjects, the provirus from basal ganglia was clonal, with four intact proviruses from the lymph node
- In multiple instances in the other of the two subjects, clones of HIV-1–infected cells were distributed across different autologous CNS tissues
Avenues for Future Research
Combination ART extends the life expectancy of people living with HIV but doesn't lead to sustained drug-free remission. Finding a way to eliminate HIV-1 reservoir cells remains critical to finding a cure.
This study suggests HIV-1 reservoir cells seeded to the brain via hematogenous spread can proliferate in the immune microenvironment of the CNS. It also shows, for the first time, that CNS tissue can be involved in the multi-compartment dissemination of large clones of HIV-1 proviruses in ART-treated persons.
These observations emphasize the difficulties in eliminating HIV-1 from the body but may also provide clues to the strategies needed.
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