Mechanisms of HIV reservoir cells in the face of elimination

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ART reduces virus levels, but a small population of infected cells persist indefinitely and have not been identified or characterized until now.

At present, cure from HIV-1 infection is considered difficult because infected cells harboring genome-intact, chromosomally integrated viral DNA persist long-term despite antiretroviral suppression.


After initiation of ART, the frequency of these cells, referred to here as HIV-1 reservoir cells, decreases over time. However, this process is slow and the underlying mechanisms are not well understood. Instead, immune mechanisms are likely to play an important role, particularly in the decline of the small subset of cells encoding intact, functional proviral sequences in the genome.


Researchers from the MGH Ragon Institute, MIT and Harvard ; The National Institute of Allergy and Infectious Diseases  and the founding members of Mass General Brigham , Brigham and Women  's Hospital, and Massachusetts General Hospital  (USA) report the application of a technology that allows multidimensional characterization of individual cells (proteogenomic profiling). unicellular) Reactsnews to study HIV reservoir cells isolated directly from people living with HIV-1.


With this new technical approach, they have discovered characteristic surface markers that could explain how some of them can persist in the long term and resist host immune responses.


The researchers collected peripheral blood cells from five HIV-positive study participants. Four of the participants had been on antiretroviral treatment for about 10 years and one of them was an "elite controller" who had undetectable blood levels despite not being on antiretroviral treatment. Previous blood samples from two of these participants after 1 to 2 years of ART and lymph node cells from three HIV-positive participants who had been on treatment for 10 to 15 years were also analysed. From these samples, they isolated memory CD4+ T. Newspaperfiles


The researchers developed a new experimental strategy called phenotypic and proviral sequencing (PheP-Seq), to assess biomarkers on the surface of individual virus-infected cells. More than 530,000 individual cells from peripheral blood and 396,000 individual cells from lymph nodes were analyzed.


Blood cells containing intact proviruses, complete viral genomes that have been incorporated into the host cell's DNA, frequently displayed surface biomarkers associated with increased resistance to killing by cytotoxic T and NK cells, two types of immune cells that typically protect against viral infection. They also had elevated expression of immune checkpoint markers that limit viral gene transcription. This means that some have specific characteristics that can reduce exposure to and destruction by the immune system, which could explain why they persist in the body.


Taken together, the results suggest that only a small subset of infected cells is optimally adapted to evade the immune system and survive during long-term antiretroviral treatment. Furthermore, the data indicate that the human immune system is capable of exerting effective immune selection pressure on most HIV reservoir cells. Mechables


The researchers note that these biomarkers are unlikely to be universal across all HIV-positive people on ART, as selection may vary due to differences in individual immune responses. Even so, the identification of phenotypic biomarkers that distinguish viral reservoir cells could serve as the basis for future research on a cure for HIV-1.