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Researchers from IDMIT (CEA-Jacob) and the Institut Pasteur teamed for a study in which they showed that the antiviral activity of CD8+ T lymphocytes remained limited in the first two weeks of infection but grew progressively and durably thereafter in macaques able to control simian immunodeficiency virus infection (the equivalent of HIV infection in non-human primates). Their results suggest that the early development of highly effective memory CD8+ T-cells is essential for achieving viral control.
Supported by the ANRS, the MSDAvenir foundation and the ANR's Investments for the Future program, the study was published in the 22 September 2020 edition of
The rare individuals able to control infection by the human immunodeficiency virus without treatment are referred to as HIV controllers. Within this setting, a number of studies have highlighted the key role played by CD8+ T lymphocytes, the immune system cells that recognize and rapidly eliminate HIV-infected cells. The CD8+ T-cells of controllers appear to have a molecular program different from those of non-controllers during the chronic HIV infection phase.
To determine what happens during the acute phase, a team of researchers from
Institut Pasteur, the University of Paris, Paul Sabatier University (Toulouse) the Cardiff University School of Medicine, and the AP-HP teamed to carry out a study using a non-human primate model of HIV. Specifically, they used simian immunodeficiency virus (SIV)-infected cynomolgus macaques, some of which naturally become SIV controllers in the same way that some humans become HIV controllers. In their unprecedented work, the team was able to monitor, from day one of infection, the events that led or not to natural viral control and observe how the CD8+ T-cells of controllers differed from those of non-controllers.
They reported that during the first 15 days following infection, all subjects developed large quantities of SIV-specific CD8+ T-cells, but the ability of these latter to eliminate SIV-infected CD4 lymphocytes was limited. However, over the next few weeks of infection, they observed in some subjects—exactly those that would go on to become controllers—a progressive increase in the antiviral activity of the CD8+ T-cells. In those subjects, the CD8+ T-cells were able to progressively reduce viral loads and establish sustained control of the SIV infection without antiretroviral treatment. The researchers determined that two to three months were needed for the maturation of the CD8+ T-cell response and the establishment of natural infection control in the lucky few.
Nonetheless, they also determined that the path toward controller status was laid in the first two weeks of infection. Although the CD8+ T-cells conferred a response in early infection in non-controllers, their performance weakened over time in the continuing presence of SIV. In contrast, SIV controllers developed memory CD8+ T-cells that continued regenerating new cells in response to repeated SIV stimulation. The researchers hypothesized that this difference may find its roots in the early preservation of lymph nodes, as those of the controller macaques presented fewer infected cells during the first days of infection.
The results of this study, published in Cell Reports, complement and consolidate those of
earlier works involving the IDMIT team, and furthermore introduce the concept of a maturation pathway for the antiviral potential of CD8+ T-cells during SIV or HIV infection.
That concept opens important vistas for the development of novel vaccinal or immunotherapeutic approaches aimed at obtaining HIV infection remission.
Optimal Maturation of the SIV-Specific CD8+ T Cell Response after Primary Infection Is Associated with Natural Control of SIV : ANRS SIC Study I Cell Reports
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.