Abstract
The understanding of protective immunity during HIV infection remains elusive. Here we showed that CD160 defines a polyfunctional and proliferative CD8+ T cell subset with a protective role during chronic HIV-1 infection. CD160+ CD8+ T cells derived from HIV+ patients correlated with slow progressions both in a cross-sectional study and in a 60-month longitudinal cohort, displaying enhanced cytotoxicity and proliferative capacity in response to HIV Gag stimulation; triggering CD160 promoted their functionalities through MEK–ERK and PI3K–AKT pathways. These observations were corroborated by studying chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. The genetic ablation of CD160 severely impaired LCMV-specific CD8+ T cell functionalities and thereby resulted in loss of virus control. Interestingly, transcriptional profiling showed multiple costimulatory and survival pathways likely to be involved in CD160+ T cell development. Our data demonstrated that CD160 acts as a costimulatory molecule positively regulating CD8+ T cells during chronic viral infections, thus representing a potential target for immune intervention.
Highlights
It is known that CD8+ cytotoxic T lymphocytes play a critical role in the containment of virus replication during HIV-1 and SIV infections, despite being incapable of preventing the progression to AIDS in most cases [1]
To explore the function of CD160 in CD8+ T cells during chronic HIV-1 infection, we first examined the enrichment of CD160-positive CD8+ T cells from three groups (Supplementary Table S1): HIV-1-infected slow progressors (SP), HIV-1-infected typical progressors (TP), and HIV-seronegative individuals
We observed an elevation of CD160+ CD8+ T cell frequencies in HIV-1-infected individuals compared with HIVseronegative controls (Figures 1A,B)
Summary
It is known that CD8+ cytotoxic T lymphocytes play a critical role in the containment of virus replication during HIV-1 and SIV infections, despite being incapable of preventing the progression to AIDS in most cases [1]. In the case of persistent HIV-1 infection, CD8+ T cells lose their functions in a hierarchical manner, successively impaired in producing IL-2, proliferating, delivering cytotoxic molecules like perforin and granzymes, producing TNF, IFN-γ, and MIP-1β, and attaining a so-called exhausted state [3]. The exact mechanisms involved have not been clarified in detail, known co-inhibitory receptors such as PD-1, CTLA-4, Tim-3, and LAG-3 have been proposed to contribute to the exhaustion of T cells, as they were accumulated in HIV-1-specific T cells [3, 4]. Single/combined blockade of co-inhibitory receptor has been attempted to restore T cell function in both SIV- and HIV-1-infected models and has shown promising results [6,7,8,9,10,11,12]
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