Abstract
The loss of Memory CD4 T-cells (Mem) is a major hallmark of HIV-1 immuno-pathogenesis and occurs early during the first months of primary infection. A lot of effort has been put into understanding the molecular mechanisms behind this loss, yet they still have not been fully identified. In this study, we unveil the unreported role of USP18 in the deleterious effects of sustained type I IFN signaling on Mem, including HIV-1-specific CD4 T-cells. We find that interfering with IFN-I signaling pathway in infected patients, notably by targeting the interferon-stimulated gene USP18, resulted in reduced PTEN expression similar to those observed in uninfected control donors. We show that AKT activation in response to cytokine treatment, T-cell receptor (TcR) triggering, as well as HIV-1 Gag stimulation was significantly improved in infected patients when PTEN or USP18 were inhibited. Finally, our data demonstrate that higher USP18 in Mem from infected patients prevent proper cell survival and long-lasting maintenance in an AKT-dependent manner. Altogether, we establish a direct role for type I IFN/USP18 signaling in the maintenance of total and virus-specific Mem and provide a new mechanism for the reduced survival of these populations during primary HIV-1 infection.
Highlights
The maintenance of memory CD4 T-cells (Mem) represents a key component for long-lasting immune protection during persistent infections with human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) [1,2,3,4]
We expend our knowledge of how type I interferons (IFN-I) leads to memory CD4 T-cell defective survival by unveiling the molecular mechanism behind such impairments, placing ubiquitin specific peptidase 18 (USP18) at its center
To assess the IFN-I signaling intrinsic to Mem, we measured in PHI, CHI and HIVfree subjects the constitutive phosphorylation levels of STAT1 and IRF7, two IFN-I-induced transcription factors, in ex vivo Mem by PhosFlow
Summary
The maintenance of memory CD4 T-cells (Mem) represents a key component for long-lasting immune protection during persistent infections with human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) [1,2,3,4]. In this context, the elite controllers, who naturally control HIV-1 infection for decades in the absence of anti-retroviral therapy (ART), display the ability to maintain a large pool of Mem [4, 5]. Shedding light on such a network will enable better treatment, since individual factors are not enough to understand the full clinical picture of the disease
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