Abstract
T cells are critical for the control of viral infections and T cell responses are regulated by a dynamic network of non-coding RNAs, including microRNAs (miR) and long non-coding RNAs (lncRNA). Here we show that an activation-induced decline of lncRNA growth arrest-specific transcript 5 (GAS5) activates DNA damage response (DDR), and regulates cellular functions and apoptosis in CD4 T cells derived from people living with HIV (PLHIV) via upregulation of miR-21. Notably, GAS5-miR21-mediated DDR and T cell dysfunction are observed in PLHIV on antiretroviral therapy (ART), who often exhibit immune activation due to low-grade inflammation despite robust virologic control. We found that GAS5 negatively regulates miR-21 expression, which in turn controls critical signaling pathways involved in DNA damage and cellular response. The sustained stimulation of T cells decreased GAS5, increased miR-21 and, as a result, caused dysfunction and apoptosis in CD4 T cells. Importantly, this inflammation-driven T cell over-activation and aberrant apoptosis in ART-controlled PLHIV and healthy subjects (HS) could be reversed by antagonizing the GAS5-miR-21 axis. Also, mutation of the miR-21 binding site on exon 4 of GAS5 gene to generate a GAS5 mutant abolished its ability to regulate miR-21 expression as well as T cell activation and apoptosis markers compared to the wild-type GAS5 transcript. Our data suggest that GAS5 regulates TCR-mediated activation and apoptosis in CD4 T cells during HIV infection through miR-21-mediated signaling. However, GAS5 effects on T cell exhaustion during HIV infection may be mediated by a mechanism beyond the GAS5-miR-21-mediated signaling. These results indicate that targeting the GAS5-miR-21 axis may improve activity and longevity of CD4 T cells in ART-treated PLHIV. This approach may also be useful for targeting other infectious or inflammatory diseases associated with T cell over-activation, exhaustion, and premature immune aging.
Highlights
HIV/AIDS pandemic affects 1.1 million individuals in the United States and more than 36 million people worldwide [1, 2]
As a first step to elucidate the role of growth arrest-specific transcript 5 (GAS5) in T cell regulation during HIV infection, we measured its expression in CD4 T cells isolated from antiretroviral therapy (ART)-controlled people living with HIV (PLHIV) and age-matched healthy subjects (HS)
To determine whether GAS5 plays a role in T cell dysfunctions via regulating miR-21 expression during HIV infection, we measured miR-21 levels in CD4 T cells isolated from ARTcontrolled PLHIV and HS by RT-qPCR
Summary
HIV/AIDS pandemic affects 1.1 million individuals in the United States and more than 36 million people worldwide [1, 2]. The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells, with progressive decline of host immunity, leading to an increased susceptibility to opportunistic infections, malignancies, and death [3, 4]. While combined antiretroviral therapy (ART) can effectively control viral replication in the majority of people living with HIV (PLHIV), ART does not always result in complete recovery of CD4 T cells [5, 6]. The inflammaging imposed by latent HIV infection exposes the immune system to unique challenges that lead to profound T cell exhaustion and senescence, a major driver of increased infections, cancers, cardiovascular diseases, and neurodegeneration, and similar to what is observed in the elderly [11, 12]. It is fundamentally important to elucidate the mechanisms underlying T cell aging in PLHIV with ARTcontrolled latent infection
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