Abstract
The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells. Despite effective control by antiretroviral therapy (ART), a significant subgroup of people living with HIV (PLHIV) fails to achieve complete immune reconstitution, deemed as immune non-responders (INRs). The mechanisms underlying incomplete CD4 T cell recovery in PLHIV remain unclear. In this study, CD4 T cells from PLHIV were phenotyped and functionally characterized, focusing on their mitochondrial functions. The results show that while total CD4 T cells are diminished, cycling cells are expanded in PLHIV, especially in INRs. HIV-INR CD4 T cells are more activated, displaying exhausted and senescent phenotypes with compromised mitochondrial functions. Transcriptional profiling and flow cytometry analysis showed remarkable repression of mitochondrial transcription factor A (mtTFA) in CD4 T cells from PLHIV, leading to abnormal mitochondrial and T cell homeostasis. These results demonstrate a sequential cellular paradigm of T cell over-activation, proliferation, exhaustion, senescence, apoptosis, and depletion, which correlates with compromised mitochondrial functions. Therefore, reconstituting the mtTFA pathway may provide an adjunctive immunological approach to revitalizing CD4 T cells in ART-treated PLHIV, especially in INRs.
Highlights
HIV/AIDS is characterized by a progressive depletion of CD4 T cells, leading to a gradual deficiency in host immunity, along with increased susceptibility to opportunistic infections and, death [1]
We demonstrate that CD4 T cell homeostasis is disrupted in antiretroviral therapy (ART)-controlled people living with HIV (PLHIV) and that CD4 T cells exhibit characteristics of cellular activation, exhaustion, senescence, apoptosis, and decreased proliferation and mitochondrial fitness
We believe that the mitochondrial and CD4 T cell dysregulations observed in these virus-controlled PLHIV are caused by either immunologic scarring during early active viral infection or, more likely, by low-grade inflammation during latent viral infection, or both
Summary
HIV/AIDS is characterized by a progressive depletion of CD4 T cells, leading to a gradual deficiency in host immunity, along with increased susceptibility to opportunistic infections and, death [1]. Even with satisfactory recovery of CD4 T cell numbers, viruscontrolled subjects often exhibit both immunologic scarring and low-grade inflammation, leading to an “inflammaging” phenotype that is characterized by accelerated telomere loss, reduced proliferative capacity, low IL-2/IFN-g production, and poor vaccine responses [5, 6]. This inflammaging process exposes the immune system to unique challenges that induce T cell exhaustion and senescence, a major driver of the increased incidences of infections, cancers, cardiovascular, and neurodegenerative diseases in ART-controlled PLHIV - similar to the phenotypes often observed in the elderly [7,8,9,10]. ART-controlled, virus-suppressed HIV infection provides an excellent model for studying inflammaging in humans, and it is fundamentally important to elucidate the mechanisms underlying T cell exhaustion and senescence in PLHIV, especially in INRs
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.