Abstract
An emerging paradigm in immunology suggests that metabolic reprogramming and immune cell activation and functions are intricately linked. Viral infections, such as HIV infection, as well as cancer force immune cells to undergo major metabolic challenges. Cells must divert energy resources in order to mount an effective immune response. However, the fact that immune cells adopt specific metabolic programs to provide host defense against intracellular pathogens and how this metabolic shift impacts immune cell functions and the natural course of diseases have only recently been appreciated. A clearer insight into how these processes are inter-related will affect our understanding of several fundamental aspects of HIV persistence. Even in patients with long-term use of anti-retroviral therapies, HIV infection persists and continues to cause chronic immune activation and inflammation, ongoing and cumulative damage to multiple organs systems, and a reduction in life expectancy. HIV-associated fundamental changes to the metabolic machinery of the immune system can promote a state of “inflammaging”, a chronic, low-grade inflammation with specific immune changes that characterize aging, and can also contribute to the persistence of HIV in its reservoirs. In this commentary, we will bring into focus evolving concepts on how HIV modulates the metabolic machinery of immune cells in order to persist in reservoirs and how metabolic reprogramming facilitates a chronic state of inflammation that underlies the development of age-related comorbidities. We will discuss how immunometabolism is facilitating the changing paradigms in HIV cure research and outline the novel therapeutic opportunities for preventing inflammaging and premature development of age-related conditions in HIV + individuals.
Highlights
Activation of immune cells in response to infection leads to upregulation of metabolic pathways for energy generation as well as biosynthesis to support proliferation and effector molecule production[1,2]
The impact of key metabolic pathways on immune cell development, fate, and functions is well described, only a handful of studies have focused on determining the impact of pathogens on the intrinsic immune cellular metabolic activities[3,4,5]
Challenges associated with HIV-associated inflammation and HIV reservoir persistence Despite effective anti-retroviral therapy (ART), two key clinical challenges remain elusive
Summary
Activation of immune cells in response to infection leads to upregulation of metabolic pathways for energy generation as well as biosynthesis to support proliferation and effector molecule production[1,2]. Whereas the “block and lock” predominantly focusses on limiting the transcription of latent HIV DNA through mTOR suppression, the “starve” model earlier proposed by Palmer et al posits subduing the metabolic activity of reservoir cells to limit homeostatic proliferation while controlling the metabolic state within T cells and macrophages, essential for viral infectivity[36,78]. MTOR and latency-reversing agents: toward an HIV cure Recent work by Siliciano’s group has provided an experimental model supporting an interesting combination approach by which mTOR drugs could mitigate LRA-mediated inflammatory responses and toxicity while maximally reactivating the HIV reservoir[80] In their in vitro latency model, rapamycin did not inhibit HIV reactivation in a dose-dependent manner in activated CD4+ T cells from individuals on suppressive ART. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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