Exploiting immune cell metabolic machinery for functional HIV cure and the prevention of inflammaging

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.

Keywords: HIV; immune cells; immunometabolism; metabolic shift.

Figure 1.. CD4 ⁺ T cells reprogram glucose metabolism during infection from oxidative phosphorylation (OXphos) toward glycolysis marked by increased cell surface Glut1 and mTOR activation.

( a) mTOR regulates HIV transcription critical for viral reactivation and ongoing replication. Glycolysis regulated by mTOR provides precursors for DNA and cell wall synthesis which support homeostatic proliferation of infected CD4 ⁺ T cells. ( b) Similar to CD4 ⁺ T cells, mTOR/PI3Kinase regulates monocyte/macrophage Glut1 cell surface expression and metabolism. A metabolic shift toward glycolysis supports pro-inflammatory cytokine production in monocytes/macrophages. Glut1, glucose transporter 1; mTOR, mechanistic target of rapamycin.