The article reviews the complex interplay between chronic inflammation, immune metabolism, and T cell dysfunction in HIV infection. Despite advancements in antiretroviral therapy (ART), which have transformed HIV from a fatal disease into a manageable chronic condition, a definitive cure remains elusive. Chronic inflammation, characterized by persistent immune cell metabolic dysregulation and cellular exhaustion, is strongly associated with HIV disease progression. The review highlights the role of type I interferons (IFNs) in driving immune activation and chronic inflammation, and discusses the use of humanized mouse models to study HIV immune pathogenesis and develop novel therapeutic strategies. Humanized mouse models, particularly the BLT (humanized bone marrow-liver-thymus) model, have emerged as powerful tools for studying HIV infection, immune metabolism, and T cell dysfunction. These models allow for the investigation of various therapeutic approaches, including gene and cell therapies, and have contributed to the development of anti-HIV treatments. The article also explores the potential of CAR T cell therapies in HIV treatment, emphasizing the importance of preventing T cell exhaustion and improving metabolic fitness. Overall, the review underscores the need for further research to understand and address the complex mechanisms underlying HIV infection and to develop more effective therapies.The article reviews the complex interplay between chronic inflammation, immune metabolism, and T cell dysfunction in HIV infection. Despite advancements in antiretroviral therapy (ART), which have transformed HIV from a fatal disease into a manageable chronic condition, a definitive cure remains elusive. Chronic inflammation, characterized by persistent immune cell metabolic dysregulation and cellular exhaustion, is strongly associated with HIV disease progression. The review highlights the role of type I interferons (IFNs) in driving immune activation and chronic inflammation, and discusses the use of humanized mouse models to study HIV immune pathogenesis and develop novel therapeutic strategies. Humanized mouse models, particularly the BLT (humanized bone marrow-liver-thymus) model, have emerged as powerful tools for studying HIV infection, immune metabolism, and T cell dysfunction. These models allow for the investigation of various therapeutic approaches, including gene and cell therapies, and have contributed to the development of anti-HIV treatments. The article also explores the potential of CAR T cell therapies in HIV treatment, emphasizing the importance of preventing T cell exhaustion and improving metabolic fitness. Overall, the review underscores the need for further research to understand and address the complex mechanisms underlying HIV infection and to develop more effective therapies.