Chronic HIV infection remains a major global health challenge despite advances in antiretroviral therapy (ART). While ART effectively controls viral replication, it does not eliminate HIV, leading to persistent immune activation and inflammation, which are strongly linked to disease progression. This review explores the interplay between chronic inflammation, immune metabolism, and T cell dysfunction in HIV infection, emphasizing the role of humanized mouse models in studying HIV pathogenesis and developing new therapies. Chronic inflammation is characterized by immune cell metabolic dysregulation and T cell exhaustion, which contribute to immune dysfunction. Type I interferons (IFN-Is) play a dual role in HIV infection, promoting antiviral responses but also driving chronic inflammation. Metabolic stress during HIV infection affects immune cell function, leading to lipid and glucose metabolism disorders, which exacerbate immune activation and T cell exhaustion. T cell exhaustion is marked by the expression of inhibitory receptors and metabolic alterations, impairing antiviral responses. Humanized mouse models are valuable tools for studying HIV pathogenesis, as they recapitulate human immune responses and allow for the investigation of immune metabolism and therapeutic strategies. These models have been used to evaluate the efficacy of CAR T cell therapies and to explore metabolic interventions that improve T cell function and viral control. Overall, understanding the complex interactions between immune activation, metabolism, and T cell dysfunction is crucial for developing effective HIV treatments.Chronic HIV infection remains a major global health challenge despite advances in antiretroviral therapy (ART). While ART effectively controls viral replication, it does not eliminate HIV, leading to persistent immune activation and inflammation, which are strongly linked to disease progression. This review explores the interplay between chronic inflammation, immune metabolism, and T cell dysfunction in HIV infection, emphasizing the role of humanized mouse models in studying HIV pathogenesis and developing new therapies. Chronic inflammation is characterized by immune cell metabolic dysregulation and T cell exhaustion, which contribute to immune dysfunction. Type I interferons (IFN-Is) play a dual role in HIV infection, promoting antiviral responses but also driving chronic inflammation. Metabolic stress during HIV infection affects immune cell function, leading to lipid and glucose metabolism disorders, which exacerbate immune activation and T cell exhaustion. T cell exhaustion is marked by the expression of inhibitory receptors and metabolic alterations, impairing antiviral responses. Humanized mouse models are valuable tools for studying HIV pathogenesis, as they recapitulate human immune responses and allow for the investigation of immune metabolism and therapeutic strategies. These models have been used to evaluate the efficacy of CAR T cell therapies and to explore metabolic interventions that improve T cell function and viral control. Overall, understanding the complex interactions between immune activation, metabolism, and T cell dysfunction is crucial for developing effective HIV treatments.