HIV Nef drives immune dysfunction and susceptibility to opportunistic infection

In the fifth decade of the HIV/AIDS pandemic, more than 40 million people worldwide are living with HIV. Although antiretroviral therapy (ART) has transformed HIV into a manageable chronic condition, challenges such as drug resistance, persistent viral reservoirs, and immune dysregulation continue to hinder complete viral eradication. Immune subversion particularly weakens the defences that normally control opportunistic pathogens, contributing to conditions such as candidiasis, cryptococcal meningitis, cytomegalovirus disease, viral hepatitis, toxoplasmosis, cryptosporidiosis, tuberculosis, and listeriosis, as well as AIDS-defining malignancies including Kaposi sarcoma. The HIV accessory protein Nef impairs T cell function, antigen presentation, and intracellular trafficking, making it a candidate driver of this immune vulnerability. To define the immunological consequences of persistent Nef expression in vivo, we developed a transgenic mouse model expressing Nef under the murine CD4 promoter, enabling expression in CD4 + T cells, macrophages, and dendritic cells. Sustained Nef expression caused profound immune remodelling in transgenic mice, including contraction of the CD4 + T cell compartment in both the thymus and the periphery. Antigen-specific CD8 + T cell responses were impaired following both viral and bacterial challenges. Listeria monocytogenes also persisted after secondary challenge of the transgenic mice, indicating a defect in recall immunity. These findings establish Nef as a central driver of immune dysfunction during chronic HIV infection, leading to susceptibility to opportunistic pathogens. By simultaneously disrupting T cell homeostasis and weakening antigen-specific responses, Nef undermines the coordinated immune mechanisms required to control pathogenicity, providing a mechanistic explanation for the persistent burden of co-infections in people living with HIV despite effective antiretroviral therapy. This causal role elevates Nef to a priority therapeutic target whose neutralisation may restore immune control of opportunistic infection.