Nef as a driver of immunodeficiency and HIV-associated diseases: insights from mouse models

Nef is a non-structural regulatory protein of human immunodeficiency virus (HIV) that exerts pleiotropic effects on the immune system. In infected cells, Nef modulates the surface expression of molecules critical for immune responses and regulates cytokine production, vesicular trafficking, and lipid metabolism as well as apoptosis and autophagy. Despite significant improvements in antiretroviral therapy (ART), Nef is detected in the circulation of HIV-infected individuals as a soluble protein and in association with virions and extracellular vesicles, and it is regarded as a driver of a broad spectrum of HIV-associated comorbidities. Serum Nef concentrations range from a few to several tens of ng/mL, comparable to systemic levels of certain proinflammatory cytokines in inflammatory diseases. This reflects the fact that the primary sources of Nef are cellular viral reservoirs in which ART does not suppress viral protein expression. Among these reservoirs, long-lived HIV-infected memory CD4⁺ T cells and tissue-resident macrophages are considered the major contributors to systemic Nef production. Due to the need for a more comprehensive understanding of the in vivo functions of Nef and the molecular mechanisms by which it contributes to HIV-associated pathogenesis, a variety of mouse models expressing Nef were developed. This review summarizes existing transgenic mouse models with cell type-specific Nef expression and humanized mouse models used in HIV research, including models based on Nef-deficient strains. The development and systematic characterization of such models are essential for providing experimental validation for the clinical implementation of Nef inhibitors in combination with established ART.