The impact of HIV-1 Nef on CD4 ⁺ T cells

Human immunodeficiency virus type 1 (HIV-1) negative factor (Nef) is a multifunctional accessory protein that plays a central role in HIV-1 immunopathogenesis by compromising CD4⁺ T cell integrity and disrupting immune homeostasis. Although dispensable for viral replication <i>in vitro</i>, <i>in vivo</i> studies consistently demonstrate that Nef drives high viral burdens, facilitates immune evasion, and accelerates CD4⁺ T cell loss. Nef accomplishes these effects through a wide array of host-directed mechanisms, including the targeted downregulation of CD4 and major histocompatibility complex class I (MHC-I) molecules; perturbation of T cell receptor (TCR) signaling <i>via</i> mis-localization of the kinase Lck and disruption of immunological synapse formation; enhancement of cell-to-cell viral transmission by optimizing viral assembly and conditioning target cells for efficient infection; modulation of uninfected bystander cells through extracellular vesicles that amplify inflammatory signaling and promote permissiveness; and interference with CD4⁺ T cell trafficking by altering cytoskeletal dynamics and polarity, thereby limiting immune surveillance and facilitating viral dissemination. Evidence from non-human primate models, humanized mouse studies, and individuals infected with <i>nef</i>-defective HIV-1 strains underscores the protein's indispensable contribution to disease progression. Importantly, Nef remains active within tissue reservoirs even under suppressive antiretroviral therapy (ART), sustaining chronic immune dysfunction. Collectively, these features position Nef as an attractive therapeutic target whose inhibition may help restore immune competence and support efforts toward achieving a functional HIV-1 cure.