Human immunodeficiency virus type 1 Negative Regulatory Factor – Src-family kinase Src homology 3 interface (Nef-SH3 interface)

HIV-1 Nef is a multifunctional accessory protein that is essential for the high-titer replication of the human immunodeficiency virus and the progression to AIDS [1, 4]. Lacking enzymatic activity, Nef functions as a molecular adaptor that hijacks host cell signaling and trafficking machinery through various protein-protein interactions [1, 6]. A key interaction involves the binding of the conserved PxxPxR motif in Nef to the Src homology 3 (SH3) domains of host Src-family kinases (SFKs), such as Hck, Lyn, and c-Src [3, 9]. This interaction displaces the SH3 domain from its auto-inhibitory position, leading to the constitutive activation of the kinase [7, 8]. This signaling event is critical for enhancing viral infectivity and promoting immune evasion by facilitating the downregulation of major histocompatibility complex class I (MHC-I) from the surface of infected cells [6, 11, 15]. Small-molecule inhibitors targeting the Nef-SH3 interface are being developed to disrupt these processes, thereby suppressing viral replication and restoring the immune system's ability to recognize and eliminate HIV-infected cells [10, 11, 14]. These inhibitors offer a novel therapeutic approach that could complement existing antiretroviral therapies by targeting viral persistence and immune escape mechanisms [6, 11]. Preclinical studies have identified several chemical scaffolds, including hydroxypyrazoles and isothiazolones, that effectively block this interaction and its downstream effects [10, 11]. The development of these agents faces challenges such as ensuring specificity to avoid interfering with normal host kinase functions and addressing the high mutation rate of the HIV-1 genome [2, 6]. Overall, the Nef-SH3 interface represents a high-value target for the next generation of HIV treatments aimed at achieving a functional cure [1, 14].

Other names

Nef-Hck interactionNef-SFK interactionNef-SH3 domain interactionNef-PxxPxR motif interactionHIV-1 Nef-Src homology 3 domain complex

Inhibition of the protein-protein interaction between HIV-1 Nef and host Src-family kinase SH3 domains, preventing allosteric kinase activation and restoring MHC-I surface expression.