HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

Abstract

HIV-1 negative factor (Nef) elevates virus replication and contributes to immune evasion in vivo. As one of its established in vitro activities, Nef interferes with T-lymphocyte chemotaxis by reducing host cell actin dynamics. To explore Nef’s influence on in vivo recirculation of T lymphocytes, we assessed lymph-node homing of Nef-expressing primary murine lymphocytes and found a drastic impairment in homing to peripheral lymph nodes. Intravital imaging and 3D immunofluorescence reconstruction of lymph nodes revealed that Nef potently impaired T-lymphocyte extravasation through high endothelial venules and reduced subsequent parenchymal motility. Ex vivo analyses of transendothelial migration revealed that Nef disrupted T-lymphocyte polarization and interfered with diapedesis and migration in the narrow subendothelial space. Consistently, Nef specifically affected T-lymphocyte motility modes used in dense environments that pose high physical barriers to migration. Mechanistically, inhibition of lymph node homing, subendothelial migration and cell polarization, but not diapedesis, depended on Nef’s ability to inhibit host cell actin remodeling. Nef-mediated interference with in vivo recirculation of T lymphocytes may compromise T-cell help and thus represents an important mechanism for its function as a HIV pathogenicity factor.

Rho’ing in and out of cells

“…Nef-mediated interference with in vivo recirculation of T lymphocytes may compromise T-cell help and therefore may function as a HIV pathogenicity factor. 191 In general, increasing evidence supports the hypothesis that the combined effects of Nef-PAK2 on T cell activity and signaling allow sufficient T cell activation necessary for optimal virus replication in this cell type, but at the same time prevent excessive antiviral T cell activation, ultimately leading to an increase in virus replication and spread. This strategy allows Nef to optimize viral replication in CD4+ T lymphocytes and at the same time disturb efficient antiviral immunity.…”

HIV-1 Nef and Vpu Interfere with L-Selectin (CD62L) Cell Surface Expression To Inhibit Adhesion and Signaling in Infected CD4+T Lymphocytes

“…Therefore, the CD62L downregulation activity evolved by HIV-1 arms the virus with a strong spreading potential. On the other hand, circulating CD4 ϩ T lymphocytes in vivo, specifically impairing their homing to lymph nodes at the transmigration step from the HEV into the lymph node parenchyma (43). The authors suggested that Nef-mediated constraint of murine T cell homing to lymph nodes relies, in large part, on the inhibition of actin remodeling via the F 195 Nef residue, but also on additional mechanisms potentially involving reduced expression of CD62L and the CCR7 chemokine receptor.…”

The Nef-Like Effect of Murine Leukemia Virus Glycosylated Gag on HIV-1 Infectivity Is Mediated by Its Cytoplasmic Domain and Depends on the AP-2 Adaptor Complex

“…Among several other cell surface proteins whose trafficking is affected by Nef are major histocompatibility class I molecules, which are downregulated by Nef to protect infected cells from recognition and lysis by cytotoxic T cells (10)(11)(12)(13)(14). Nef also modulates T cell antigen receptor signaling (15)(16)(17)(18)(19), interferes with T cell chemotaxis by inhibiting the remodeling of the actin cytoskeleton (20,21), and triggers the release of extracellular vesicles (22)(23)(24). Furthermore, the Nef proteins of certain simian immunodeficiency viruses counteract the restriction factor BST2 (25,26), which tethers budded virions to the cell surface (27).…”