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

Abstract

Leukocyte recirculation between blood and lymphoid tissues is required for the generation and maintenance of immune responses against pathogens and is crucially controlled by the L-selectin (CD62L) leukocyte homing receptor. CD62L has adhesion and signaling functions and initiates the capture and rolling on the vascular endothelium of cells entering peripheral lymph nodes. This study reveals that CD62L is strongly downregulated on primary CD4؉ T lymphocytes upon infection with human immunodeficiency virus type 1 (HIV-1). Reduced cell surface CD62L expression was attributable to the Nef and Vpu viral proteins and not due to increased shedding via matrix metalloproteases. Both Nef and Vpu associated with and sequestered CD62L in perinuclear compartments, thereby impeding CD62L transport to the plasma membrane. In addition, Nef decreased total CD62L protein levels. Importantly, infection with wild-type, but not Nef-and Vpu-deficient, HIV-1 inhibited the capacity of primary CD4؉ T lymphocytes to adhere to immobilized fibronectin in response to CD62L ligation. Moreover, HIV-1 infection impaired the signaling pathways and costimulatory signals triggered in primary CD4؉ T cells by CD62L ligation. We propose that HIV-1 dysregulates CD62L expression to interfere with the trafficking and activation of infected T cells. Altogether, this novel HIV-1 function could contribute to virus dissemination and evasion of host immune responses. Effective immune surveillance is dependent on the constitutive recirculation of lymphocytes through anatomically dispersed secondary organs. To gain entry to the peripheral lymph nodes (PLNs), lymphocytes must bind and traverse high endothelial venules (HEVs) through a multistep process that is initiated by the interaction of the lectin-like receptor L-selectin (CD62L) on the surfaces of lymphocytes with glycoproteins expressed by HEVs (e.g., CD34 and GlyCAM-1) (1). CD62L knockout mouse models demonstrated that CD62L plays an essential role in leukocyte homing to lymphoid tissues and sites of inflammation (2), as well as in the generation of T cell responses (3). Engagement of CD62L supports the capture of T lymphocytes from the bloodstream, followed by their rolling along HEVs. Upon binding its ligands, CD62L also initiates a number of events, including activation of signaling cascades, rearrangement of the actin cytoskeleton, and enhancement of integrin binding to components of the extracellular matrix expressed by HEVs, which is a prerequisite for T cell arrest and transmigration (4). In addition, CD62L cross talks with the T cell receptor (TCR), since triggering of CD62L provides a costimulatory signal for lymphocyte activation via the TCR (5) and TCR activation enhances the binding activity of CD62L (6).Upon antigen (Ag) stimulation of T cells, the ectodomain of CD62L is cleaved by activated matrix metalloproteases (MMPs) and released in a soluble form (sCD62L), thus allowing reentry into circulation of T cells with helper and effector functions (7). Shedding of CD62L has importa...

Mass Cytometric Analysis of HIV Entry, Replication, and Remodeling in Tissue CD4+ T Cells

“…Four proteins in our panel—CD4, CCR5, CD28, and CD62L—were shown to be down-modulated by Nef (Garcia and Miller, 1991; Michel et al, 2005; Swigut et al, 2001; Vassena et al, 2015). Exclusion of these four markers during t-SNE analysis (i.e.…”

Progesterone Levels Associate with a Novel Population of CCR5+CD38+ CD4 T Cells Resident in the Genital Mucosa with Lymphoid Trafficking Potential

“…However, HIV viral proteins have been shown to interfere with lymph homing signaling pathways in infected cells (42). FGT memory CD4 T cells co-express CCR7 and markers of HIV susceptibility, but whether these cells could support virus trafficking into lymph nodes via CCR7-mediated chemotaxis is unknown.…”

HIV-1 Vpu Downmodulates ICAM-1 Expression, Resulting in Decreased Killing of Infected CD4 + T Cells by NK Cells

“…They include immunoreceptors, such as human leukocyte antigen C (HLA-C) (20), NK-T-B antigen (NTB-A) (21), CD1d (22), and poliovirus receptor (PVR) (23); homing molecules, like CCR7 (24) and CD62L (25); sodium-coupled neutral amino acid transporter 1 (SNAT1) (26); and numerous members of the tetraspanin family (27). These downregulations lead to a wide array of immunomodulatory effects, including immune evasion and metabolic dysfunction.…”