High Level of Coreceptor-independent HIV Transfer Induced by Contacts between Primary CD4 T Cells

Abstract

Cell-to-cell virus transmission is one of the most efficient mechanisms of human immunodeficiency virus (HIV) spread, requires CD4 and coreceptor expression in target cells, and may also lead to syncytium formation and cell death. Here, we show that in addition to this classical coreceptor-mediated transmission, the contact between HIV-producing cells and primary CD4 T cells lacking the appropriate coreceptor induced the uptake of HIV particles by target cells in the absence of membrane fusion or productive HIV replication. HIV uptake by CD4 T cells required cellular contacts mediated by the binding of gp120 to CD4 and intact actin cytoskeleton. HIV antigens taken up by CD4 T cells were rapidly endocytosed to trypsin-resistant compartments inducing a partial disappearance of CD4 molecules from the cell surface. Once the cellular contact was stopped, captured HIV were released as infectious particles. Electron microscopy revealed that HIV particles attached to the surface of target cells and accumulated in large (0.5-1.0 m) intracellular vesicles containing 1-14 virions, without any evidence for massive clathrin-mediated HIV endocytosis. The capture of HIV particles into trypsin-resistant compartments required the availability of the gp120 binding site of CD4 but was independent of the intracytoplasmic tail of CD4. In conclusion, we describe a novel mechanism of HIV transmission, activated by the contact of infected and uninfected primary CD4 T cells, by which HIV could exploit CD4 T cells lacking the appropriate coreceptor as an itinerant virus reservoir.For many viruses, cell-to-cell virus transmission is the most efficient mechanism of viral spread because of the extremely low infectivity of free viral particles (1). In the case of human immunodeficiency virus (HIV), 1 free viral particles are infectious but show a short life span at 37°C (2) and lower infective capacity than cell-to-cell transmission (3). This latter phenomenon is favored by the polarization of viral production in the infected cell (4) and the viral receptors and coreceptors in the target cell leading to the formation of a functional (infectious) virological synapse (5, 6). Cell-to-cell virus transmission is probably involved in the spread of HIV among different populations of CD4 ϩ cells in vivo and seems to play an essential role in sexual or vertical transmission through epithelia (7,8).The process of membrane fusion induced by the envelope glycoprotein complex of HIV is independent of pH, and therefore endocytic internalization and endosomal acidification are not required to activate HIV entry into the cytoplasm (9 -12). Instead, viral entry involves direct fusion of viral and plasma cell membrane that allows for the delivery of the viral core into the cytoplasm of target cells (13). First, HIV envelope (gp120/gp41, Env) binds to CD4 and then to a chemokine receptor (CXCR4 for X4 strains and CCR5 for R5 strains), which is used by HIV particles to activate the gp41-mediated membrane fusion.A variety of cell types such as macrophages, endot...

Predominant Mode of Human Immunodeficiency Virus Transfer between T Cells Is Mediated by Sustained Env-Dependent Neutralization-Resistant Virological Synapses

“…Viral Gag antigen in the target T cells was detected following contact with infected donor cells. Others have reported that coreceptor-independent transfer of HIV is promoted by cell-to-cell contact (3) and that limiting cell contact in vitro by continuously agitating cells can reduce viral spread in culture (59). These studies all suggest that the process of cell-to-cell viral transfer is coordinated to maximize vectorial transfer of virus into uninfected cells.…”

Human immunodeficiency virus (HIV)-1 proteins and cytoskeleton: partners in viral life and host cell death

“…This may result in the formation of the so-called viral 'synapse' 52 with consequent viral entry in target cells, but also in profound cytopathic events, such as cell-to-cell fusion. 53 The generation of syncytia, leading to the well-known cytopathic effect of HIV-1, can result in immune cell death. 54 Together, these findings point to the cortical boundary line of actin-associated cytoskeleton as regulator of cell polarity in terms of cell infection, viral particle spreading and, as further described below, in cell death.…”

Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs

“…Different models that have been proposed for T cell VS-mediated transmission are distinguished by the extent to which cell-free virions accumulate at the cell-cell interface. While it has been suggested that cell-free particles may gather at the cell-cell junction and fuse at the cell surface (8,12,14), other studies indicate that HIV-1 is first transferred across VS in a coreceptorindependent manner (1,(14)(15)(16)(17)(18) and is concentrated in trypsin-resistant endocytic compartments where viral fusion occurs (1,18). In live imaging studies of VS formation, Env/CD4-dependent cell adhesion can be observed before Gag is recruited to the site of cell-cell contact, indicating that Env may first function as a cell adhesion molecule even prior to the time at which the virus particle is formed (16).…”