Mechanisms of enhanced HIV spread through T‐cell virological synapses

Abstract

An elaborate network of cell-cell interactions in the immune system is essential for vertebrates to mount adaptive immune responses against invading pathogens. For lymphotropic viruses such as the human immunodeficiency virus type 1 (HIV-1), these immune cell interactions can also promote the spread of the virus within the host. The main target of HIV-1 infection is the CD4(+) helper T lymphocyte, a cell type that is responsible for coordinating immune responses and modulating effector responses to foreign antigens. As part of their normal immune surveillance duties, these cells migrate actively within lymphoid tissues and can travel from inductive sites to effector sites in search of their cognate antigen. For CD4(+) T cells, there is an ongoing search for a unique peptide antigen presented in the context of class II MHC that can activate a proliferative or tolerogenic response. This iterative and continual probing and interrogation of other cells determine the outcome of immune responses. Recent studies in vitro have revealed that the viral infection program induces cell-cell interactions called virological synapses between infected and uninfected CD4(+) T cells. These long-lived, virally induced adhesive contacts greatly enhance the rate of productive infection and may be central to the spread of the virus in vivo. Here, we review aspects of this efficient mode of cell-to-cell infection and the implications for our understanding of HIV-1 pathogenesis.

Vaccine-Induced HIV-1 Envelope gp120 Constant Region 1-Specific Antibodies Expose a CD4-Inducible Epitope and Block the Interaction of HIV-1 gp140 with Galactosylceramide

“…Previous studies showed that CD4-independent infection of epithelial or neural cells by certain strains of HIV-1 can occur, suggesting that HIV-1 can employ alternate receptors for mucosal entry (7)(8)(9)(10). The interaction of HIV-1 with such alternate receptors can be adhesive in nature, like those described for cell-cell transmission (11,12), and therefore could potentially facilitate the mucosal entry of HIV-1. Thus, any mode of disruption of viral adhesion to epithelial cells could be a strategy to hinder mucosal entry of HIV-1.…”

Binding of HIV-1 virions to α4β7 expressing cells and impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells

“…The phenomenon of anti-integrin induced cell aggregation has been used as a common approach to investigate integrin function as reported by several studies (Andrew D P, et al, 1994;Ruegg C, et al, 1992;Zeller Y, et al, 2001). The formation of cell aggregates increases cell-cell contact, which in turn enhances viral infection (Alvarez R A, et al, 2011;Dale B M, et al, 2013;Liao Z, et al, 2000). This represents an important confounder and suggests that antibody engagement of α 4 β 7 is not an appropriate approach to determine the significance of α 4 β 7 in HIV-1 infection of primary lymphocytes (Parrish N F, et al, 2012).…”

Impact of HIV-1 infection pathways on susceptibility to antiviral drugs and on virus spread

“…In cell-free infection, infectious viral particles present in the extracellular milieu infect CD4 þ T cells via diffusion-limited spread. In cell-to-cell infection, on the other hand, HIV-1 is conveyed more directly from infected to uninfected cells, where virions are captured in narrow intercellular clefts and the physical connection formed between donor and target cells, known as the virological synapse, actively contributes to the efficient viral expansion (Dale et al, 2013;Sattentau, 2008;Zhong et al, 2013b). Moreover, events in the process of cell-to-cell HIV infection are chronologically specified, i.e., HIV viral transfer, an early event observed immediately after formation of cell-to-cell contact, is followed by a later, sometimes independent, event, HIV productive transmission, which ensures the infection .…”