Mechanisms of HIV-1 cell-to-cell transmission and the establishment of the latent reservoir

Abstract

HIV-1 spreads through both the release of cell-free particles and by cell-to-cell transmission. Mounting evidence indicates that cell-to-cell transmission is more efficient than cell-free transmission of particles and likely influences the pathogenesis of HIV-1 infection. This mode of viral transmission also influences the generation and maintenance of the latent reservoir, which represents the main obstacle for curing the infection. In this review we will discuss general cell contact-dependent mechanisms that HIV-1 utilizes for its spread and the evidence pointing to cellto-cell transmission as a mechanism for the establishment and maintenance of latent infection.

Cell-to-cell transport in viral families: faster than usual

“…Cell-tocell infection, at least in vitro is more efficient (Chen et al, 2007;Sourisseau et al, 2007), enables the resistance of the virus to certain classes of antiviral drugs (Sigal et al, 2011;Titanji et al, 2013) and to broadly neutralizing antibodies (Li et al, 2017;Reh et al, 2015). What more, cell-to-cell transmission of HIV-1 is an important route that leads to the establishment of latent infection (Pedro et al, 2019). VS can also take place between adjacent cells or on relatively long distances such as in the case of filopodia (Sherer et al, 2007;Sowinski et al, 2008).…”

“…The infectious synapse forms when the virus is captured by a cell without itself becoming infected and directs the intact particle to the target cell through the cell-cell contact (Kijewski and Gummuluru, 2015). Trans-infection is usually associated with transmission from myeloid antigen presenting cells to CD4 + T cells, such as macrophages and dendritic cells, but can occur between different other cell types (Pedro et al, 2019). Usually, HIV-1 is captured by surface molecules of APC, such as C-type lectin SIGLEC-1 and stored in nonlysosomal compartments where it avoids degradation and antibody neutralization (Gummuluru et al, 2014).…”

“…Meanwhile, complimentary processes accompanied by the cytoskeleton reorganization, are occurring in the CD4 + T cell. Variety of molecules are directed to the site of contact including CD4, CXCR4 and CCR5 and the receptors required by HIV-1 entry (Pedro et al, 2019).…”

“…Also synapse independent cell-cell transmissions are utilized by HIV-1, such as phagocytosis, where macrophages phagocytosing dying HIV-1-infected CD4 + T cells subsequently become infected (Baxter et al, 2014); syncytium formation, which occurs as a consequence of HIV-1-gp120 on infected cells interacting with CD4 on uninfected cells resulting in the fusion of the two cell membranes (Bracq et al, 2018); tunneling nanotubes, where the virus usually transfers through the nanotubes inside the endosomes (Kadiu and Gendelman, 2011a,b); and transcytosis (Pedro et al, 2019).…”

Modeling the dynamics of viral infections in presence of latently infected cells

“…A recent study found that cell-to-cell transmission contributes to the production of latently infected cells [1] . This mode of viral transmission is found to contribute to both the spread and pathogenesis of the virus in vivo and to the production and maintenance of latent reservoirs that represent a serious barrier to the curing of the infection [19] .…”