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 cell-to-cell transmission as a mechanism for the establishment and maintenance of latent infection.

Keywords: CD4 T cells; Dendritic cells; HIV cell-to-cell transmission; HIV latency; Infectious synapse; Resting CD4 T cells; Virological synapse.

Figure 1.. Cell-cell synapse-dependent transmission of HIV-1.

A. The infectious synapse. HIV-1 is captured by cell surface molecules such as CD169 (SIGLEC-1) and sequestered as intact particles in non-lysosomal compartments. Upon cell-cell contact and attachment via LFA-1 and ICAM-1, bound virus is brought to the site of contact where it is brought into close proximity with CD4, CXCR4 and CCR5 on the uninfected target CD4+ T cell, facilitating efficient transmission of virus. B. The virological synapse. A productively infected donor cell establishes contact with an uninfected CD4+ T cell in a gp120-CD4-dependent manner. The interaction is strengthened by binding of the attachment proteins LFA-1 and ICAM-1, and the HIV-1 co-receptors CCR5 and CXCR4 are trafficked to the site. Polarization of the infected donor cell towards the target cell results in the directed release of de novo viral particles across the synapse towards the uninfected target cell. Both forms of cell-to-cell transmission generate antigen-independent cell signaling likely impacting the outcome of HIV-1 infection in the target CD4+ T cell.

Figure 2.. The efficiency of establishing and reversing latent infection is dependent on the mechanism of resting CD4+ T cell infection.

Various modes of HIV-1 infection of resting CD4+ T cells are depicted with their corresponding efficiency for establishing infection and reversible latent infection. Although no study has compared all of these mechanisms side-by-side, we estimated infection and latency reversal efficiency qualitatively based on published observations. Light blue arrows represent lower relative levels of HIV-1 infection or latency reversion and dark blue arrows correspond to higher relative levels. A. Cell-free infection results in lower relative levels of infection (light blue arrow) but the establishment of a moderately inducible latent population (medium blue)(Agosto et al., 2018; Lassen et al., 2012; Swiggard et al., 2005). B. Cell-free infections aided by chemokines, such as CCL19 and CCL21, result in increased resting cell susceptibility to infection compared to infections without added chemokines and a moderately inducible latent population (Cameron et al., 2010; Kumar et al., 2018; Saleh et al., 2007). C. An uninfected HIV-1-carrying cell contacts an uninfected CD4+ T cell. Virus is transmitted in trans via the infectious synapse. This mode of transmission promotes latent infection of resting CD4+ T cells. However, the reversion of latent infection varies widely depending on the HIV-1-transmitting cell type, indicated by the light, medium and dark blue arrows (Kumar et al., 2015). The efficiency of latency reversion also depends whether or not the target cells are proliferating during infection in APC co-cultures (Kumar et al., 2018). D. An infected donor cell establishes contact with an uninfected donor cell and transmits HIV-1 via a virological synapse. This is an efficient method of transmission and results in moderate levels of resting cell infection. However, although latent infection can be detected in target cells by HIV-1 DNA, viral re-expression is not readily induced (Agosto et al., 2018). E. The susceptibility of resting CD4+ T cells to HIV-1 infection increases when in contact with endothelial cells and enables the establishment inducible latent infection (Choi et al., 2005a; Choi et al., 2005b; Schilthuis et al., 2018; Shen et al., 2013).