Cell-to-cell transmission of retroviruses: Innate immunity and interferon-induced restriction factors

Abstract

It has been known for some time that retroviruses can disseminate between immune cells either by conventional cell-free transmission or by directed cell-to-cell spread. Over the past few years there has been increasing interest in how retroviruses may use cell-to-cell spread to promote more rapid infection kinetics and circumvent humoral immunity. Effective humoral immune responses are intimately linked with innate immunity and the interplay between retroviruses and innate immunity is a rapidly expanding area of research that has been advanced considerably by the identification of cellular restriction factors that provide barriers to retroviral infection. The effect of innate immunity and restriction factors on retroviral cell-to-cell spread has been comparatively little studied; however recent work suggests this maybe changing. Here I will review some recent advances in what is a budding area of retroviral research.

Fig. 1

Scanning electron micrographs (SEM) showing the characteristic tetherin-mediated restriction of HIV-1 release from T cells. A) Jurkat T cells infected with Vpu-defective HIV-1 (ΔVpu- HIV-1) and B) Jurkat T cells infected with Vpu-expressing WT HIV-1 (WT HIV-1) were imaged by SEM at 7 days post-infection. Left hand panel scale bar = 500nm. Right hand panels show higher magnification of the T cell plasma membrane arrows, scale bar = 200nm. Some example virions are indicated with arrows. Note that more virions are tethered at the plasma membrane of cells infected with Vpu-defective virus (upper panels).

Fig. 2

A proposed model for cell-to-cell spread of Vpu-defective HIV-1 in the presence of different amounts of unantagonized tetherin on the surface of the virus-producing cell. Under conditions where the donor cell expresses lower levels of tetherin (e.g., endogenous expression on T cells) cell-to-cell spread can occur and target T cells become productively infected. When the donor cell expresses very high levels of tetherin (e.g., epithelial cells such as HeLa cells or cells over-expressing plasmid-encoded tetherin) then virus could be transferred as unusually large, tethered aggregates that cannot fuse appropriately at the plasma membrane and productive infection would be blocked.