Cell-to-Cell Spread of HIV and Viral Pathogenesis

Abstract

Human immunodeficiency virus type 1 (HIV-1) gives rise to a chronic infection that progressively depletes CD4(+) T lymphocytes. CD4(+) T lymphocytes play a central coordinating role in adaptive cellular and humoral immune responses, and to do so they migrate and interact within lymphoid compartments and at effector sites to mount immune responses. While cell-free virus serves as an excellent prognostic indicator for patient survival, interactions of infected T cells or virus-scavenging immune cells with uninfected T cells can greatly enhance viral spread. HIV can induce interactions between infected and uninfected T cells that are triggered by cell surface expression of viral Env, which serves as a cell adhesion molecule that interacts with CD4 on the target cell, before it acts as the viral membrane fusion protein. These interactions are called virological synapses and promote replication in the face of selective pressure of humoral immune responses and antiretroviral therapy. Other infection-enhancing cell-cell interactions occur between virus-concentrating antigen-presenting cells and recipient T cells, called infectious synapses. The exact roles that these cell-cell interactions play in each stage of infection, from viral acquisition, systemic dissemination, to chronic persistence are still being determined. Infection-promoting immune cell interactions are likely to contribute to viral persistence and enhance the ability of HIV-1 to evade adaptive immune responses.

Keywords: Cell-to-cell transmission; Drug resistance; HIV-1; Infectious synapse; Neutralizing antibodies; Sexual transmission; Viral reservoir; Virological synapse.

Fig. 1

Routes of HIV-1 dissemination. (A) Cell-free HIV-1 infection is mediated by virus released to the extracellular milieu that binds to CD4⁺ T cells at a distance from the infected cell. (B) T cell-to-T-cell virological synapse occurs when an infected CD4 T cell binds to an uninfected T cell through the engagement of HIV-1 Env on the surface of the infected cell and CD4 on the surface of the target cell. Cell adhesion occurs before virus particles are recruited to the synapse. (C) Dendritic cell-to-T-cell infectious synapse occurs via DC that has internalized virus into a sequestered compartment by binding to CD169/Siglec-1, DC-SIGN, or other virus-binding lectin. Binding of T cell does not require CD4, but does result in the enhanced infection of interacting CD4 T cells through a process of trans-infection. (D) Macrophage-to-T-cell infectious synapse can occur when macrophages internalize HIV-1 within plasma membrane invaginations through CD169/Siglec-1. These can mediate trans-infection through an infectious synapse, which resembles that between DC and T cells. (E) T cell-to-macrophage interaction can occur when an infected CD4⁺ T cell is phagocytosed by a macrophage. The process of phagocytosis can result in the enhanced infection of the macrophage. (See the color plate.)