Mechanism of cell-associated HIV-1 transmission

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS in humans. Dendritic cells (DCs) are one of the initial cell types that are targeted by the virus early following virus transmission to a naive host, and play a critical role in the establishment of productive virus infection and dissemination of HIV-1 in vivo. While DCs themselves are invariably infected, HIV-1 particles captured by DCs are efficiently transmitted to CD4+ T cells, a mechanism of HIV-1 trans infection. Though studied extensively, the mechanisms by which HIV-1 particles invade DCs and evade intracellular defenses have remained elusive. A number of dendritic cell-specific HIV-1 attachment factors have been proposed to account for DC-mediated virus capture in a HIV-1 envelope gp120 dependent manner. But targeted neutralization of any or all of these previously proposed HIV-1 attachment factors in DCs, fails neither to inhibit virus capture nor transmission of captured HIV-1 particles from DCs to T cells, suggesting the existence of gp120-independent virus capture mechanism(s) in DCs. We propose that HIV-1 can bind DCs using glycosphingolipids expressed in the lipid bilayer of the virus particle membrane. One of the major goals of this project is to identify the receptor that captures HIV-1 particles in a glycosphingolipid-dependent manner. Based on our preliminary findings, we will focus our attentions on GPI-linked proteins expressed on DC-surface. We will identify the putative receptor amongst this subset of proteins whose expression is induced upon differentiation from monocytes into DCs and whose expression is significantly enhanced upon maturation of DCs. We will define the nature of the endocytic compartment accessed by HIV-1 particles within DCs upon GSL-dependent HIV binding to this putative receptor and the ensuing intracellular trafficking mechanism that targets captured virus particles away from lysosomal degradation pathways. Finally, we will compare and contrast the fate of virus particles upon accessing a gp120-dependent versus GSL-dependent attachment factor(s) and determine if GSLs present in the virus particle membrane are crucial for targeting HIV-1 particles to the DC-mediated T cell trans infection pathway. Understanding the mechanism by which this occurs will provide information about a key step in the HIV - dendritic cell interaction pathway, and provide insights into the role of dendritic cells in HIV-1 pathogenesis. Furthermore, elucidation of this mechanism of HIV-1 attachment to DCs might provide novel targets for design of anti-virals that specifically target an early step in the HIV-1 life cycle. PUBLIC HEALTH RELEVANCE: The aim of this project is to identify the mechanism(s) by which human immunodeficiency virus type 1 (HIV-1) is captured by dendritic cells, a critical step in the establishment of infection and dissemination of virus in vivo. A detailed understanding of the receptor that captures HIV-1 in a Env-independent, glycosphingolipid-dependent manner, and results in sequestration of HIV infectivity within DCs is a crucial step in HIV-1 pathogenesis, and could lead to the development of anti-virals such as microbicides that prevent transmission of HIV-1 to a naive host.