Elucidating the role of B cell mediated trans infection in the establishment of the latent HIV-1 reservoir

点击翻译按钮获取中文摘要

SUMMARY HIV-1 can proliferate through both the release of cell-free particles (cis-infection) and by cell-to-cell transmission (trans-infection). Prior studies have shown that HIV-1 trans-infection: (i) is significantly more efficient than cis-infection; (ii) can efficiently infect resting CD4+ T cells, which are inherently resistant to cis- infection; and (iii) is largely insensitive to inhibition by antiretroviral therapy (ART). Consequently, HIV-1 trans- infection is thought to play a key role in the pathogenesis of HIV-1 infection. Direct evidence of HIV-1 trans- infection in vivo, however, is lacking! Our group was the first to demonstrate that activated B cells express the C-type lectin DC-SIGN and have the ability to sequester and then efficiently transfer HIV-1 to bystander CD4+T cells. B cells have a greater capacity to transfer HIV-1 to CD4+ T cells than other antigen presenting cells, including dendritic cells (DCs) and macrophages. We recently found that B cells, but not immature or mature DC, also have the unique ability to efficiently trans-infect CD4+ naïve (TN) cells – which do not express the CCR5 receptor – with R5-tropic HIV-1. Importantly, we have reported that B cells from HIV-infected nonprogressors (NPs, individuals who control viremia in the absence of ART) do not support HIV-1 trans- infection of CD4+ T cells. Consistent with these findings, purified CD4+ TN cells isolated from NPs harbor a very small (or even negligible) reservoir of total HIV-1 DNA, compared to ART-treated progressors. In this R01 application, our overarching hypothesis is that B lymphocyte-mediated cell-to-cell HIV-1 trans-infection contributes to the establishment and replenishment of the latent viral reservoir in resting CD4+ T cells, in particular CD4+ TN and T follicular helper cells. We propose to use novel state-of the-art approaches to investigate this hypothesis, and expect to provide the first evidence that HIV-1 trans-infection plays a key role in viral pathogenesis.