Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers.

Enrique Martin-Gayo,Taylor Hickman,Bruce D Walker,Maria Jose Buzon,Mathias Lichterfeld,Dina Pimenova,Xu G Yu,Zhengyu Ouyang,Jacqueline Cronin,Guido Silvestri

doi:10.1371/journal.ppat.1004930

Abstract

The majority of HIV-1 elite controllers (EC) restrict HIV-1 replication through highly functional HIV-1-specific T cell responses, but mechanisms supporting the evolution of effective HIV-1-specific T cell immunity in these patients remain undefined. Cytosolic immune recognition of HIV-1 in conventional dendritic cells (cDC) can facilitate priming and expansion of HIV-1-specific T cells; however, HIV-1 seems to be able to avoid intracellular immune recognition in cDCs in most infected individuals. Here, we show that exposure of cDCs from EC to HIV-1 leads to a rapid and sustained production of type I interferons and upregulation of several interferon-stimulated effector genes. Emergence of these cell-intrinsic immune responses was associated with a reduced induction of SAMHD1 and LEDGF/p75, and an accumulation of viral reverse transcripts, but inhibited by pharmacological blockade of viral reverse transcription or siRNA-mediated silencing of the cytosolic DNA sensor cGAS. Importantly, improved cell-intrinsic immune recognition of HIV-1 in cDCs from elite controllers translated into stronger abilities to stimulate and expand HIV-1-specific CD8 T cell responses. These data suggest an important role of cell-intrinsic type I interferon secretion in dendritic cells for the induction of effective HIV-1-specific CD8 T cells, and may be helpful for eliciting functional T cell immunity against HIV-1 for preventative or therapeutic clinical purposes.

Highlights

Elite controllers can maintain undetectable levels of HIV-1 viral replication in the absence of antiretroviral therapy, at least in part through the generation of highly-efficient HIV-1-specific T cell responses [1,2,3,4]
To determine whether human primary conventional dendritic cells (cDC) from Elite controllers (EC) are capable of mounting cell-intrinsic type I IFN responses against HIV-1, we conducted ex-vivo infection experiments with PBMC from different study cohorts with a GFP-encoding vesicular stomatitis virus G envelope protein (VSV-G) pseudotyped HIV-1 virus causing single rounds of viral infections [16]; this viral construct infects cells independently of viral coreceptor-mediated entry processes, but can be intracellularly sensed in a similar way as R5-tropic primary HIV-1 isolates [27]
Cells from untreated, chronically HIV-1-infected patients (CP), HIV-1-infected patients receiving suppressive antiretroviral therapy (HAART) and HIV-1-uninfected persons were used for comparison

Summary

Introduction

Elite controllers can maintain undetectable levels of HIV-1 viral replication in the absence of antiretroviral therapy, at least in part through the generation of highly-efficient HIV-1-specific T cell responses [1,2,3,4] As such, these patients provide living evidence that in principle, the human immune system is capable of generating a T cell-mediated immune response that allows to effectively controlling HIV-1 replication. These patients provide living evidence that in principle, the human immune system is capable of generating a T cell-mediated immune response that allows to effectively controlling HIV-1 replication It is uncertain why such immune responses occur only in very few patients, and what mechanisms support the development of highly-effective T cell immune responses in such a small number of individuals, and not in the majority of alternative individuals. Understanding the mechanisms that facilitate the induction of effective HIV-1-specific T cells by dendritic cells is of critical interest for developing improved immunologic approaches for HIV-1 treatment and prevention, since most HIV-1 vaccine candidates rely on dendritic cells for inducing HIV-1-specific immune responses

Methods

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Discussion

Conclusion