A costimulatory power-boost for HIV-specific T-cells through GITR activation

A costimulatory power-boost for HIV-specific T-cells through GITR activation

Project

People infected with HIV have nowadays almost the average life expectancy of the general population. However, not all individuals control the infection well with the current therapies, and eventually progress towards AIDS. The HIV research community believes that the immune system from these individuals is still partially functional, and optimized stimulation regiments could help suppress the disease progression. We propose here that additional activation pathways, i.e., costimulation, can be used as a powerful immunotherapy to boost the functionality of HIV-specific T cells. Increasing the effector function of HIV-specific T cells can open new opportunities to halt the progression to AIDS in patients that fail to control the chronic infection with standard treatments.

Project details

Time frame
31 July 2017 - 30 November 2018
Budget
€ 74,800
Active in
Netherlands

Objectives

The main goal is to enhance functionality of HIV-specific T-cells by triggering the GITR costimulatory pathway. First, we will assess if GITR expression can be induced in attenuated HIV-specific T-cells. We will focus on the progressors, which will most likely benefit from this treatment, because their T-cells are the most dysfunctional. If GITR can be expressed by the virus-specific T-cells, we will trigger it –alone or in combination with blockade of inhibitory pathways- and determine the functionality. The choice of functional readouts will be based in described alterations in T-cells from HIV progressors.

Community groups

Our findings will reach researchers worldwide that are involved in T cell physiology in general and HIV-specific immunotherapy in particular.

Background

T-cell responses are critical to control HIV replication, yet not all individuals achieve viral control via their T-cells. In fact, high viral load correlates with poor T-cell functionality and high expression of inhibitory receptors in HIV-specific T-cells. Checkpoint blockade immunotherapies, aimed at blocking inhibitory receptors, have proven very effective in increasing anti-tumor T-cell function in different cancers, suggesting that this strategy could also be translated to HIV. However, clinical data from cancer patients indicate that blocking one pathway is not sufficient to fully restore T-cell function. Combined therapy that influences several non-redundant pathways will be a more effective approach.

We have recently shown that enhanced GITR triggering leads to increased protection against chronic LCMV infection, resulting in early control of viral replication and prevention of T-cell dysfunction (Pascutti et al, PLoS Pathog, 2015). Importantly, GITR triggering after establishment of chronicity increased T-cell function and decreased viral load in LCMV-infected mice, suggesting that attenuated T-cell responses are susceptible to costimulation. A unique feature of the GITR pathway, which makes it attractive for immunotherapy, is that GITR triggering simultaneously enhances the function of effector T-cells and Tregs, leading to a balanced response in the absence of pathology.

Goals

A cure for HIV
100%
Contributed within this project

Partners

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2016 RfP - Scientific Research High Risk, High Gain

This project is part of 2016 RfP - Scientific Research High Risk, High Gain

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