Targeting BAF complex to reverse HIV latency

Targeting BAF complex to reverse HIV latency

Project

There is no drug that can cure HIV. The HIV virus can become latent and therefore difficult to eliminate. There are many ways latent HIV ‘hides’ in the DNA of our cells. One way is to hide in a cell’s folded DNA. The BAF complex is a group of proteins that play a role in the DNA folding process. EMC researchers aim to determine whether latent HIV can be re-activated by inhibiting the BAF complex.

Project details

Time frame
29 September 2014 - 29 September 2017
Budget
€ 250,000
Active in
Netherlands

Objectives

The aim of this proposal is to investigate if BAF is a highly attractive candidate for targeted inhibition in the development of shock and kill strategies that might lead to cure.

#Aim1. to determine the molecular requirements of BAF-mediated latency, explore role of YY-1 and other sequence-specific transcription factors in BAF recruitment and activity.
#Aim2. to target BAF for inhibition using a novel class of small molecule inhibitors recently available through a formal collaboration (Dr. Palmer, Broad Institute) in spectrum of CD4+ T cell systems reflecting HIV latency available in our laboratory, and determine biomarkers and molecular mechanism of BAF inhibitors.
#Aim3. to examine effectiveness of BAF inhibitors in activation of latent HIV-1 alone and in combination with other latency reversing agents.
#Aim4. to validate and test the effects of candidate small molecule BAF inhibitors for HIV-1 activation in primary memory CD4+ T cells, the in vivo reservoir for latent HIV-1 in 30 people with HIV.

This could contribute to an HIV cure.

Community groups

scientific community
people living with HIV

Background

Currently, there is no drug that can cure HIV. The HIV virus can become latent and therefore difficult to eliminate. There are many ways latent HIV ‘hides’ in the DNA of our cells. One way is to hide in a cell’s folded DNA.

The concept of eradication of the Human Immune Deficiency Virus (HIV-1) from infected patients has gained much attention in the last few years. Recently, new pharmaceutical strategies aimed at HIV-1 eradication have focused on molecules able to induce HIV-1 replication from latently infected cells in order to render them susceptible to viral cytopathic effects, antiviral immune responses and antiretroviral drugs. In focusing towards approaches to purge the latent HIV-1 infected reservoir from patients, there is an increasing boost for the identification of new cellular targets than can be modulated to achieve HIV-1 activation from latently infected cells. We recently identified the BAF complex as a major player in the establishment of HIV-1 latency through nucleosome positioning. Due to the fundamental role of BAF in establishing and maintaining HIV-1 latency, we believe that this complex can be a promising target for HIV-1 purging therapies.

Goals

A cure for HIV
100%
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