Activation of latent HIV virus

Activation of latent HIV virus

Project

HIV therapy keeps the virus under control, but does not provide a cure. One cause is because HIV ‘hides’ in viral reservoirs, where it remains latent and invisible to the immune system. AMC researcher, Prof. Ben Berkhout, aims to identify how to re-activate latent HIV so that the virus can then be suppressed. He will study how antibodies interact and determine which factors are important for the re-activation of latent HIV.

Project details

Time frame
31 January 2014 - 31 January 2017
Budget
€ 250,000
Active in
Netherlands

Objectives

This project aims to study the activation of latent HIV-1 proviruses in primary T cells by dendritic cells.
The aims are:
1. To study the molecular mechanism of the DC-induced HIV-1 activation in primary T cells and determine the factors involved.
2 - To study HIV-1 activation from proviral latency in ex vivo experiments with HIV-1 infected CD4+ T cells from patients and different DC subsets.
3 - To study the different HIV-1 subtypes in their latency establishment and activation in primary T cells.

We have designed a model system using primary cells and wild-type virus to study HIV-1 latency early after infection and this may give us more information about the establishment and activation of this proviral reservoir.

Community groups

scientific community
people living with HIV

Background

Eradication of HIV-1 from an infected individual cannot be achieved by the current drug regimens (2-4). Viral reservoirs are established early during infection, remain unaffected by anti-retroviral therapy and are able to restart systemic infection upon interruption of treatment. These viral reservoirs are not static but are replenished over time and represent the history of infection. Therapeutic targeting of viral latency will require a better understanding of the basic mechanisms underlying the establishment and long-term maintenance of these silent HIV 1 proviruses. This is particularly true for the resting memory CD4+ T cells that form the most prominent reservoir of transcriptional silent proviruses. The molecular mechanisms that control long-term transcriptional silencing of proviral gene expression in these cells are still poorly understood. Exploring the molecular details of viral latency establishment and activation in a physiological setting will provide new insights for future therapeutics that aim at viral eradication.

Recent findings that HIV-1 uses cellular pathways to maintain latency implies that the latent phase is an intrinsic property of the virus and not just a consequence of infection into cell types that do not sustain viral replication. For instance, it has been demonstrated that recruitment of HDACs to the HIV-1 promoter induces chromatin rearrangements that promote a latent phenotype (1). In addition, HIV-1 uses specific cellular miRNAs to maintain latency in quiescent cells (7). Activation of the cells results in downregulation of these miRNAs and subsequent activation of the HIV-1 provirus.
Quiescent memory T cells form the major reservoir of latent HIV-1 and current estimates indicate that there is one latent infection per million CD4+ T cells. However, patient samples are not well suited for analysis since latently infected cells can hardly be distinguished phenotypically from uninfected cells. The presence of proviral DNA is an obvious difference, but there are currently no validated methods to quantify or select for latently infected cells. It is also difficult to distinguish cells with defective versus latent proviruses, although reactivation is an option. Several model systems have been developed to study latency under in vitro conditions.

Goals

A cure for HIV
100%
Contributed within this project

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