Navigation path

HIDDEN HIV CHALLENGE


HIV/AIDS

Challenging the Hidden HIV: Understanding the Block on Transcriptional Reactivation to Eradicate Infection
Framework programme:
6
Call:
2
Project number:
LSHP-CT-2004-012182
EC contribution:
€ 657,998
Duration:
36 months
Type:
STREP
Starting date:
1 January 2005

Keywords: AIDS; latency; integration; reactivation; viral factors; cellular factors; chromatin; siRNA

Summary:

Highly active antiretroviral therapy (HAART) has profoundly decreased morbidity and mortality in human immunodeficiency virus type 1 (HIV-1)-infected individuals. Nonetheless, HIV-1 has not been eradicated by HAART. Factors affecting HIV-1 latency present formidable obstacles for therapeutic intervention and the need for novel therapeutic strategies specifically targeting HIV-1 latency has become evident. However, therapeutic targeting of HIV-1 latency requires an understanding of the basic mechanisms regulating viral quiescence and activation. Exploring the scientific possibilities of new therapies targeting HIV-1 latency may hold new promise of eventual HIV-1 eradication.

Background:

HIV-1 infection is a dynamic process involving a continuous round of infection, replication and cell death. Continuous viral replication causes the loss of CD4+ T cells and therefore determines the rate of progression to immunodeficiency in infected individuals. The use of highly active anti-retroviral therapy (HAART) has recently raised the possibility of a cure for HIV-infected individuals. Despite this success, there have been reports of viral rebound after interruption of HAART in infected individuals in whom HIV plasma viremia was undetectable. The persistence of latently infected, resting CD4+ T cells, containing an integrated DNA provirus that is neither visible to the immune system nor accessible to current anti-HIV therapies, seriously challenges the hope of complete viral eradication. This latent reservoir of HIV, in the pool of resting CD4+ T cells, is established rapidly in primary HIV infection and can persist for an extended period of time. Assuming that this reservoir is only 105 cells per individual, it will take 10 to 60 years of HAART treatment (depending on the study) to totally eradicate the virus. Several combinations of activating stimuli induce HIV expression from this pool of latently infected cells. Viewed in this context, it is critical to define the molecular mechanisms involved in the establishment of latency and the reactivation of the viral expression. Recent studies have clearly shown that chromatin is an integral component of HIV replication. First, the heterogeneous structure of cellular chromatin controls viral expression by directly regulating (i) integration site selection, and (ii) transcriptional reactivation. Moreover, interaction between HIV-1 infection and the RNAi/miRNA pathway could result in the establishment and maintenance of HIV-1 latency. These aspects are being investigated within this project.

[+] Read More