Deacetylase inhibitors : a new hope in eradication of HIV-1 latent reservoirs ?

Demonté, D1., Quivy, V1., Adam, E1., Moutschen, M2., Hermans, P3.,  Burny, A1., Piette, J4., Van Lint, C1.

(1) Université Libre de Bruxelles, Laboratoire de Virologie Moléculaire, Service de Chimie Biologique, IBMM, Gosselies, Belgium. (2)  ULG, Centre d’Immunologie de Liège/Centre de Référence de Liège , Belgium.  (3) ULB, Service des maladies infectieuses, CHU St Pierre, Bruxelles, Belgium. (4) ULG, Laboratoire de virologie et d'immunologie, Liège (Belgium)

The discovery of powerful antiviral compounds in the 90's raised the hope that HIV-1 might be eradicated.  However, if these drugs actually succeed in decreasing and controlling viral replication, complete eradication of the virus is nowadays impossible.

The persistence of virus even after long periods of HAART mainly results from the presence of cellular reservoirs that contain transcriptionally competent latent viruses capable of producing infectious particles. These latently infected cells are a permanent source for virus reactivation and lead to a rebound of the viral load after interruption of HAART.

Activation of HIV gene expression in these cells combined with an effective HAART has been proposed as an adjuvant therapy that could lead to the elimination of the latently infected cells and then to the eradication of the infection.

In this context, we have previously demonstrated that deacetylase inhibitors (TSA and NaBut) synergize with TNF-induced NF-B to activate the HIV-1 promoter from subtypes A through G of the HIV-1 group M.  The physiological relevance of the TNF-TSA (NaBut) synergism was shown both on reactivation of HIV-1 expression in the U1 cell line, a postintegration latency cell culture model, and on HIV-1 replication in the context of a de novo viral infection (Quivy et al., 2002).

We are now testing the reactivation of HIV expression in latently infected resting CD4+ T cells by deacetylase inhibitors alone or in combination with TNF.  Our first results and the administration of deacetylase inhibitors together with continuous HAART as a new potential therapeutic perspective to decrease the pool of latent HIV reservoirs will be discussed in the poster.

Reference :

Quivy V, Adam E, Collette Y, Demonte D, Chariot A, Vanhulle C, Berkhout B, Castellano R, de Launoit Y, Burny A, Piette J, Bours V, Van Lint C.  Synergistic activation of human immunodeficiency virus type 1 promoter activity by NF-kappaB and inhibitors of deacetylases: potential perspectives for the development of therapeutic strategies.  J Virol. 2002 Nov;76(21; 11091-103.