Experimental compounds to target viral expression in latent cells

Earlier studies were have investigated the use of IL-7 to stimulate latently infected CD4 cells to express HIV and therefore render them susceptible to effect of antiretroviral treatment. If this response was sufficiently extensive and robust, this would re-open discussions on possibilities of HIV eradication.

An abstract at the meeting reported further ex-vivo research in cell cultures with IL-7 and two previously unreported drugs: valproic acid (VPA), an inhibitor of histone deacetylase (HDAC), a host mediator of gene expression; and an investigational p38 kinase inhibitor that should similarly inhibit HDAC. All three drugs induced outgrowth in cells from 4/4, 5/5 and 2/2, patients ‘at concentrations achievable in vivo’ of IL-7, VPA and the p38 KI respectively, without inducing cell activation.

Comment

This preliminary work is complementary to research using other approaches aimed at draining the latent reservoir, such as prostatin. Novel agents which can either selectively kill HIV infected cells (virucidal agents) or induce expression of virus in the latent reservoir so that the currently licensed virustatic antiretroviral drugs can clear that remaining virus are the most promising leads we currently have towards viral eradication.

However a serious problem with viral induction is that promotion of global T-cell activation leads to highly problematic inflammatory consequences.

Such approaches have been investigated before, for example using combined IL-2 and anti-CD3 monoclonal antibody therapy, and were extremely toxic (ref: Kulkosky J et al. Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood. 2001; 98:3006-15).

The new strategy described here, which does not involve cellular activation, is unlikely to be dogged by the same problems.

Margolis DM, Lehrman G, Archin NM et al. Targetting reservoirs of HIV infection: inducing latent viral expression without host cell activation. XIII Intl HIV Drug Resistance Workshop, 2004. Abstract 68. Antiviral Therapy 2004; 9:S77.