Achieving a cure for HIV infection: do we have reasons to be optimistic?

Abstract

The introduction of highly active antiretroviral therapy (HAART) in 1996 has transformed a lethal disease to a chronic pathology with a dramatic decrease in mortality and morbidity of AIDS-related symptoms in infected patients. However, HAART has not allowed the cure of HIV infection, the main obstacle to HIV eradication being the existence of quiescent reservoirs. Several other problems have been encountered with HAART (such as side effects, adherence to medication, emergence of resistance and cost of treatment), and these motivate the search for new ways to treat these patients. Recent advances hold promise for the ultimate cure of HIV infection, which is the topic of this review. Besides these new strategies aiming to eliminate the virus, efforts must be made to improve current HAART. We believe that the cure of HIV infection will not be attained in the short term and that a strategy based on purging the reservoirs has to be associated with an aggressive HAART strategy.

Figure 1.

Promising new approaches to cure patients of HIV-1: molecular mechanisms at the macrophage level. Beside increasing the pool of new molecules and improving the currently used ones in HAART, new approaches are required to reach a full recovery from HIV-1 infection. To date, HAART can only control and prevent viral replication, but fails to achieve total viral clearance. New potential strategies include virus eradication through gene therapy and clearance of the viral reservoirs. The first strategy derived from the observation of the Δ32 CCR5 bone marrow transplanted German patient, who seems to be free of HIV-1 infection. Owing to the high risk associated with surgery and the impossibility of using this method in a large number of patients, gene therapy could be a way to disrupt the CCR5-mediated infection in order to mimic the previous results of the German patient (1). The second strategy relies on associating the current HAART with molecules activating the viral transcription and/or targeting host proteins favouring HIV-1 latency. On the one hand, the early stage of viral replication requires the transcription activator NF-κB, thus cytokines such as TNF-α may allow the recovery of full viral transcription in latent reservoirs (2). On the other hand, chromatin-modifying enzymes have been associated with HIV-1 transcription extinction through fine modifications of the epigenetic code on the viral promoter. Limiting DNA methylation of the CpG islands (3), increasing activation marks, such as acetylation of histones from Nuc-1 (4), and/or avoiding marks associated with heterochromatin, such as simultaneous trimethylation of lysine 4 and lysine 9 (5,6) of histone H3 in Nuc-1 may revert the latently infected state back to productively infected macrophages. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.