Strategies and Obstacles to Cure HIV Infection: an update
Three articles published in early 2013 allow to recap the different approaches currently studied to reach an HIV cure and the various obstacles that have emerged from the first clinical trials that have been performed. HIV cure is definitely a research priority and scientific knowledge is increasing about the mechanisms of HIV persistence. However, in vitro and in vivo studies have also shown that we still need new biological tools and new drug candidates to achieve it.
The first 2 reviews emphazise the therapeutic strategies that can be tested to reach a cure (1, 2):
The 'Induction and Clearance Strategies':
Also known as 'kick and kill', their goal is to induce transcription of quiescent, replication-competent HIV proviruses, making them susceptible to immune clearance and the effect of cART. Several drugs are currently tested or ready to be:
Histone deacetylase inhibitors
Although valproic acid did not induce HIV, 2 trials using vorinostat have shown that this molecule induces an increase in viral RNA production in cells.
Other drugs of this category are potent candidates for clinical trials.
In 1 clinical trial, Disulfiram induced a modest but significant increase in plasma HIV RNA in patients on cART with undetectable viremia.
PD-1 antibodies are supposed to both activate HIV transcription and reverse immune exhaustion caused by HIV.
Other potential targets
Drugs like Bryostatin or HMBA act via other pathways to reactivate latent HIV.
Removal of proviral DNA
The technological hurdles to achieving removal of HIV proviruses from cells DNA are enormous. However, HIV-specific recombinase enzymes have been evolved to recognize sequences within the HIV LTRs and to remove the intervening HIV DNA.
Creating HIV-resistant Cells
Zinc-finger nucleases (ZFNs) have been used to manipulate CCR5 expression and reached clinical trials. ZFNs targeting CXCR4 are studied in cell lines and humanized mice.
Modification of Hematopoietic Progenitor Cells with RNA-based Therapeutics
Many RNA-based tools, such as ribozyme biochemistry and RNA interference (RNAi) are being investigated.
Most studies have targeted viral mRNAs by RNAi with the hope of holding viral
replication in check.
Triple-R combines expression of an anti-CCR5 ribozyme, anti-Tat and rev short hairpin RNAs, and a transactivation response element decoy RNA containing a nucleolar localization tag.
The third review (3) focuses on obstacles for curing HIV infection. In this paper, Shan and siliciano defined 3 critical issues in HIV cure research that have urgently to be resolved:
A Way to Quantitatively Measure Virus Reactivation in vivo
Intracellular viral RNA levels are currently used but only confirm that the drug tested has an effect and does not indicate how many of these latently resting infected cells are induced.
A Way to Measure the Size of the Latent HIV Reservoir
PCR assays also measure defective viruses; the gold standard coculture assay needs a huge amount of cells; all assays lack the dynamic range needed to prove HIV eradication.
A Way to Kill Resting CD4 Cells in which Latent HIV has been Reactivated
As the reversal of HIV latency does not induce cell death by cytopathic effects or CTL response, restoring CTL functions in vivo is an important area for future studies.
1-Barton KM, Burch BD, Soriano-Sarabia N, Margolis DM. Prospects for Treatment of Latent HIV. Clin Pharmacol Ther 2013; 93(1): 46-56
2-Katlama C, Deeks SG, Autran B et al. Barriers to a cure for HIV: new ways to target and eradicate HIV reservoirs. Lancet 2013 Mar 28. doi:pii: S0140-6736(13)60104-X. 10.1016/S0140-6736(13)60104-X. [Epub ahead of print]
3-Shan L, Siliciano R. From reactivation of latent HIV-1 to elimination of the latent reservoir: The presence of multiple barriers to viral eradication. Bioessays 2013 Apr 24. doi: 10.1002/bies.201200170. [Epub ahead of print]
Key words: HDAC, HIV cure, HIV eradication, HIV latency, HIV persistence, HIV reservoirs