Friday, August 15, 2014

Questioning use of HDACi against HIV


Fig 1: Rhomidepsin.
Source: Wikipedia
     Recently the Mississippi baby, had cast doubts on potential long-term cure for HIV (Link). The findings has impacted HIV research. Retrovirology research, there still is a long path to be covered. There seems to be more negative news on the ground. Several new approaches are currently evaluated, for potential therapeutic effect (Link). One among the approach, that was considered as potential intervention is the use of HDAC (histone deacetylase) inhibitors (HDACi, such as Vorinostat or SAHA (suberanilohydroxamic acid); Link). Other HDACi under current investigation include Romidepsin, Panobinostat, Givinostat, Belinostat etc.

   Romidepsin (Also known as FK228, FR 901228, NSC 630176, and Istodax) is , a bicyclic synthesized by a Gram negative bacterium Chromobacterium violaceum. It was reported as a chemical with very low antibacterial activity, but was anti-cancerous drug. It is known to interact with multiple genes involved in neoplasm and can induce apoptosis in target cells. Currently, chemical is owned by Celgene.

    LBH-589 or Panobinostat is an experimental drug, developed by Novartis. Chemically it is It is a hydroxamic acid. Other similar drugs include Givinostata and Belinostat. Panobinostat has been recently submitted to FDA for approval, for treating Multiple Myeloma. As per some studies, Pnobinostat represents an excellent pan-HDACi with superior results against HIV.

Fig 2: A shows toxicity in lymphocytes and
U1 cells treated with HDAC inhibitors. B shows cell death in U1 cells
treated with panobinostat. Source

    HDACi is a very broad term in context with cell. There are 18 different types of HDAC under 4 families and the action of inhibitors determined by the type of drug and dose. Moreover, HDACi interacts with other key genes such as NF-kB, p53, STAT3 etc. The issue of non specificity is reflected in a possible side effect.

    In the recently published PLoS paper by Walker etal, it was shown that romidepsin was toxic and induced death in CTL (Cytotoxic T Lytmphocytes). Toxicity studies have been studied earlier by Tolstrup etal. See Fig 2. This paper shows similar findings. Of concern, All three drugs also rapidly suppressed IFN-gamma. The net effect is there is an impaired ability of CTL to kill HIV-infected immune cells. The very purpose of using HDACi is thus brought under scrutiny.

The findings has put forward a very important question. What will be the Long-term effect of using HDACi as a anti retroviral strategy. It is too early to put forward an answer. For example, Vorinostat has been tried on patients with good results. It is important to note that in the study, the patient is given Anti retroviral therapy (ART) plus HDACi, in which case, impaired CTL is compensated by the drug.

The best answer is a clinical trial. Panobinostat is currently in a phase I/II clinical trial. The trial involved 15 patients receiving oral panobinostat 20 mg 3 times/week every other week for 8 weeks while maintaining combination antiretroviral therapy (cART). The finding was eight weeks of cyclic therapy with panobinostat was safe and well tolerated. These trials are done to assess the safety of the drug. Considering the findings, the next level of trial should answer the effectiveness of such treatment module and its long term effects.
VanderMolen KM, McCulloch W, Pearce CJ, & Oberlies NH (2011). Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphoma. The Journal of antibiotics, 64 (8), 525-31 PMID: 21587264

Ueda H, Nakajima H, Hori Y, Fujita T, Nishimura M, Goto T, & Okuhara M (1994). FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity. The Journal of antibiotics, 47 (3), 301-10 PMID: 7513682

Rasmussen TA, Schmeltz Søgaard O, Brinkmann C, Wightman F, Lewin SR, Melchjorsen J, Dinarello C, Østergaard L, & Tolstrup M (2013). Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Human vaccines & immunotherapeutics, 9 (5), 993-1001 PMID: 23370291

Jones RB, O'Connor R, Mueller S, Foley M, Szeto GL, Karel D, Lichterfeld M, Kovacs C, Ostrowski MA, Trocha A, Irvine DJ, & Walker BD (2014). Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes. PLoS pathogens, 10 (8) PMID: 25122219

Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, & Margolis DM (2012). Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature, 487 (7408), 482-5 PMID: 22837004