Innate immunity and HIV DNA declines in panobinostat recipients

1 August 2015. Related: Cure-related research, Basic science and immunology.

Richard Jefferys, TAG

Results from a phase I trial of the candidate latency reversing agent panobinostat were published last year in The Lancet HIV. [1, 2]

The paper notes that in an exploratory analysis, a subset of four (out of a total of 15) participants experienced a significant decline in cell-associated HIV DNA levels of around 70-80%, although there was no detectable change in the trial cohort overall. Furthermore, the HIV DNA reduction in these four individuals was associated with a slightly longer time to viral load rebound during an analytical ART interruption. At the NIAID-sponsored Strategies for an HIV Cure meeting in October 2014, Matthias Lichterfeld reported that several measures of innate immunity correlated with the observed diminution of HIV DNA, and these analyses have now been published online in the Journal of Virology. [3]

The most prominent finding is an association between natural killer (NK) cells expressing markers of enhanced functionality (including CD57, associated with cytotoxic activity) and reductions in HIV DNA during the trial. The researchers suggest the effect might be due to reversal of HIV latency causing up-regulation of receptors that activate NK cells on infected CD4 T cells and/or causing down-regulation of HLA class I receptors on these cells (both phenomena would promote NK cell-mediated killing of the CD4 T cells). Complementary correlations were seen with additional markers of innate immunity, including expression of interferon-stimulated genes and plasmacytoid dendritic cell frequencies. The IL28B “CC” genotype, which has been linked to superior innate immune function against hepatitis C, [4] was also associated with a greater reduction of HIV DNA during panobinostat treatment.

HIV-specific CD8 T cell responses, which have been suggested to be important for mediating clearance of the HIV reservoir after latency reversal, did not correlate with HIV DNA levels. The researchers note that this could be due to the HIV-specific CD8 T cell dysfunction [5] that is known to occur in chronic infection and the presence of escape mutations in the latent HIV reservoir [6] that abrogate CD8 T cell recognition. No evidence of an inhibitory effect of panobinostat on HIV-specific CD8 T cells (a possibility raised by a prior laboratory study) [7] was found. Interestingly, a larger HIV-specific CD4 T cell response at baseline (but not at any other timepoint) was associated with a greater HIV DNA decline during the trial; the explanation for this finding is not known but will be probed in future work.

The discussion section of the paper emphasises that the research involves small numbers and exploratory subset analyses, so the results must be interpreted very cautiously. But the idea that promoting innate immunity may aid in the clearance of the HIV reservoir after latency reversal is encouraging, and will be explored further in ongoing and new clinical trials. For example, toll-like receptor (TLR) agonists may have the capacity to stimulate innate immunity, and several are now being tested in HIV positive people on ART to assess any effects on the latent reservoir (see TAG’s cure-related clinical trials page [8] under latency-reversing drugs).

Source:

TAG BSVC Blog (4 August 2015)
http://tagbasicscienceproject.typepad.com

References:

1. Rammussen T et al. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. doi: 10.1016/S2352-3018(14)70014-1.
   http://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(14)70014-1/abstract
2. Jeffreys R. Michael Palm HIV Basic Science, Vaccines, and Cure Project Blog doi:10.1016/S2352-3018(14)70014-1 Published Online: 16 September 2014
   http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2014/11/panobinostat-as-a-latency-reversing-agent-phase-i-trial-results-published.html
3. Olesen R et al. Innate immune activity correlates with CD4 T cell-associated HIV-1 DNA decline during latency-reversing treatment with panobinostat. J Virol. 2015 Jul 29. pii: JVI.01484-15. [Epub ahead of print], doi: 10.1128/JVI.01484-15.
   http://jvi.asm.org/content/early/2015/07/24/JVI.01484-15.abstract
4. Meng Q et al. Natural Cytotoxicity Receptor-Dependent Natural Killer Cytolytic activity Directed at Hepatitis C Virus (HCV) Is Associated With Liver Inflammation, African American Race, IL28B Genotype, and Response to Pegylated Interferon/Ribavirin Therapy in Chronic HCV Infection. J Infect Dis. 2014 May 15; 209(10): 1591-1601. (Published online 2 Dec 2013). doi: 10.1093/infdis/jit677.
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997579
5. Liang S et al. Stimulation of HIV-1-specific cytolytic T-lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Published online 2012 Mar 8. doi: 10.1016/j.immuni.2012.01.014
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501645/
6. Deng K et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517, 381-385 (15 January 2015) doi:10.1038/nature14053.
   http://www.nature.com/nature/journal/v517/n7534/full/nature14053.html
7. Jones R B et al. Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes. Published: August 14, 2014. DOI: 10.1371/journal.ppat.1004287.
   http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004287
8. Jefferys R. Research Toward a Cure Trials (27 July 2015).
   http://www.treatmentactiongroup.org/cure/trials