Results from a phase I trial of the candidate latency reversing agent panobinostat were published last year in The Lancet HIV (see blog post from November 2014). 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.
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-regulatiion 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, 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 that is known to occur in chronic infection and the presence of escape mutations in the latent HIV reservoir 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) 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 emphasizes 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 under latency-reversing agents).
J Virol. 2015 Jul 29. pii: JVI.01484-15. [Epub ahead of print]
Olesen R, Vigano S, Rasmussen T, Søgaard OS, Ouyang Z, Buzon M, Bashirova A, Carrington M, Palmer S, Brinkmann CR, Yu XG, Østergaard L, Tolstrup M, Lichterfeld M.
Abstract
Pharmaceutical reactivation of dormant HIV-1 proviruses by histone deacetylase inhibitors (HDACi) represents a possible strategy to reduce the reservoir of HIV-1 infected cells in individuals treated with suppressive antiretroviral combination therapy (cART). However, effects of such latency-reversing agents on the viral reservoir size are likely to be influenced by host immune responses. Here, we analyzed immune factors associated with changes in proviral HIV-1 DNA levels during treatment with the potent HDACi panobinostat in a human clinical trial involving 15 cART-treated HIV-1 patients. We observed that the magnitude, breadth, and cytokine-secretion profile of HIV-1-specific CD8 T cell responses were unrelated to HIV-1 DNA changes in CD4 T cells during panobinostat treatment. In contrast, proportions of CD3- CD56+ total NK cells and CD16+ CD56dim NK cells were inversely correlated with HIV-1 DNA throughout the study, and changes of HIV-1 DNA during panobinostat treatment were negatively associated with corresponding changes in CD69+ NK cells. Decreasing levels of HIV-1 DNA during latency-reversing treatment were also related to proportions of plasmacytoid dendritic cells, to distinct gene expression patterns of interferon-stimulated genes and to expression of the IL28B "CC" genotype. Together, these data suggest that innate immune activity can critically modulate effects of latency-reversing agents on the viral reservoir and may represent a target for future immunotherapeutic interventions in HIV-1 eradication studies.
IMPORTANCE: Currently available antiretroviral drugs are highly effective in suppressing HIV-1 replication, but the virus persists despite treatment in a latent form that does not actively express HIV-1 gene products. One approach to eliminate these cells, colloquially termed as the "shock and kill" strategy, focuses on the use of latency-reversing agents that induce active viral gene expression in latently infected cells, followed by immune-mediated killing. Panobinostat, a histone deacetylase inhibitor, demonstrated potent activities in reversing HIV-1 latency in a recent pilot clinical trial, and reduce HIV-1 DNA in a subset of patients. Interestingly, we found that innate immune factors, such as natural killer cells, plasmacytoid dendritic cells and expression patterns of Interferon-stimulated genes, were most closely linked to a decline of HIV-1 DNA during treatment with panobinostat. These data suggest that innate immune activity may play an important role in reducing the residual reservoir of HIV-1 infected cells.
Comments