Reviewing strategies for draining HIV reservoirs

Richard Jefferys, TAG

The April issue of Human Vaccines & Immunotherapeutics features an excellent open access review by Thomas Rasmussen and colleagues describing approaches to eliminating HIV reservoirs that are advancing into clinical trials. [1]

Prominently featured are histone deacetylase (HDAC) inhibitors, which have emerged has lead candidates for liberating latent HIV from cellular lockdown. The paper offers detailed descriptions of the various HDAC inhibitors being studied – or considered for study – and notes that the authors, who are based at the University of Aarhus in Denmark, have launched a phase I trial of one such drug, panobinostat, in people with HIV. [2] Also cited is their companion study in the January issue of the same journal (now available open access) that compares the activity of several HDAC inhibitors in clinical development. [3]

Among the less-discussed aspects of HDAC inhibitors that are highlighted in the review are the potential for both pro- and anti-inflammatory effects depending on the individual compound (the latter effect could conceivably be beneficial in HIV infection).

Since the review was published, additional relevant data has emerged from CROI: results from Sharon Lewin’s trial of vorinostat were presented, [4] and George Wei from Gilead Sciences gave a glimpse at the first in vitro data on romidepsin, reporting that it is 500 times more potent at reactivating latent HIV than vorinostat (the ACTG is now planning a phase I trial). [5]

Not all the news was positive, however: as discussed in an April 4th Nature Medicine news article by Elie Dolgin, [6] Antony Cillo described study results indicating that HDAC inhibitors may only induce a small fraction of latently infected cells to produce viral proteins, possibly meaning that combinations of anti-latency approaches will be needed to comprehensively target HIV reservoirs. [7]

Potentially supplementing the armamentarium are immune-based strategies such as those targeting toll-like receptors (TLRs). TLRs are involved in the recognition of pathogenic organisms and, as the review by Rasmussen and colleagues explains, there is evidence that compounds that stimulate TLRs (TLR agonists) can induce HIV expression by latently infected cells. They reference their own study of a TLR9 agonist named CPG 7909 as a pneumococcal vaccine adjuvant in people with HIV, that—in an example of scientific kismet—allowed them the opportunity to go back and investigate its effect on the latent HIV reservoir. The results were reported at CROI and, while exploratory, showed a significant mean reduction in HIV DNA levels of 12.6% after each immunisation. The decline in HIV DNA correlated with an increase in HIV-specific CD8 T cells expressing CD107a (a marker for their release of cell-killing substances) and the chemokine MIP1-beta. [8]

Other research groups are also looking at the anti-latency properties of TLR agonists. At CROI, Camille Novis from the laboratory of Alberto Bosque presented a poster showing that Pam3CSK4, which targets TLR2/1, was able to reactivate HIV from latently infected CD4 T cells without causing T cell activation. [9]

Romas Geleziunas has cited plans to study GS-9620, a TLR7 agonist, in several presentations describing the Gilead Sciences HIV eradication programme (further details are included in his slides from the 2012 International Symposium HIV & Emerging Infectious Diseases). [10]

The review by Rasmussen et al mentions the cytokine IL-7 as a possible immunotherapy to reduce HIV reservoirs, under evaluation in a trial named Eramune 01 at the time the paper was written. Results debuted at CROI in a poster and, disappointingly, IL-7 added to intensified antiretroviral therapy (ART) was not successful in reducing HIV DNA levels (there was some evidence it may have slightly increased levels due to causing transient proliferation of latently infected CD4 T cells). Despite this outcome, IL-7 had a beneficial impact on CD4 and CD8 T cell counts, as seen in prior studies, and remains the lead candidate for enhancing immune reconstitution in individuals with poor CD4 recovery despite HIV suppression by ART (in this population, the increased risk of morbidity and mortality is a far greater concern than small changes in HIV DNA levels). [11]

The topic of targeting HIV reservoirs is the subject of another recent review, by Christine Katlama and colleagues in The Lancet. Sadly, however, this paper is not open access and requires a subscription (although it may eventually appear in PubMed’s full text archive). [12]

Source: TAG basic science blog (12 Apr 2013).

References:

Rasmussen TA et al. Eliminating the latent HIV reservoir by reactivation strategies: Advancing to clinical trials. Human Vaccines and Immunotherapeutics. 9(4); 786-795. April 2013.
http://dx.doi.org/10.4161/hv.23202
Safety and Effect of The HDAC inhibitor panobinostat on HIV-1 expression in patients on suppressive HAART (CLEAR)
http://clinicaltrials.gov/ct2/show/NCT01680094
Rasmussen TA et al. Comparison of HDAC inhibitors in clinical development. Human Vaccines & Immunotherapeutics 9(5);1–9; May 2013;
http://www.landesbioscience.com/journals/vaccines/2012HV0359R.pdf (PDF)
Elliot J et al. The safety and effect of multiple doses of vorinostat on HIV transcription in HIV+ patients receiving cART. 20th CROI, 2013. Oral late breaker abstract LB50.
http://www.retroconference.org/2013b/Abstracts/47969.htm
Wei G et al. Histone deacetylase inhibitor romidepsin induces HIV in CD4+ T cells from ART-suppressed subjects at concentrations achieved by clinical dosing. 20th CROI, 2013. Poster abstract 376.
http://www.retroconference.org/2013b/Abstracts/45794.htm
Dolgin E. Underestimate of HIV reservoirs threatens purging approach. Nature Medicine, 19, 384–385 (2013) doi:10.1038/nm0413-384.
http://www.nature.com/nm/journal/v19/n4/full/nm0413-384.html
Cillo A et al. Only a small fraction of HIV-1 proviruses in resting CD4+ T cells can be induced to produce virions ex vivo with anti-CD3/CD28 or vorinostat. 20th CROI, 2013. Poster abstract 371.
http://www.retroconference.org/2013b/Abstracts/46139.htm
http://www.retroconference.org/2013b/PDFs/371.pdf (PDF)
Winckelmann A et al. Toll-like receptor 9 agonist treatment decreases the proviral reservoir in peripheral blood and could impact HIV-specific immunity in patients on cART. 20th CROI, 2013. Poster abstract 381.
http://www.retroconference.org/2013b/Abstracts/46243.htm
Novis C et al. Reactivation of latent HIV-1 in primary memory CD4+ T cells through TLR stimulation. 20th CROI, 2013. Poster abstract 384.
http://www.retroconference.org/2013b/Abstracts/47646.htm
Geleziunas R. Gilead HIV eradication programme. International Symposium on HIV & Emerging Infectious Diseases (ISHEID), 2012.
http://www.isheid.com/presentations/vendredi/12-30/geleziunas/Geleziunas.pdf (PDF)
Katlama C et al. Impact of interleukin 7 and raltegravir plus maraviroc intensification on total HIV DNA reservoir: results from ERAMUNE 01. 20th CROI, 2013. Oral late breaker abstract LB170a.
http://www.retroconference.org/2013b/Abstracts/47940.htm
http://www.retroconference.org/2013b/PDFs/170aLB.pdf
Katlama C et al. Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs. Lancet. 2013 Mar 29. doi: 10.1016/S0140-6736(13)60104-X. [Epub ahead of print]
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60104-X/fulltext