Monkey viral reservoir study goes for gold

1 December 2011. Related: Basic science and immunology.

Richard Jefferys, TAG

A small study of auranofin, a gold-based drug developed to treat rheumatoid arthritis, suggests it may be able to reduce the reservoir of SIV-infected CD4 T cells in macaques on antiretroviral therapy (ART). The paper appears in the 17 July issue of the journal AIDS [1], and previously generated some excitable media coverage when it appeared online-ahead-of-print in April (the researchers issued a press release at the time entitled ‘Gold-based Drug May Pave the Way to a Cure for AIDS’ [2]).

The mechanism of action of auranofin is not fully understood, but it has been shown to inhibit proliferation of CD4 T cells and thus may prevent the expansion of latently infected cells and/or shift these cells from a long-lived to short-lived phenotype. The authors note that there is one published case report on the use of auranofin in an individual with HIV, and it did not show an adverse effect on overall CD4 T cell numbers. [3]

A key issue in interpreting this or any other cure-related research study in rhesus macaques is that there is no consensus regarding the most appropriate way to try and model combination antiretroviral treatment of HIV infection in humans, because not all HIV drugs work against SIV. The researchers in this instance used a new approach that they first described last year, in which macaques are infected with SIVmac251 and treated with the combination of tenofovir+emtricitabine (Truvada) and raltegravir (Isentress). [4]

However, in this initial description of the model, follow-up was for 52 days and viral replication and persistence were only analysed in blood samples, not tissues, making the extent and durability of SIV suppression unclear.

The uncertainty regarding the animal model is thrown into sharp relief by the initial results of the new experiment in which auranofin was added to ART in six macaques: SIV DNA levels declined to undetectable levels after four weeks but rebounded by eight weeks. It is uncertain whether this reflects a transient effect of auranofin or some limitation of the ART combination to fully suppress SIVmac251.

In the second part of the study, the same six macaques had ART intensified by the addition of ritonavir-boosted Prezista (darunavir). Two control macaques on the same ART combination without auranofin were also added to the experiment at this juncture. After around two months of follow-up, the researchers report a trend toward declining SIV DNA levels in the auranofin group but not the controls; however the very small number of controls makes this data hard to interpret. An attempt was then made to see if the compound SAHA could stimulate production of virus in the auranofin-treated macaques. SAHA is a histone deacetylase (HDAC) inhibitor that can induce replication of latent HIV. SIV viral load did not increase after SAHA administration in the auranofin-treated macaques, but it’s not clear from the paper if SAHA was given to the two cont

Finally, ART was stopped in 5 out of 6 of the auranofin-treated macaques (one animal was spirited away to participate in another study) and both of the real-time controls. There was, on average, a slight delay in SIV viral load rebound in the auranofin group compared to the real-time two controls that just about achieved statistical significance. Set point viral loads were also lower than those documented prior to ART in the same animals, but the statistical significance of this finding was borderline and appeared to be driven by results in one macaque. There was absolutely no evidence that auranofin had led to a cure of SIV infection in any of the treated macaques, as all showed viral load rebounds.

In sum, these experiments may have identified a compound deserving of further evaluation in the context of efforts to deplete the latent HIV reservoir. However, the data are by no means clear-cut due to the use of a new macaque model of ART that is not well characterised, the small numbers of animals involved, and the use of historical controls (issues that likely reflect limitations on funding and access to macaques). Hopefully the publication of the data will help the researchers obtain the support necessary to conduct a larger and more rigorous evaluation of the reservoir-depleting potential of auranofin.

Additional background on the use of the drug in rheumatoid arthritis, along with an excellent potted history of the use of gold in medicine, can be found in a review published in 1997 in the British Journal of Rheumatology (free to access online). [5]

Source: TAG basic science blog (26 Jul 2011).

http://tagbasicscienceproject.typepad.com/

References

1. Lewis MG et al. Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension. AIDS: 17 July 2011 – Volume 25 – Issue 11 – p 1347?1356.
   http://journals.lww.com/aidsonline/Abstract/2011/07170/Gold_drug_auranofin_restricts_the_viral_reservoir.1.aspx
2. Press release. Gold-based Drug May Pave the Way to a Cure for AIDS.
   http://www.hiv-reservoir.net/index.php/Latest-News-on-HIV-Reservoirs-Eradication/gold-based-drug-to-hit-hiv-reservoirs.html
3. http://www.ncbi.nlm.nih.gov/pubmed/8895167
4. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853490/?tool=pubmed
5. British Journal of Rheumatology, 1997.
   http://rheumatology.oxfordjournals.org/content/36/5/560.full.pdf (PDF)