A gold-based drug already used for treatment of rheumatoid arthritis significantly reduced the reservoir of viral DNA and the population of long-lived HIV-infected memory CD4+ cells in a study conducted in six monkeys, Italian and American researchers report in the journal AIDS.
However the decrease in viral DNA was transient in animals that received three-drug antiretroviral therapy, and was sustained only in those that received an intensified antiretroviral regimen alongside the gold-based drug auranofin.
Reduction of the number of cells containing integrated HIV DNA is likely to be an essential step in achieving a functional cure for HIV infection. A functional cure is usually defined as a reduction in the reservoir of HIV-infected cells that allows HIV treatment to be stopped without viral rebound.
So far, no cure for HIV infection has been achieved except in the most challenging circumstances.
However more researchers are becoming optimistic about the prospects for a cure for HIV infection, and the International AIDS Society has launched an international working group to develop a Global Scientific Strategy that will speed up research in this area.
The Italian study used a drug called auranofin, a gold-based oral drug used to treat rheumatoid arthritis. One effect of this drug is to decrease the pool of central memory T-lymphocytes without affecting the body’s ability to generate new T-lymphocytes. It also shortens the lifespan of newly generated T-cells, limiting the replenishment of the reservoir.
Central memory CD4+ T-cells may live for many years. This group of cells is infected by HIV, and forms a very long-lasting reservoir of HIV in the body of every infected person.
As soon as treatment is halted, the reservoir of HIV DNA integrated into these cells begins to fuel viral replication once more, eventually resulting in a rebound of HIV to pre-treatment levels. Previous attempts to cure HIV infection using intensive antiretroviral therapy have always run up against this barrier.
A treatment which could remove these cells and limit the production of new cells for a period, alongside antiretroviral therapy, might have potential for achieving a functional cure.
Auranofin’s effect on the HIV reservoir was tested in six macaques infected with SIV, a simian equivalent of HIV. The animals had been treated with an antiretroviral regimen of tenofovir, FTC and raltegravir and had had undetectable viral load for at least eight weeks.
They were treated with 1.5mg/kg twice daily for one week, and received 2mg/kg per twice daily thereafter, along with antiretroviral therapy.
Auranofin treatment resulted in:
- Shortening of the lifespan of the longest-lived CD4+ T-cells after one month, and reduction in the size of this population;
- No effect on the size of the naïve T-cell population;
- Stable CD4+ T-cell counts
- No change in undetectable plasma viral load;
- A significant reduction in SIV DNA, to below the limits of detection for four weeks in animals treated with three-drug ART, followed by a rebound, but persistent undetectability to eleven weeks in animals that received an ART regimen intensified with darunavir boosted with ritonavir.
Six animals treated with intensified ART also received two three-day cycles of vorinostat at week 10. Vorinostat is an HDAC inhibitor, a type of drug which can stimulate HIV or SIV replication from cells in which the virus is lying dormant. No rebound in viral load occurred in these animals, but in two control animals that did not receive auranofin, viral load rebounded after one cycle, suggesting that in the intensively treated animals the viral reservoir had been substantially depleted.
The researchers also tested what happened when all treatment was removed. In control animals treated only with intensified ART virus levels rebounded after an average of 1.5 weeks to pre-therapy levels. In comparison animals treated with auranofin showed viral rebound to levels significantly lower than before treatment in most cases, and this took 7-8 weeks.
One macaque still had very low viral load seven months after the treatment was stopped, and a stable CD4 count. In other cases CD4 counts declined very little after viral rebound.
The research was carried out by Dr Andrea Savarino and colleagues at the Istituto Superiore di Sanità in Rome.
“As the side effects of this approach in the presence of HIV are as yet largely unexplored”, Dr. Savarino warned in a press release. “I strongly recommend that people living with HIV/AIDS do not buy the drug from uncontrolled sources such as e-Bay and start self-treatment outside highly medicalised settings.”
The authors of the study have decided to wait a little before moving to clinical trials. “We prefer not to involve people in a trial of the drug immediately”, said Dr. Enrico Garaci, president of the Italian Institute of Health, and co-author of the study, “that’s because in this phase the trial could only be a proof-of-concept study, and we have already this proof in monkeys. We prefer to put all our effort in the intensification of the attack on the virus reservoir in monkeys by using a combined approach”. “This will also allow”, he adds, “a more thorough evaluation of the safety of the approach”.
Lewis MG et al. Gold drug auranofin restricts the viral reservoir in the momkey AIDS model and induces containment of viral load following ART suspension. AIDS, advance online publication, April 20, 2011. (View free abstract here).