Exploiting natural HIV defence
being destroyed by HIV and could open up a new way of fighting the
effects of the virus, according to new research.
Paolo Lusso and colleagues at the US National Institutes of Health (NIH) showed that a molecule called interleukin-7 (IL-7) prevents HIV from inducing immune system T-cells to commit suicide (apoptosis) and could therefore be used to reconstitute and repair an immune system damaged by HIV.
Lusso explained to DrugResearcher.com: "As it is increasingly emerging, people successfully treated with anti-retroviral therapy can control virus replication for years and halt the progression of the disease.
"Nevertheless their immune system rarely goes back to full functional competence. There is a sort of immunologic scar that the virus leaves and that is very slow to heal - if it ever does."
Current treatments do not address this scarring and lower T-cell counts lead to a defective immune system that can't respond properly to infections.
Lusso said: "This is the reason why 'immunoreconstituents' such as IL-7 may be very helpful to bring back the immune system to full competence in a reasonably short time."
IL-7 would only ever be used in conjunction with other anti-retroviral therapy because on its own it has "no suppressive effects on HIV."
When HIV infects the body, it attacks the immune system by hiding in T helper cells. From there, the virus uses the T-cell to replicate, killing it in the process. HIV can even destroy other T-cells not directly infected with the virus. Normally, when activated, T helper cells produce cytokine proteins that allow cells to communicate between themselves and so regulate the immune response. The more T-cells that are killed, the weaker the immune system.
IL-7 is a cytokine that promotes cell survival. Lusso collected T-cells from 24 people suffering from different stages of HIV - as revealed by counting the number of T-cells still present in the blood. The effect of IL-7 on cell survival was monitored.
Another cytokine, interleukin-2, which also prevents apoptosis, was used as a positive control. Cells treated with IL-7 showed lower levels of apoptosis. Surprisingly, the more damaged the immune system is, the better interleukin works and so any potential treatment would work even on those with advanced HIV.
A Phase I clinical trial to study the safety of using IL-7 in combination with other anti-HIV drugs was recently completed and Lusso said that "no significant toxicity," was seen during the tests. A larger Phase II study will begin soon in the US and France. Lusso points out that just because IL-7 is a natural compound, it doesn't mean the molecule will necessarily sail through trials.
"The immune system is a tightly regulated and extremely complex network. If you touch one element you can also induce a lot of compensatory side-effects in the big system."
There are 40 million people infected with HIV worldwide with the majority in sub-Saharan Africa, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS). Although treatment for HIV has been available since the 1980s, HIV can quickly become resistant to available drugs.
The first ever HIV drug was zidovudine. It is a nucleoside molecule and although it was originally developed to treat cancer in the 1960s, it was dropped for not being effective enough and having too many side effects. It was then that Burroughs Wellcome (now GlaxoSmithKline) began looking at the compound as an anti-AIDS drug. When it was approved in 1987, it was marketed as Retrovir but came off patent in March 2006. The drug works through inhibiting reverse transcriptase - a protein that HIV uses to reproduce.
Next came HIV protease inhibitors such as Roche's Invirase/Fortovase (saquinavir), Abbott Laboratories Norvir (ritonavir), Merck & Co's Crixivan (indinavir) and Pfizer's Viracept (nelfinavir). The drugs prevent protease enzymes breaking up other proteins to use in new virus particles.
A third class of anti-retrovirals, called fusion inhibitors, block HIV from entering the cell. The first fusion inhibitor was Roche's Fuzeon (enfuvirtide), approved in 2003. It is, however, costly to prescribe and because of this, it is generally reserved for patients with multi-drug resistant HIV.
Several other drugs that are designed to prevent HIV from entering T-cells are in development. One such entry inhibitor is Pfizer's maraviroc (UK-427857), which prevents HIV from binding to chemokine (C-C motif) receptor 5 (CCR5). The FDA recently announced that its antiviral drugs advisory committee will meet on April 24th to assess the safety and effectiveness of the drug. If approved, maraviroc would be the first in a new class of HIV drugs.
Although HIV can become resistant to many of these marketed therapies, that won't be a problem for IL-7 because its target is not the virus. However, IL-7 is not is not without its own problems.
"Like other natural substances - say hormones - too high or too close doses may induce a state of desensitisation, presumably due to downmodulation of its responsive pathways, mainly its cell surface receptor (CD127)," continued Lusso.
"To some extent, unfortunately, this is mirrored by what happens in vivo in patients with more advanced HIV disease: the IL-7 levels are increased in an attempt by the body to reconstitute the lost T-cell pool. As a consequence CD127 is downmodulated. This, and probably other defects inherent to CD127, most likely limit the efficacy of IL-7 in these patients."
Depite this, Lusso is hopeful that "if given early enough, IL-7 might even help to prevent the very formation of that 'immunologic scar' that HIV almost invariably induces in the immune system, thereby possibly changing the natural history of the disease."
Lusso and his team will shortly begin testing IL-7 in monkeys with the simian form of the virus.
He said: "The big question that we want to answer is whether blocking apoptosis may in the long run halt the disease progression."
The scientists are also conducting research into how exactly IL-7 works. If they can understand how the immune system responds to IL-7, "alternative treatment approaches may emerge, which do not require the natural cytokine itself."
Vaccines in trials
However, the greatest hope for reversing the pandemic remains a preventative vaccine. A recent report from the International AIDS Vaccine Initiative (IAVI) states that there are currently more than 30 clinical trials in 24 countries trying to establish the safety and efficacy of different vaccine candidates.
Merck & Co. and Sanofi-Aventis are running two of the most advanced trials in progress. Merck & Co. is running a Phase IIb trial of its adenovirus serotype 5 vaccine (MRKAd5 HIV-1), while according to the report, the only trial in Phase III is Sanofi's test of its combined prophylactic vaccine ALVAC-HIV (vCP 1521) boosted with VaxGen technology.
GeoVax are preparing to begin larger scale human clinical trials of its HIV vaccine on the basis of good preclinical results, which showed a positive immune response with a reduced dose.
However, not all research is going so well. A recent trial studying the effectiveness of a cellulose sulfate gel designed to prevent HIV infection was stopped after it was found it could potentially lead to an increased risk of infection. As a precaution, a further Phase III cellulose sulfate trial in Nigeria was also halted.
Cellulose sulphate (Ushercell) was developed by US company PolyDex Pharmaceuticals, and is one of four microbicide gels currently in trials for prevention of HIV and other sexually transmitted infections.
“It was our hope that this product would have helped women in protecting themselves from HIV," said Dr Lut Van Damme, principal investigator on the Ushercell trial.
"While the findings are unexpected and disappointing, we will learn scientifically important information from this trial that will inform future HIV prevention research.”
