Miles to go before…
A very disappointing piece of news has just emerged; the most promising vaccine for HIV has just failed to show any significant effects. Researchers had pinned their hopes on the trial of the vaccine, which involved more than a thousand volunteers. The titlehead of the news piece announcing this in Science was a revealing photo- it showed a tense boxer, full of conviction but also apprehension, bracing himself against a wily, slim, faceless and insidious foe dressed in black. The head of the foe is the black, spherical shape of the HIV virus, glycoproteins jutting out of it. The picture denotes how defensive and weak we are still against HIV, and how far we still have to go.
The trial focused on a different aspect of the immune system than one that’s usually targeted. If we think about vaccines, they traditionally consist of pieces of whatever microorganism they are supposed to fight. The basic concept that’s taught to us in school is that the immune system will then “remember” the constitution of these pieces. In earlier times, and not without danger, these pieces where attenuated viruses. As time went on, more sophiticated approaches came up, where the specific molecules on the surface of the virus that elicit the immune response were identified. Instead of the virus, the vaccine was then made of these molecules.
In the case of HIV, these traditional strategies don’t work, both with vaccines and drugs, and it’s worth taking a look at the reasons. As most of us probably know, this is because the virus is a diabolical chimerical agent, changing its composition every time we try to kill it. For those who scorn evolution, this is its most resplendent morbid achievement. Nature, with its billions of years of tinkering and experimentation, came up with something much better than a human being - the AIDS virus. The earliest drugs against HIV quickly failed, as the virus developed mutations and adapted into new forms that were resistant to these. As more and more drugs against HIV are pumped into the body, the virus evolves against them by developing more mutations. The “fit” mutants survive and carry on the work of destruction. Right now, the only avenue of treatment for HIV is to put the patient on a regimen of three or more drugs, each targeting a different enzyme in its survival and replication strategy, hoping that it would be much more difficult for the virus to develop mutations against all of the drugs. Needless to say, this strategy sometimes fails but moreover, such a cocktail of drugs is sometimes worse than the infection itself and causes serious side effects. Because of these, the patient cannot bear to take the drugs regularly. Once he or she takes a break from the medication, the virus gets an even better oportunity to gain a foothold, and returns with a vengeance. The fight against HIV is surely as tragic and relentless a fight as human beings have ever waged.
However, it is also true that HIV has become much more manageable now. With such a cocktail of drugs, viral levels can be kept low, thus sparing the patient’s immune system from becoming completely disabled and unable to fight against infections; after all, it’s not HIV per se but a weakened immune system that opens up the body to infections, infections that we usually would successfully fight against and win. One of the big problems of course is that few in the developing world can afford this cocktail. But there’s also a catch. As my advisor points out, even in an ideal world where every one of these antivirals is available to everyone in the world free of charge in unlimited supply, the AIDS problem would still be quite widespread and serious. That’s because there are myriad mutated strains of HIV, and unless we know which particular strain the virus is going to mutate to, we cannot always prescribe the right drug against that strain. In the more affluent countries, “phenotypic profiling” can be done, in which viral composition in blood is periodically assessed, and the mutant strain identified. Known drugs against those strains can then be given. In other countries, this is naturally much more difficult to implement, and as noted above, any interruption of treatment just worsens matters.
The same problems that plague drug development also hinder vaccine development. Ideally, you could include in a vaccine all the parts of all the mutant viruses theoretically possible and then perhaps train the immune system to recognise these different forms of the virus. I am not an immunologist and I don’t know if the problem will be solved then, but it clearly sounds impossible to do this. In the current trial, they tried to circumvent this problem and pursue a novel route. Killer T cells are critical components of the immune system that seem to have the special capacity to recognise cells infected by HIV and then destroy them. Most importantly, these T cells seem to work against many strains of the virus. Thus, if they potentially could be “trained” to recognise the viral genes, T cells could recognise an HIV attack right after it began, and thus possibly beat back the virus before it got a foothold. It may not prevent infection, just make it more unlikely and harder.
However, the trial not only did not show promising results, it showed results that look bizarre and depressing. The volunteer group consisted of 1500 people, most of whom were male homosexuals. As the news piece quotes, “In participants who received at least one dose of the vaccine, 24 of the 741 vaccinated people became infected, compared with 21 of the 762 participants who received a dummy shot. More discouraging still, there was virtually no difference in viral loads between the two groups”. The first piece of data looks really strange; more people who were vaccinated apparently became infected than those who were not. I am assuming that the level of sexual activity of both groups was same or at least normalised, otherwise it’s not a controlled experiment. It’s also naturally too early to say what exactly happened in the doomed patients.
In any case, this piece of news must be disheartening to hundreds of researchers, and now they must gather themselves up, brush off the dust and continue to fight the good fight. It seems that when it comes to HIV, many results seem to turn expectations on their head. Another bizarre trial conducted a few years ago was of a microbicide that was supposed to be smeared on a condom or inside the vagina before sexual activity. Devastatingly, the group who used the microbicide was more often infected than the control. The reason? Something which nobody had thought about- the microbicide turned out to be a vaginal irritant and led to lesions through which the virus could very easily enter. This ease of entry overwhelmed any possible benefit the microbicide might have had. Clearly, HIV has more than one surprise in store for researchers. Drug therapy, vaccine development, and other therapeutic developments each seem to be plagued with special and general problems.
In addition to these scientific problems, we can only scrape the surface of the social and cultural barriers that make AIDS such a complex and painful problem to tackle. These include social perceptions in countries like India and Africa (and even developed countries like the US) leading to infected people becoming outcasts. Because of this possibility, many HIV positive individuals don’t get tested, hide their problem, and very likely pass on the virus to others in this interim. Political and corporate wrangling over setting the prices of drugs continues as millions die of the contagion. Religious groups’ proscription about condoms is horribly twisted and despicable, and remains a serious problem. As scientists, our job is not to deliberate on moral issues, but as scientists, we can also not help but objectively document how these religious injunctions cause manyfold more harm than good. In the end, human nature makes it all the more harder to bring the problem under control.
This piece of news is saddening and debilitating. With this latest disappointing development, we need to again regroup and carry on mankind’s eternal fight against disease and infection. If anything, this failure should make us wiser. It should teach us about evolution, about how versatile nature is, and about our fragility in the face of our self-proclaimed status as masters of the planet.
© Ashutosh Jogalekar