The hidden dangers of HIV

HIV particles swarming the defenses of a macrophage

I have written a few times about the myriad obstacles thwarting our efforts to design drugs against pressing medical problems, but perhaps none are as formidable as some of the challenges that evolution itself has set up for us. A disturbing example of this challenge in the context of HIV treatment is described by the husband and wife team of Robert and Janet Siliciano at Johns Hopkins in a recent Science perspective. The article talks about why a "cure" for AIDS may be far more difficult than we thought. It comes on the heels of the much-hyped 'Mississippi Baby', an infant who was thought to be 'cured' but who turned out to still harbor the infection. As of now the only known HIV-free human being is the remarkable so-called 'Berlin patient', but articles like these make even his case one of cautious optimism.

The authors focus on a troubling discovery made in the late 90s, around the same time that the new HIV protease inhibitors were leading to a striking decrease in the death rate. It was found that even when these drugs were effective, they were still unable to kill all the virus because some of the virus essentially went into hiding in the form of a latent state in which it integrates its DNA in 'resting' CD4 cells. This latent reservoir of hidden virions is like a Trojan horse full of deadly warriors, waiting to regroup and rebound after infection kills all the 'visible' viral particles and is discontinued for reasons of side effects or patient compliance. Ironically in this process, as biologist Alison Hill from Harvard explains in a helpful NOVA article about purported HIV 'cures', the virus is actually taking advantage of T cells' usually helpful property to preserve the 'memory' of infections and get reactivated.

But this reservoir of hidden HIV is why, in spite of early hopes, it has been impossible to completely eradicate the virus even when its levels in the blood become undetectable. Interestingly in the Science article the Silicianos make it clear that the problem is not one of lack of sensitive detection methods - the current methods are good enough to detect even a single latent cell in principle - but that of sampling, that is, getting enough tissue from the right places to detect the virus. The ultimate problem is that in the absence of detection of this latent reservoir, we will always be stuck with having the infection remerge even when treatments purportedly have rendered it undetectable.

From a drug discovery standpoint there is some hope. As long ago as the late 90s scientists were trying to adopt a 'shock and kill' strategy in which they tried to essentially smoke the virus out of hiding and the  neutralize it. But early efforts to do this involved administering large doses of interleukins, which basically put the immune system into overdrive and caused some very unpleasant reactions. Since then many other potential therapies, most notably histone deacetylase inhibitors, have been tried in order to get the resting viral DNA to reactivate itself. 

Another promising treatment that the article does not mention comes from Paul Wender's laboratory at Stanford. Wender and a few others have found out that a natural product from the American Samoan Mamala tree called prostratin can reactive latent and kill HIV at very low concentrations; in fact from what I can tell, prostratin was first described by researchers from the NCI in the Journal of Medicinal Chemistry as far back as 1992. Pre-clinical studies are underway (if successful, this would almost be a fairy tale story of drugs from nature, akin to that of taxol). Finally, a paper that just came out in Cell last week talks about using a combination of drugs like histone deacetylase inhibitors to smoke the virus out of hiding and then using antibodies against the glycoprotein envelope of the virus to finally silence it.

The hope is that some or all of these therapies - small molecules to force the virus out of hiding and a combination of small molecules and antibodies to kill it and potentially render immunity to further infection - will at some point work. There is always the issue of how tolerable the side effects of these combination therapies will be. But more than anything else, the complex challenge illustrates both the necessity of researchers from different fields adopting a variety of strategies to fight AIDS as well as the formidable barriers that the virus has set up for us. 

Ultimately as the article says though, an achievable goal might be more modest; we might be able to keep patients on and off treatment for long enough so that they can live normal lives in spite of potential viral rebound. Even that chronic treatment scenario will be a great achievement, no less attractive than a mythical 'cure'.

Image: Wikipedia.

First potential HIV vaccine

This just came off the press:

A new AIDS vaccine tested on more than 16,000 volunteers in Thailand has protected a significant minority against infection, the first time any vaccine against the disease has even partly succeeded in a clinical trial...Col. Jerome H. Kim, a physician who is manager of the army’s H.I.V. vaccine program, said half the 16,402 volunteers were given six doses of two vaccines in 2006 and half were given placebos. They then got regular tests for the AIDS virus for three years. Of those who got placebos, 74 became infected, while only 51 of those who got the vaccines did. Results of the trial of the vaccine, known as RV 144, were released at 2 a.m. Eastern time Thursday in Thailand by the partners that ran the trial, by far the largest of an AIDS vaccine: the United States Army, the Thai Ministry of Public Health, Dr. Fauci’s institute, and the patent-holders in the two parts of the vaccine, Sanofi-Pasteur and Global Solutions for Infectious Diseases.

However this also came off the same press:

Scientists said they were delighted but puzzled by the result. The vaccine — a combination of two genetically engineered vaccines, neither of which had worked before in humans — protected too few people to be declared an unqualified success. And the researchers do not know why it worked...The most confusing aspect of the trial, Dr. Kim said, was that everyone who did become infected developed roughly the same amount of virus in their blood whether they got the vaccine or a placebo. Normally, any vaccine that gives only partial protection — a mismatched flu shot, for example — at least lowers the viral load.

Nevertheless, after a decade of failures, at least it's a definite starting point scientifically.

2008 Medicine Nobel: Montagnier finally wins

If you knew little about the Nobel prizes, you could be easily forgiven for assuming that somebody must have already won the Nobel for discovering the AIDS virus. Many people probably do assume this. It just seems hard that such an important discovery has not already been recognized by the prize.

And yet, those who know the history know about the acrimonious dispute between Frenchman Luc Montagnier and American Robert Gallo about priority. The two were involved in a protracted and cantankerous debate with both camps claiming that they were the ones who discovered HIV and demonstrated its action. When I read the history, to me it was always clear that it was Montagnier whose team not only undoubtedly first isolated the virus, but actually proved that HIV causes AIDS, an absolutely crucial step in establishing the identity of a causative agent and a diagnostic step for the disease. While Gallo also played an important role in the latter, the history also indicated to me that he had engaged in some pretty cunning and disingenuous political manipulation to claim priority for the discovery.

It didn't really seem that the prize would be awarded to both of them. It may well have not been awarded to any of them. The Nobel committee usually steers clear of controversial people and topics. But it seems to have realized that it can no longer neglect the truly important people behind such an obviously groundbreaking discovery. So Luc Montaginer, along with Francois-Barre Sinoussi have finally been awarded the 2008 Nobel Prize for Physiology and Medicine. Barre-Sinoussi first isolated HIV. The committee clearly is trying to avoid controversy by specifically saying that the prize is for discovering HIV. Even Gallo should not have a problem conceding that it was Montagnier and Barre-Sinoussi who first saw and isolated the virus.

The other half deservedly goes to Harald Zur Hausen, discoverer of the human papilloma virus which causes cervical cancer.

I would recommend reading Virus, Montagnier's story of his life and his work.

Semen gives us a Christmas gift

In what for me is one of the most novel papers I have read this year, researchers in the US, Spain and Germany have found that human semen has a protein that aids HIV in increasing its transmission and attachment to host cells in the female genital tract. This paper in Cell is fascinating and reveals a novel mode through which HIV acts to its advantage by latching on to a rare protein in semen. This protein can possibly increase the spread of infectious HIV through sex more than 100,000 times.

In a nutshell, the authors found a protein in human semen- prostatic acidic phosphatase (PAP)- which can kind of pick up infectious HIV particles and transmit them. This protein can increase the transmission of HIV several thousand fold. As an interesting and significant side-point, the rate of transmission of HIV through sex is actually pretty crummy and that is one of the reasons the AIDS epidemic is not as bad as it could have been (No, I am not advocating unsafe sex...unless your favourite game is Russian roulette)

But in an even more novel development, the authors find that PAP forms amyloid fibrils that constitutes the form in which HIV gets transmitted. HIV latches on to this amyloid form and then infects host cells much more efficiently. Interestingly, now about 30 disorders have been found in which amyloid has been involved. Nor is amyloid restricted to Alzheimer's Aß peptide. Many proteins can form the characteristic conformational signature of amyloid under the right conditions. Amyloid increasingly seems to be a timeless passenger whose fate has been possibly intertwined with ours for millennia.

I will leave it to you to read the paper and will probably have more detailed thoughts later. But the paper illustrates several points; firstly, how evolution again may have adapted HIV to take advantage of its natural environment. Semen is the lifeblood of HIV when it's sexually transmitted and any modification that allows the virus to thrive in semen and take advantage of the biomolecular machinery in semen will prove hugely important to it. Several other substances in semen also buttress HIV, a virus that is so fragile that exposure to the natural environment incapacitates it in seconds. Basic amines in semen like spermine for example can neutralise the dangerous acidic environment of the vagina. It is one of the grim ironies of nature that a life-form that is extraordinarily susceptible to the elements wreaks havoc in the human world on an unparalleled scale. The paper also illustrates a possible point of intervention in stopping the transmission of HIV, although much detail needs to be fleshed out before rational therapy can be contemplated.

But most importantly, the paper again indicates how fascinating science is, where novel insights keep on transforming both basic and applied science. Stem cells, a novel and hiterto unnoticed paradigm about how antibiotics work, and now this. Good year for the biomedical community and good year for Cell. And this paper is definitely one of the better Christmas gifts the medical world could have received.

Opinion

Miles to go before...

A recent and highly promising trial of an HIV vaccine has failed and shown depressing results. This setback reminds us of how complex a problem HIV/AIDS is, with so many daunting scientific, economic, political and sociocultural ramifications...

Read the rest of the post on Desipundit...