Prospects for immunotherapy

Dr Bruce Walker of Massachusetts General Hospital and Harvard Medical School opened proceedings on Saturday 8 September at the AIDS Vaccine 2001 conference in Philadelphia.

Dr Walker presented the latest results of an ongoing clinical trial using treatment interruptions to boost immune responses in people who have been treated very early in the course of HIV infection. Of 13 patients, 6 have controlled viral load for up to 600 days off treatment, though none are below “detectability” with current viral load tests. 11 out of 13 are “below criteria for starting treatment” (based on viral load). However, there has been great variability in viral load and CD4 trends, with some late “breakthroughs”, some “spikes” that went on to be controlled without treatment, and some declining CD4 counts despite relatively low viral load.

Dr Walker pointed out that this study involves a very special group of people with HIV, treated very early in the course of infection, and that his results have not been matched by studies in “chronic” infection. He also observed that some of his patients had been on treatment for many months or even years, and it was completely unknown how long treatment would need to last before this strategy might be effective.

He stressed that he would prefer to have explored immunotherapy using methods less drastic than taking people off treatment to expose their immune systems to live HIV. He expressed frustration that some of the vaccines he would like to have tested have been unavailable to him, primarily for commercial reasons.

There is no question, said Dr Walker, that you can boost immune responses in people who are already infected, although the strongest evidence is clearly for people treated in acute [i.e. very early] infection.

What, he asked, might be different about acute infection?

One answer is the preservation of helper T-cell responses to HIV; another, which may be important, may be viral diversification – in other words, the variety of different viruses present in the body – which may be contained by early treatment. Virus-specific neutralising antibodies may be much more effective when virus is diversity is low.

A serious problem with much research until now has been that immune responses have been measured against “reference strains” of HIV, NOT the actual circulating strains within the person’s body. In fact, as such research has begun, it has emerged that there are commonly important differences between the two and often very strong and varied immune responses against the actual infecting virus which have simply been missed by tests based on other viruses.

He said we actually have no data on even a single patient to really understand the breadth and specificity of their immune response to their own viruses. (This omission was dramatically corrected in a late breaker presentation – see below.)

There were reasons for optimism for therapeutic immunisation with new products becoming available that could be better at stimulating CTL responses in particular. It also seemed, from the famous MACS study that even a modest reduction in viral load, if sustained, could make all the difference to the course of someone’s life. However, there remained serious obstacles including “original antigenic sin” – the tendency to boost ineffective responses rather than generate new and effective ones, when two antigens are similar to each other but not quite similar enough.

He went on to discuss viral escape from immune responses, and argued that one of the reasons why children who acquired HIV from their mothers tend to fare worse than adults is because they inherit half their immune system genes (the HLA genes) from their mother, along with a virus that is pre-adapted to escape from immune responses that depend on those HLA genes. He presented cases which showed this dramatically, in that an HLA gene which is normally protective in adults, leading to non-progression, had not protected children who inherited that gene from their mother. On the other hand, a child who had inherited the same gene from his father was protected in just the same way as the adults were.

Therapeutic immunisation must be a continuing research priority, but it is the diagnostic technology to analyse immune responses in minute detail which is really going to be critical to the development of this field.

An almost breathtaking late-breaker presentation by Dr George Shaw of the University of Alabama at Birmingham reported on a collaborative study that has been following the evolution of HIV and immune responses to the virus in a number of individuals in the UK and the USA, from before seroconversion, i.e. after infection but before antibodies appeared in the blood.

This showed that immune responses against the virus, both in terms of neutralising antibodies and CTLs drive the evolution of the virus in a powerful way, with differing outcomes for the individuals depending very much on the breadth and relevance of CTL responses to different targets on the infecting virus.

Therapeutic immunisation needs to move, at least for a period, from blunderbusses to rifles, trying to stimulate very specific immune responses to particular viruses. At last, the tools to do this are becoming available, but it is unlikely that they will ever be cheap. Hopefully, however, the results of such research can guide the design of new vaccines that will be of genuine value to many people living with HIV.