A constantly changing enemy

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It is 30 years since the first cases of AIDS were described in the United States. In the West, drugs have transformed this fatal disease into a chronic condition. But in Africa millions of people still die every year. Now researchers have started to turn away from the idea of a vaccine and are looking instead for a cure.

In June 1981, the Centers for Disease Control and Prevention (CDC) in the United States reported for the first time on an unusual collection of symptoms in a number of homosexual men from Los Angeles and New York. At first there was no name for the condition, but after about a year the authority launched the term AIDS (acquired immune deficiency syndrome). But it was still not known what the disease was due to.

It would take another year before the guilty virus was identified, described and eventually given the name HIV (human immunodeficiency virus).

Despite the first cases of AIDS being described in 1981, the disease is considerably older than that. Researchers have examined old saved blood samples and have found a man in Congo who was carrying the HIV virus in 1959. And he was not the first, the researchers are sure about that.

"With the aid of mathematical models it has been established that the virus probably crossed over from monkeys to humans during the period from the second half of the 19th century to 1920," says Anders Sönnerborg, adjunct professor of virology at the Department of Medicine, Huddinge, Karolinska Institutet.

HIV infection first arrived in Sweden in 1976, but only in the form of a visiting tourist who was treated at Roslagtull Hospital before returning home. It took a few more years for the virus to take hold here.

"In December 1979 HIV was introduced among men who have sex with men. Among drug addicts it came a little later, with the first cases dating from 1982, but it exploded at the end of 1983 and in 1984, among drug abusers in Stockholm," says Sönnerborg.

This has been established through checks on saved blood samples to find out how the infection was spread. The first test for HIV did not come until 1984, so at first it was only the ones who developed symptoms of AIDS who were noticed. But as it normally takes an average of ten years to develop AIDS, they were just the tip of the iceberg. It also meant that most people infected with HIV were completely unaware of the situation and were able infect many others during this time.

Search for a treatment more difficult than expected

Since the virus was identified in 1983, researchers have worked intensively to discover ways of protecting, curing and treating. But the virus has proved considerably more difficult to crack than first thought. This is amply illustrated by the famous statement of then Secretary of Health in the United States, Margaret Heckler, who in 1984 promised that there would be a protective vaccine within two years, something the world is still waiting for.

It has gone all the better with regard to treatment of the infection, but it has been a bumpy road, particularly for the patients. The first medicine that started to be used clinically, in 1987, was zidovudine, better known as AZT, a "nucleoside analogue" that enters the DNA of the virus as a false building block. This drug lit a candle of hope in the dying AIDS patients, which was then abruptly extinguished. AZT already lost its effectiveness after a few months of treatment as HIV developed resistance to the drug. And the patients died.

When a new type of medicine called protease inhibitors was then approved two years later, few people infected with HIV dared to hold out hope any longer. But when a protease inhibitor was added to AZT and 3TC in a triple treatment, there was suddenly a dramatic and lasting effect on mortality.

"We were involved in the first study on protease inhibitors on twelve patients in 1995. Six were randomised to placebo and they all died within eight months, while the other six were randomised to protease inhibitor, and all of those are still alive today. That illustrates what a great effect the new treatment had," says Sönnerborg.

But why is it so difficult to get at the HIV virus? And why do three drugs work when one or two drug failed to?

"In a patient without a disease-modifying drug 10 billion virus particles a day are produced. And when the virus is copied to the next generation, almost one mutation for every new virus particle is produced. This means that around ten billion new virus particles are produced every day in every infected person," says Jan Albert, professor of clinical virology at the Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet.

His research involves mapping and discovering how HIV can vary so much, and using the mutations to map the spread of infection between individuals.

The fact that the virus mutates so much means that there are always many different variants of the virus and that there is always some variant that has a certain degree of resistance to individual drugs.

"But if a cocktail of several different drugs is used, it is not sufficient for the virus just to have a single mutation to escape, several of them are needed at the same time", says Prof. Albert.

And the treatment is really effective, 90 per cent of all HIV patients in Sweden have virus levels that are below those that can be discovered by the methods of measurement used in medical care. These well-treated patients today have a level of mortality that differs only marginally from that of healthy patients. The treatment even works so well that many researches now believe that well-treated patients no longer need to be regarded as a transmission risk in sexual contact.

"No, I do not think they are infectious provided they take their medication as instructed and do not have simultaneous sexually transmitted diseases," says Sönnerborg.

The issue of infectivity is now under discussion in the research community, and there are experts who hold differing views, but the treatment has quite clearly changed the prospects for patients in a very dramatic way.

Long-term effects still unknown

The actual drug treatment of HIV has also improved substantially since the breakthrough in the mid-1990s, when patients often had to take 15-20 tablets a day according to complex regimens with quite unpleasant side-effects.

Today a single tablet with mild or no side-effects is often all that is needed for treatment. But there are still clouds on the horizon, such as an increased risk of cardiovascular disease and possibly also of various types of cancer. And then there are the long-effects, of course.

"The long-term effects are still completely unknown. What happens when patients are treated with nucleoside analogues for over such a long period? Is there an increased risk of the development of cancer? We are actually conducting a gigantic experiment, no one has treated patients for such a long time with this type of drug previously, but the alternative is death," says Sönnerborg.

Overall, an effective drug treatment has nevertheless transformed a disease that was fatal in a hundred per cent of cases into a chronic condition it is possible to live with. That´s how it is in the West. In Africa, the situation is entirely different. Around two-thirds of the world´s approximately 33 million people infected with AIDS live there, and there they continue to die.

In all the descriptions of HIV in Africa, a distinction must be made between north and south. It is principally in southern Africa, in countries such as South Africa, Botswana, Namibia, Zambia and Zimbabwe that the incidence of HIV is really high.

"The incidence of HIV ranges between 10 and 30 per cent, but in some subgroups, such as women between the ages of 19 and 24, in shanty towns and in various provinces in South Africa it´s up to 40 per cent," says Anna Mia Ekström, professor and epidemiologist at the Department of Public Health Sciences, Karolinska Institutet who has specialised in HIV in Africa.

In contrast to the West, where men still dominate, the majority of the people infected in southern Africa are women.

"It´s principally a heterosexual epidemic where women are both biologically and socially susceptible to HIV. Firstly it´s easier for women to be infected through vaginal intercourse and secondly not all women are able to choose who they have sex with," she says.

But she is careful to point out at the same time that it is not simply a case of women being victims in a male-dominated society, but that a complex mixture of causes has meant that the HIV epidemic has spread so much in southern Africa.

Social factors have an impact

An important factor in the spread of HIV is, for example, that young men are expected to have several female partners to prove their masculinity, which gives them higher status in the shanty towns and in the countryside. Certain groups of girls in South Africa have recently also adopted this form of behaviour as they do not want to be worse than the boys. And the system of parallel partners gives the virus tremendous opportunities to spread.

"It´s not uncommon for someone to have a main girlfriend and some secondary girlfriends, a main boyfriend and some secondary boyfriends and occasional partners. If anyone in this network is infected, it spreads quickly," says Ekström,

It may appear odd that people carry on with this life style when it increases the risk of being infected with HIV so much, but as is always the case with social and cultural patterns of behaviour, it is difficult to change. The outlook on life is also very different.

"Death is more ever-present here, so the thought 'imagine if I'm infected with HIV and die in 10-15 years' is perhaps not as frightening, as the risk of dying of something else is greater. It is also often a case of young people who feel immortal and who find it difficult to see the point of living for a long time. It´s a young people´s thing more than anything else," says Ekström.

Alongside several cultural causes of spread, there is obviously also the common old unwillingness to use condoms.

"I have interviewed women in Kenya who say that they tell the men they have HIV but the men still dont use a condom. Men also say that the women want to have children and that many of them refuse to accept condoms for that reason," says Ekström.

However incomprehensible it may appear to decide against using condoms in such a situation, she points out that condom use in general is nevertheless far better in countries like Kenya than it is in Sweden.

"There are fewer young people in Sweden who use condoms in sex with a new partner than in Uganda and Kenya. The populations of countries with a high incidence of HIV are generally far more aware and better at using condoms," she says. Despite the great problems in southern Africa, there are in any case some positive new developments. More and more people infected with HIV are gaining access to disease-modifying drugs, which is reducing both mortality rates and the spread of infection. But despite drug treatment increasing, disease-modifying drugs are still only available to 37 per cent of all the people who need them in southern Africa, according to UNAIDS, the UN body for the coordination of issues related to HIV and AIDS.

The number who are newly infected per year has also fallen steadily throughout the 21st century. UNAIDS reports that 2.2 million people were infected in Africa in 2001, and in 2009 the figure was down to 1.8 million.

"Although it´s decreasing slightly, far too many people are still being infected," says Ekström. As well as everything that is already being done with information, propaganda for condoms or abstinence and distribution of disease-modifying drugs, there is more to be done.

In 2007 UNAIDS included male circumcision as a form of preventive treatment of HIV. The background to this is studies showing that the risk to men of being infected by women is halved if the men are circumcised.

"I think that's good, but it´s far from uncomplicated. To achieve really good results all baby boys would need to be circumcised. But in many societies it is instead traditional circumcision that is done on young men around the age of 20 as a masculine rite of passage. And they are sometimes encouraged to go out and have sex immediately after the ritual, when they are most receptive to infection," she says.

Another urgent measure is to invest in building up the health systems in the affected countries. In many countries there is a lack of both personnel and a functioning infrastructure in healthcare, which is a necessary basis for much else to function. Medication, for example. It is widely thought in the West that people in Africa infected with HIV are bad at following instructions, which increases the risk of the development of resistance. But it is more a case of the health systems failing, Ekström believes.

"Compliance is just as good as or better than in Sweden, as long as the patients receive the drugs. The problem is that access to medication varies, which means that the patients are left without medication for periods," she says.

Tough virus to vaccinate against

But with a vaccine that works against HIV everyone in the risk zone could be protected relatively easily and all other efforts could be scaled down. So one of the most important issues is how it is going with the development of the vaccine the US Secretary of Health promised in 1986.

"It´s a difficult virus to develop a vaccine against. There are no clear results yet suggesting that long-term and effective protection can be generated by vaccination," says Gunilla Karlsson Hedestam, professor of virology in the Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet.

What makes it so difficult to produce a vaccine is the enormous ability of the virus to change. As several billion new virus particles are created every day in every infected untreated individual, there are many hundreds of billions of variants of HIV in circulation in the world. The candidate vaccines that have been tested to date only appear to recognise a fraction of these viruses, which is not sufficient.

"A functioning vaccine against HIV must stimulate an immune response to something that all HIV strains have in common. Great progress has been made in understanding which parts of the virus this is, and if we can just steer the immune response towards these parts we will probably be well on the way," says Hedestam.

But we are not yet able to do so. Her own research is aimed at understanding how the B-cells - the cells that produce antibodies - are activated and regulated in infection and vaccination and how vaccine-induced antibodies bind to different parts of HIV. This is knowledge that is probably crucially important in making further progress in the search for a vaccine that works.

"More basic research is needed in this area. We have made some progress, but HIV challenges us to go into details in a completely different way than other viruses," she says.

The researchers have been trying to create a vaccine against HIV for nearly 30 years, and the question is whether it will ever be possible.

"I think it is possible to make a vaccine that provides partial protection, which can be of great benefit and reduce the global spread of infection, but I am in more doubt as to whether we will be able to produce a vaccine that provides total protection," says Hedestam.

And she is no alone in her doubts.

"I don´t think there is a sense that we are particularly close to a vaccine. I think it will take a long time before we have anything that even works in a small-scale laboratory setting, and it will take even longer to get it out into the world. No, unfortunately I'm not particularly optimistic," says Albert.

But he nevertheless adds with a certain twinkle of optimism:

"We are at least 30 years closer to a vaccine that we were 30 years ago. But I think it will take a good while yet."

Hope of a cure

More and more people are instead looking into the possibility of developing a cure for HIV and quite simply eradicating the virus from the body. This may appear to be an even more difficult task, but it is not certain that it is so. There are already disease-modifying drugs that effectively halt all virus replication in the body.

The problem is simply that a small proportion of the virus particles hide in the body so that the disease-modifying drugs cannot reach them. It is these resting HIV particles that cause the infection to flare up again within two to three weeks if the disease-modifying treatment is stopped. The idea is to tempt out the resting HIV particles in some way, cause them to start to replicate and let the disease-modifying drugs deal with them. Although that sounds simple, the research is still at a very early stage.

Bild på Sara Palmer."To be able to bring about a cure, we need to be able to clear every cell of viruses. And we do not yet know where they are," says Sarah Palmer, a researcher at the Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet and at the Swedish Institute for Communicable Disease Control.

Her own research involves searching for and identifying the cells where HIV hides. Some of them have been found, but there are more hiding places for HIV that have not yet been identified.

Another route to a cure could be through gene therapy. A successful bone marrow transplant in Germany has shown that it is actually possible to cure HIV by changing the receptor to which HIV binds in order to infect cells, CCR5. For several reasons it is not possible to perform bone marrow transplants on HIV patients in order to cure them, but it would be possible to genetically manipulate the patients´ own immune cells and knock out the genes for the CCR5 receptor and then put the immune cells back and achieve the same effect.

Several of these methods have now started to be tested in small trials on humans.

"In a few years we will know more about which strategies appear to be best," says Palmer.

But it will probably take a long time before it is possible to control HIV and cure infected patients, she thinks, with the wisdom of her experience of vaccine research.

"We have been searching for a solution for the past 30 years. I hope and believe that we will find it in the next 30-year period," she says.

Text: Fredrik Hedlund. Published in Medicinsk Vetenskap issue no 4/2011