HIV

AIDS, a quarter of century later ...

One of the first photographs of human immunodeficiency virus type 1 (HIV-1), discovered by Luc Montagnier’s team in 1983. Colourised image magnified x 100 000. © Institut Pasteur
One of the first photographs of human immunodeficiency virus type 1 (HIV-1), discovered by Luc Montagnier’s team in 1983. Colourised image magnified x 100 000. © Institut Pasteur
Four AIDS retrovirus particles seen under an electronic microscope. Bottom right: HIV particle burgeoning at the surface of an infected T4 lymphocyte. Centre: immature HIV particle that has detached itself from the infected cell. Top left: mature virus particle preparing to infect a new cell, showing the cone-shaped core.
©CNRS Photothèque/Charles Dauguet
Four AIDS retrovirus particles seen under an electronic microscope. Bottom right: HIV particle burgeoning at the surface of an infected T4 lymphocyte. Centre: immature HIV particle that has detached itself from the infected cell. Top left: mature virus particle preparing to infect a new cell, showing the cone-shaped core. ©CNRS Photothèque/Charles Dauguet
Crystal structure of the HIV-1 virus genome dimerisation initiation site (DIS). This site comprises a fragment of viral RNA containing 23 nucleotides. ©CNRS Photothèque/Eric Ennifar
Crystal structure of the HIV-1 virus genome dimerisation initiation site (DIS). This site comprises a fragment of viral RNA containing 23 nucleotides. ©CNRS Photothèque/Eric Ennifar
Molecular model of the mini-CD4 synthetic protein (in red) interacting with its target, the gp 120 surface glycoprotein of human immunodeficiency virus type 1 (HIV-1).
©CNRS Photothèque/Philippe Barthe
Molecular model of the mini-CD4 synthetic protein (in red) interacting with its target, the gp 120 surface glycoprotein of human immunodeficiency virus type 1 (HIV-1). ©CNRS Photothèque/Philippe Barthe

A sad anniversary indeed. Researchers first isolated the AIDS virus 25 years ago. The discovery marked the start of a prodigious research effort that is still far from over. Researchers Françoise Barré-Sinoussi and Luc Montagnier were awarded Nobel Prize for Medicine 2008 for their work on HIV. Here, they help trace the history of this pandemic which no vaccine hasbeen able to eradicate...

The United States, 1981. The Centers for Disease Control and Prevention (CDC) reported an abnormally high incidence of people suffering from Kaposi's sarcoma (a cancer-like skin disease caused by the herpes virus) and with Pneumocystis carinii pneumonia. Both are very rare diseases known to affect patients with weakened immune systems. At first the phenomenon was dubbed ‘gay syndrome' because it appeared to affect primarily homosexual patients. It was not long, though, before the number of cases mushroomed among drug addicts and haemophiliacs, as well as heterosexuals. After 1982, the disease became known by its acronym AIDS (acquired immune deficiency syndrome). In those days, the disease was thought to be caused by an infectious agent that was transmitted via the blood or sexually, although there was no solid evidence to support this theory.

It was not until a year later that the real culprit was identified: the human immunodeficiencyvirus (HIV)(1). Two research teams, one French, based at the Paris Institut Pasteur and the other American, a member of the National Cancer Institute, claimed that they had been the first to discover HIV. This was immaterial, as it meant that at last it was possible to develop screening tests and put together a prevention strategy. The objective: to slow down the spread of the pandemic whilst waiting for a vaccine to arrive. This was expected to take no more than two years.

A new type of virus

What was this new virus? How was it transmitted?At first it was a complete mystery. "Before long CD4+ T lymphocytes were identified as the main HIV target cells.

Macrophages and antigen-presenting cells were later added to the list," explains Françoise Barré-Sinoussi, Director of the Regulation of Retroviral Infections Unit at Institut Pasteur and member of the team that isolated the virus in France.

At the time, HIV was also known to belong to the family of retroviruses, which carry theirgenetic material as single-stranded RNA(2).

Once inside human cells, the RNA strand is converted into deoxyribonucleic acid (DNA) before binding with our chromosomes. This reverse transcription, which occurs with the aid of a specific enzyme, gives the virus enormous mutagenic potential, because unlike normal transcription, no system is at work to correct possible coding errors. "The immune depression mechanism triggered by HIV has turned out to be much more complex than was originally thought," explains Luc Montagnier, the virologist who headed the French team at Institut Pasteur back then.

Nowadays he continues his research at the World Foundation for AIDS Research and Prevention, founded in 1993 under the aegis of Unesco. "In fact, HIV does not operate in the least like a simple virus that infects and kills target cells. AIDS is a slow and chronic disease.

Fatal opportunistic diseases manifest themselves 5 to 10 years following infection. It is important to understand this prolonged latency phase where innumerable factors come into play, the foremost of which is the state of the infected person's immune system. "Recent studies point to the lymphocyte cells around the intestine as the primary target of the virus, precisely because these cells are often activated by a variety of infectious factors," adds the virologist. To survive, the virus needs activated lymphocyte cells. Lymphocyte cells are only activated when there is an infection.

It explains why, for example, a woman suffering from an ulcerative vaginal infection, like herpes or syphilis, is at greater risk of contracting the virus. According to Luc Montagnier: "Any activation of the immune system is a boon for the virus. This is why certain vaccines have failed: by stimulating the HIV target cells they promote either a resurgence of the disease or HIV infection."

A dismal failure in the hunt for an HIV vaccine...

This close link between the virus and the human immune system, combined with HIV's capacity to alter its own membrane structure to trick our natural defences, explains why after two decades of research we have yet to come up with an HIV vaccine. To beat HIV, it is futile to employ the conventional method of stimulating the body to produce antibodies by subjecting it to a harmless dose of the virus we are seeking to neutralise. On the contrary, the resultant immune activity would simply encourage the virus to spread. More circuitous strategies are therefore needed. But here, too, there are many obstacles.

For many years, researchers endeavoured to stimulate the human organism to recognise certain invariable HIV membrane proteins, like gp120. Despite their efforts, all the clinical trials ended in failure. Intermediate strategies have proven equally disappointing.

In September 2007, the pharmaceutical company Merck announced that it was suspending the STEP proof-of-concept trial designed to find out more about the safety of the MRKAd5 HIV-1 gag/pol/nef, or trivalent, vaccine in humans and to learn if it can prevent HIV infection. "This vaccine candidate was intended to induce immunity using as vector a type 5 adenovirus (the virus responsible for the common cold) to deliver three HIV genes: gag, pol and nef," explains Françoise Barré-Sinoussi. "This had yielded good results when tested on monkeys, but not only proved ineffective in humans, it even seemed to increase the risks of contracting the virus."

...but there is still hope

The bitter disappointment at the failure of STEP dashed hopes of a vaccine being developedany time soon. At the 17th InternationalAIDS Conference in Mexico in August 2008, researchers generally agreed that the virus is a much more formidable foe than was first thought.

While some now believe that another two decades of research will be needed to develop a vaccine, many are calling for a return to basic research in immunology. "We still know very little about the HIV infection itself, particularly the signals it uses to foil our natural defences," points out Françoise Barré- Sinoussi. "Recent studies have shown that after just a few hours of exposure HIV is able to impair the body's primary immune responses.

We still know very little about the mechanisms that allow it to do this." In spite of these shadowy areas, the research goes on. A team at Karolinska Institutet (SE) is working on an ‘adaptor plug' molecule that turns antibodies into HIV killers.

In vivo tests have proven the molecule to be 90% effective. In the United States, researchers at Sangamo BioSciences, a private company, are planning to sabotage the CCR5 protein, a HIV co-receptor found on the membrane of immune cells. This was inspired by the finding that all the people with a natural resistance to HIV share an inherited mutation that blocks the action of CCR5.

Luc Montagnier stresses the advantages of developing a therapeutic vaccine. "The idea is to attack the virus when it is already in the body. After restoring the immune system using triple therapy and antioxidants to remedy the oxidative stress caused by AIDS, a vaccine could be used to kill off the virus.

Unlike the vaccines tested so far, this therapeutic vaccine would not use virus proteins in the native state, but an HIV version that has been modified using molecular genetics. Besides, it is easier to ascertain the success of the molecule than of a preventive vaccine: the triple therapy can be interrupted just prior to administering the vaccine and, if the patient's viral load does not increase as a result, it means that the molecule is effective."

Elitist therapies?

Despite the many failures that have dogged vaccine research, strategies to control the disease have evolved in leaps and bounds. "The discovery of HIV's target cells and its mode of replication led to the development of one of the first antiretroviral molecules, a nucleoside reverse transcriptase inhibitor known as AZT," says Françoise Barré-Sinoussi. "Later, the emergence of AZT resistance led to the development of new combination drug therapies now known as triple therapy." Triple therapy, which emerged in 1996 and has very serious side effects (although these have been alleviated in the intervening decade), combines several antiretroviral drugs to overcome HIV's natural capacity to resist a single molecule. Antiretroviral drugs usually act on the enzyme that enables viral RNA to turn into DNA (reverse transcriptase inhibitors).

The drugs can also attack the enzyme needed to cut and assemble copies of the virus (protease inhibitors) or the enzyme that binds viral DNA with human DNA (integrase inhibitors). By acting on a specific protein, other molecules can even prevent the virus membrane from fusing with the membrane of human cells (fusion inhibitors).

Despite the efficacy of triple therapy, HIV's great mutagenicity enables it to develop resistance in the long term. The treatment must therefore be geared to tackling the mutations specific to each patient's infection, hence the variety of antiretroviral molecules. In spite of the difficulties, there have been huge strides forward. "In the early 1980s, we were totally powerless to prevent the spread of AIDS.

These days, triple therapy is controlling the viral load so effectively that sufferers can enjoy near-normal life expectancy," Professor Montagnier is delighted to add. However, this success can only be viewed from an elitist perspective. "The therapy is expensive and the length of the treatment period, as well as the cultural and social resistance associated with AIDS, make them largely inaccessible to people in poor countries, which is precisely where the worst ravages of the epidemic are being felt," he adds (see box on previous page).

In spite of the United Nations Millennium Development Goal to offer universal access to triple therapy to all those suffering from AIDS by 2010, in reality most people living in the southern hemisphere are still excluded from treatment. Françoise Barré-Sinoussi points out that "even though around 30% of AIDS sufferers in developing regions now have access to antiretroviral therapy, this is still far short of the target." As a result, some 28 people will have died from AIDS during the average seven minutes it will have taken you to read this article

Julie Van Rossom

  1. Here we refer to human immunodeficiency virus type 1 (HIV-1). In 1986, Professor Montagnier's team discovered a second strain, HIV-2, which is widespread mainly in West Africa.
  2. Ribonucleic acid, a nucleic acid consisting of a long chain of nucleotide units. While RNA is very similar to DNA in molecular terms, it has only one strand; DNA is usually double-stranded. RNA's principal role in a cell is to carry genetic information outside the cell nucleus. Before the discovery of retroviruses, it was thought that RNA travelled in only one direction, from the nucleus to the exterior.


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Meanwhile, the epidemic is growing

According to the 2008 report by the Joint United Nations Programme on HIV/AIDS (UNAIDS), the worldwide prevalence of HIV has stabilised, even though the number of HIV-positive individuals rose from 29 million in 2001 to 33.2 million in 2007. At present, more than two-thirds of sufferers are living in sub- Saharan Africa. Even though the spread of the virus has stabilised or declined in most countries in the region, the situation is still disastrous.

In 2007, sub-Saharan Africa accounted for 76% of all AIDS-related deaths. In 8 out of 13 southern African countries, the national prevalence of HIV in adults is more than 15%.

In other areas of the world, the epidemic is still growing. The highest infection rates have been reported in East Asia, especially Indonesia and Vietnam, as well as in the Commonwealth of Independent States (CIS), the former Soviet republics, where a large number of new cases have occurred in Russia and the Ukraine.


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