Some recent advances

This study, which was published in the PNAS (Proceedings of the National Academy of Sciences), was conducted by Asier Sáez-Cirión and Gianfranco Pancino (Regulation of Retroviral Infections Unit at the Institut Pasteur, led by Françoise Barré-Sinoussi) and Alain Venet (French National Institute for Health and Medical Research (Inserm), U 802, Faculty of Medicine Paris XI, Kremlin-Bicêtre), under the aegis of ANRS*, and lifted some of the mystery surrounding these “HIV controllers”.  It was based on 11 such patients, some of them diagnosed as early as 1983. Researchers first showed that these patients were indeed infected with replicative viruses and that their CD4 T lymphocytes, which are the target cells for HIV, showed no resistance to the infection.

They then studied the response of CD8 T lymphocytes: it was already known that, unlike in patients who develop the disease, this immune system cell population, containing cells capable of specifically recognizing and killing infected cells, was intact and functional in “HIV Controller” patients.

Researchers showed that CD8 T cells of HIV controllers can, without any prior stimulation, totally inhibit the infection of their CD4 T cells in vitro, with powerful and rapid destruction of infected cells. They also succeeded in characterizing the profile of these CD8 T lymphocytes, which are specific to HIV and high cytotoxic activity. They showed that two “activation markers” – some surface molecules – were expressed in very different quantities on CD8 T cells of HIV controllers compared to non-controllers. This was a potentially useful discovery, since the authors suggest that “these markers, along with the in vitro infection control test developed in the study, could in future be used in vaccine trials to assess response efficiency in cytotoxic T lymphocytes”.

* ANRS EP36 study, coordinated by Dr. Olivier Lambotte

In addition, an ANRS study of the same cohort of “controllers”, conducted by Lisa Chakrabarti (Cellular Immunogenetics Unit) and published in the Journal of Virology, showed the importance of the role of CD4 T cells in these HIV controllers. “Central memory” CD4 T cells, capable of synthesizing the interleukin-2 cytokine, are preserved, which enables maintenance of long-term immunological memory. Moreover, “effector memory” CD4 T cells are activated, and are ready to carry out an anti-viral function. These studies suggest that this combination of two types of CD4 memory enables an optimum response against HIV infection.

The immune defenses triggered by the organism in the event of attack by an external agent call upon numerous types of cells commonly known as white blood cells. Amongst these, macrophages are responsible for eliminating foreign bodies by digesting them. Macrophages are one of the targets of the AIDS virus (HIV). Researchers in Philippe Benaroch’s team, at the Institut Curie, and the Virus and Immunity Unit at the Institut Pasteur, led by Olivier Schwartz, recently discovered how HIV manages to overcome the defense strategies of the macrophages it infects. They proved that the virus accumulates in cell compartments with low acidity, thus preventing the macrophage’s digestive enzymes from degrading the virus, since they need acid in order to function. Researchers also observed that, within the same infected macrophages, the compartments without viral particles or proteins appeared to be unaffected.

By thus controlling its environment, HIV can multiply inside infected cells, and form intracellular stocks that are likely to be less accessible to antiviral therapies.

Thanks to these studies, researchers have highlighted one of the mechanisms that explains the persistence of HIV in infected individuals. The development of future treatments should certainly take this new data into account, in order to succeed in reaching and eliminating these viral reservoirs.

Today, over 95% of people infected with HIV live in developing countries. Since access to treatment is limited in these countries for economic reasons, the need is more urgent than ever for an inexpensive vaccine that can be widely distributed.

It is from this perspective that a project has been developed at the Institut Pasteur to produce an anti-AIDS vaccine using the measles vaccine: as part of the WHO vaccination campaigns, the measles vaccine is very inexpensive and widely distributed. The vaccine against measles comprises an attenuated live virus that, in a single injection, confers a strong immunity allowing a lifelong protection. The objective was to make a “recombinant” vaccine, in other words to introduce two or three HIV genes into the genome of the attenuated measles virus. A combined HIV-measles candidate vaccine is now available. The measles vaccine has proven its safety and effectiveness over a long period, which leads to the assumption that the combined vaccine should be equally well tolerated and that it will also have high immunogenic power. Such a vaccine would in theory be targeted for pediatric use, since most adults are already vaccinated against measles.

This project, coordinated by Frédéric Tangy, head of the Viral Genomics and Vaccination Laboratory at the Institut Pasteur, has benefited from several financing programs, on behalf of ANRS, the American National Institute of Health and the Institut Pasteur. Since 2005, it has also grown as a result of funding from the European Union, in partnership with GlaxoSmithKline Biologicals and in collaboration with academic research centers in France, Belgium and Britain.

In view of the results obtained in animal trials, the first clinical trials in humans are to be launched, enabling the tolerance and safety of the candidate vaccine to be assessed, along with its capacity to induce immune responses in adults with pre-existing measles immunity.

A candidate vaccine that could enable the restoration of immune defense in people infected with HIV is currently being developed at the Institut Pasteur. Developed by the Virology and Vectorology group, led by Pierre Charneau, this candidate vaccine has been tested in mice whose immune systems have been partially “humanized”: the study, published in Molecular Therapy, shows that this candidate vaccine induces strong, diverse and long-term cellular responses. The preliminary results obtained with macaques are extremely encouraging, and justify the preparation of clinical trials.