Identified the important factors that drive global HIV diversity

· The differences between viruses isolated from different regions in the world is one of the most important obstacles for HIV vaccine desing. It has caused concern as to whether a successful vaccine for global, or even regional use can ever be generated.

· The new study describes how the HIV “escapes” the immune system in a different manner depending on the genetic profile of local populations.

· The conclusions of the present study will have very direct consequences for HIV vaccine design as it shows that the genetic background of the local populations need to be taken into consideration.

·It is likely that it will be necessary to design specific vaccines for different regions in the world.

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A large international team of more than 40 investigators have combined their data on more than 2800 HIV-infected individuals across 5 continents to study the important factors that drive global HIV diversity. The study shows that global HIV diversity is dependent on the genetic profiles that are dominant in the different regions of the world. The paper, which will be published in the advance online publication in Nature on the 25 of February, has been coordinated by Philip Goulder from University of Oxford and has been conducted with the collaboration of the ICREA research professor Christian Brander, who is now the scientific coordinator, at the Institut de Recerca de la Sida IrsiCaixa, of the ambitious programme HIVACAT, a Catalan consortium for the development of therapeutic and prophylactic HIV vaccines. The conclusions of the present study will have very direct consequences for HIV vaccine design as it shows that the genetic background of the local populations need to be taken into consideration for vaccine design, likely requiring the design of specific vaccines for different regions in the world. However, scientists are also putting a great efford on studying the common genetic caracteristics that will facilitate the design of successful vaccines across different regions.

More than 33 million people worldwide are living with HIV infection today and more than 2.5 million people are infected every year, therefore, the development of an HIV vaccine is of highest priority. However, the differences between viruses isolated from different regions in the world has caused concern as to whether a successful vaccine for global, or even regional use can ever be generated. The reasons for this “viral diversity” had been unclear to date, although they have important implications for vaccine design. As Christian Brander announced, “this new study makes it clear that vaccine design needs to go hand-in-hand with human genetic studies that will help to identify differences, but also common traits, in the vaccine population.”

HIV infection induces strong T cell responses in the infected individual and it has been thought for many years that such “virus-specific” T cells are responsible for the partial control of HIV propagation and AIDS development. It has however also been shown that HIV’s great mutation capacity generates a great virus variability, which facilitates that some mutants may become essentially invisible to the immune system. The consequence of such “escape” is that the virus can grow at a faster rate in the body of the infected individual and that the progression to AIDS disease is faster if the individual is left untreated. For HIV vaccine designs, these observations are very important since one needs to understand which parts of the virus are attacked by the immune system’s T cells and which parts can resist such an attack by rapid mutations, to develop vaccines that do not allow virus to avoid being attacked.

Importantly, the immune system’s attack of the virus is orchestrated by a number of genes in the body, generally referred to as HLA genes. These genes encode for specialized proteins who’s job it is to present little pieces of the virus to HIV-specific T cells, which then can eliminate virus-infected cells. These HLA (human leukocyte antigens) genes differ from one individual to the other. Accordingly, everybody’s immune response to HIV is different as different regions of the virus will be targeted. The HLA genes are being inherited from the parents and closely related individuals will have thus similar HLA genes. On a global basis, this means that populations in specific geographic regions have overall distinct sets of common HLA genes, which can sometimes dramatically differ between populations in various places in the world. As a consequence, the HIV virus may be under different immune attack and may have evolved differently depending on the genetic profiles of the populations of the different regions.

The study included 9 different cohorts of HIV infected individuals distributed across 5 continents and looked for specific differences in the virus genes. These showed that global differences in the virus are largely due to the evolution of the virus in response to the locally most dominant genetic profile. In particular, wherever the specific HLA genes that were studied were more frequent in the human population, the virus had changed crucial pieces of its proteins to become invisible to the T cells.

The study is the culmination of a number of studies conducted by Christian Brander and colleagues, among which is Kawashima, over the last few years addressing these issues. Based on a theoretical paper in 2003 in Nature Medicine, where he suggested that global adaptation of the virus may occur, his team showed in 2006 experimental data for this observation. In a study of one specific HLA gene (referred to as “HLA-B*1503”, which is uncommon in Europe and North Americaa but very frequent in South Africa), his team could show such regional differences in viral evolution (Frahm et al Nature Immunology 2006). Indeed, virus from South Africa seemed to have changed or in some cases even completely lost the small pieces this HLA-B*1503 protein presents to the immune T cells. In contrast, in virus from Europe and North America, where the B*1503 gene is rare, the people who had this gene were able to make strong T cell responses to the virus and in most cases were able to keep viral replication to a very low level even without treatment.

The report in Nature not only extends these findings to more diverse populations and different HLA genes, but it also provides insight into HIV’s evolution, and shows that regional differences in human genetics need to be included in HIV vaccine design likely requiring the design of specific vaccines for different regions in the world.

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About HIVACAT

The HIVACAT (Catalan Centre for HIV vaccine) Project for AIDS Research and Development is one of the biggest and pioneering partnership in this field between authorities, researchers, companies and banks. It is formed by ESTEVE, Spanish bank Obra Social La Caixa, the Generalitat de Catalunya (Catalan Autonomic Government) and the Fundació Clínic, who signed an agreement with the Institut de Recerca de la Sida IrsiCaixa to develop a research project during the period 2008-2011 with a total budget of 13 milion euros. The objective: developing a therapeutic vaccine that stops HIV progression within the infected population and a preventive vaccine that avoids the infection under HIV exposure.

It is funded by Spanish bank Obra Social La Caixa, with an investment of 1.4 million euros, and by the Health and Innovation Department, Universities and Companies, a Department of Generalitat de Catalunya (Catalan Autonomic Government) as well as the Fundació Clínic, with an investment of € 400.000 each. The project has been given an extra boost with a new agreement between ESTEVE and IrsiCaixa, and the 6 million euro investment that the group will bear during next 4 years. ESTEVE’s involvement in the research process will start as soon as vaccine trial phase has been reached, taking care of the post-trial development up until its commercialization.

This initiative, first of this kind in Spain, situates the Iberian Peninsula among the International research frontline, and sees the daylight thanks to 2 prestigious AIDS research centers: the IrsiCaixa AIDS Research Institute, located at “Germans Trias i Pujol” Hospital, and AIDS & Infectious Diseases Research Centre at Barcelona’s Clinic Hospital. The investigators at these local institutions are thereby extending their work to even more sites, including clinics in Peru, where Christian Brander has ongoing studies for a number of years as well as sites in Southern and Central Africa. The work however also includes studies in well characterized groups of HIV-individuals that have been followed for many years at the two HIV clinics and which will form the basis for future HIV vaccine trials in Catalonia.