Peaceful co-existence with relatives of the AIDS virus
Virologists analyze why infected monkeys don't develop immune deficiency

Ulm University

Some monkey species can avoid developing AIDS-like disease despite being infected by close relatives of the human immunodeficiency virus. Genome sequencing has led an international group of researchers to identify potential key molecular differences to the human immune system: Contrary to HIV-infected humans, some primate species do not develop a chronic and therefore pathogenic immune reaction. The scientists, including virologists Professor Frank Kirchhoff and Juniorprofessor Daniel Sauter from Ulm, published their study in the highly renowned journal 'Nature'. The new insights contribute to a better understanding of the clinical course of infection and could translate to improved HIV therapies in the future.

The human AIDS pathogen (HIV) arose from immunodeficiency viruses (SIV) found in various African monkey species. It is thought that in the early 20th century, some SIV strains were transmitted to humans, probably through monkey hunting and handling the contaminated meat of the animals. In contrast to humans, some of the original natural monkey hosts - like the West African sooty mangabey - do not show signs of immune deficiency, even many years after an SIV infection and despite high viral loads. In order to find out how these primates avoid progressing into AIDS-like disease, researchers around Professor Guido Silvestri at Emory University (USA) determined the entire sooty mangabey genome and compared it to the genetic make-up of humans and other primate species. 'We found big differences in some proteins of the immune system, which we hope will help us better understand why sooty mangabeys avoid AIDS despite SIV infection', says first author Dr. David Palesch, who completed his doctoral degree in Ulm and now researches at Emory University. One particularly outstanding feature in the sooty mangabeys is an alteration of the TLR4 receptor. This cellular protein plays an important role in the activation of the immune system through bacteria. In HIV-infected humans, the chronic immune activation - for example through bacteria that get into the blood due to a damaged intestinal barrier after an infection - is a major contributor to the onset of AIDS. 'Using various methods, we were able to demonstrate the low activity levels of TLR4 in sooty mangabeys. This could be the reason why these monkeys don't have excessive immune reactions to an SIV infection and therefore don't develop immune deficiency,' explains Daniel Sauter, Juniorprofessor at the Institute of Molecular Virology in Ulm. That way sooty mangabeys seem to be able to maintain a healthy level of immune cells and tolerate the pathogen throughout their life.

The research team also detected the alteration in the TLR4 receptor in other natural SIV hosts, like vervet monkeys or Angola colobi. It is, however, not present in non-natural hosts like humans or rhesus macaques, who both develop chronic immune reactions and AIDS.

'We suspect that the natural SIV hosts developed alterations in the TLR4 gene throughout their evolution that allow them to peacefully co-exist with immune deficiency viruses - without progressing into immune deficiency,' explains Professor Frank Kirchhoff, Director of the Institute of Molecular Virology in Ulm.

The global approach of genome analysis afforded the researchers new insights into how the development of AIDS may be prevented. The genome of the sooty mangabey provides important new starting points for further investigations. The researchers hope to find ways to prevent the detrimental chronic activation of the immune system through HIV. This excessive defence reaction is seen even in the presence of optimal therapy and can cause premature ageing in HIV patients, among other things.

For this current study, the virologists from Ulm collaborated with scientists from American institutes, mainly from Yerkes National Primate Research Center at Emory University in Atlanta, Georgia and from the Human Genome Sequencing Center at Baylor College of Medicine in Houston, Texas. Juniorprofessor Daniel Sauter acquired funding through the DFG Priority Program 'Innate Sensing and Restriction of Retroviruses' (SPP 1923) and Professor Frank Kirchhoff received support from the Collaborative Research Centre 1279 as well as the ERC Advanced Grant 'AntiVirome'.

Text and media contact: Annika Bingmann

Literature reference:
David Palesch, Steven E. Bosinger, Gregory K. Tharp, Thomas H. Vanderford, Mirko Paiardini, Ann Chahroudi, Zachary P. Johnson, Frank Kirchhoff, Beatrice H. Hahn, Robert B. Norgren Jr, Nirav B. Patel, Donald L. Sodora, Reem A. Dawoud, Caro-Beth Stewart, Sara M. Seepo, R. Alan Harris, Yue Liu, Muthuswamy Raveendran, Yi Han, Adam English, Gregg W. C. Thomas, Matthew W. Hahn, Lenore Pipes, Christopher E. Mason, Donna M. Muzny, Richard A. Gibbs, Daniel Sauter, Kim Worley, Jeffrey Rogers & Guido Silvestri. Sooty mangabey genome sequence provides insight into AIDS resistance in a natural SIV host. Nature. doi:10.1038/nature25140
The researched monkey species sooty mangabey is native to West Africa (Photo: Yerkes National Primate Research Center, Emory University, Atlanta (USA))
Professor Frank Kirchhoff, Director of the Institute of Molecular Virology, Ulm (Photo: Elvira Eberhardt)
Dr. David Palesch completed his doctorate in Ulm and now researches at Emory University (USA) (Photo: private)