Virtual Institute on Poverty Related Diseases

14 July 2016

Aaron Diamond AIDS Research Center and Laboratory of Retrovirology (USA) has joined the EURIPRED EXTRANET

The biology and evolution of retroviruses and eukaryotic cells is very closely linked. In general, our research seeks to define how the replication of retroviruses is influenced by host gene products, with an emphasis on human and primate immunodeficiency viruses. We work in a variety of areas, but the two major themes are: (1) the identification and characterization of host-cell factors and pathways that are mimicked, manipulated and/or exploited by retroviruses and (2) identifying and understanding the mechanistic basis of host functions that have evolved specifically to provide a defense against retrovirus infection.

How the virion components Gag, Pol, Env, and RNA are transported, assembled and released from cells as infectious particles is one major focus of our efforts. The precise role of host and viral proteins in these processes has been one of the most challenging areas in retrovirology, but is gradually becoming understood. For example, we and others have shown that essentially all retroviruses, and many other enveloped viruses specifically recruit class E VPS proteins and ubiquitin ligases that normally mediate the sorting of cellular cargo at the limiting membrane of endosomes and the budding of vesicles into the endosomal lumen. Indeed, viral proteins appear able to simply redirect required cellular machinery to a different location in the cell in order to facilitate the formation of an enveloped virus particle. Other problems that we are investigating include defining how retroviral proteins select the locations within the cell at which they are assembled - in particular how this is affected by the cytoskeleton, vesicular transport pathways and the intrinsic membrane binding and multimerizing properties of Gag proteins.

Our second major area of interest is "intrinsic immunity." Throughout their evolution, most eukaryotic organisms have frequently been colononized by retrovirus. Indeed, our own genome contains a fossil record of vast numbers of now extinct retroviruses that replicated in the ancestors of modern humans, stretching back over millions of years. Because this historical barrage of retroviral infections, evolution has equipped mammals with several gene products whose primary function is to prevent or attenuate retrovirus replication. We work on several types of inhibitors that attenuate retrovirus replication: one class (exemplified by Fv1 and TRIM5) blocks infection by targeting incoming retrovirus capsids, a second comprises cytidine deaminases (eg. APOBEC3G) that induce lethal hypermutation of retroviral genomes, while a third (as yet poorly understood) activity appears to prevent the release of retroviruses from infected cells. We are also working to discover new types of natural antiretroviral defenses. Understanding how these defenses work, how ancient retroviruses may have been extinguished by them and how some retroviruses have acquired new functions that confer resistance to natural defenses could provide new opportunities to develop improved animal models of AIDS, as well as new therapies.