INTRODUCTION

The purpose of this white paper is to compare genetic and functional features of immunity and the response to infection in humans and major nonhuman primate species currently used in biomedical research. The search for appropriate disease models has been stimulated by the need to understand the most intractable of the persistent and lethal pathogens, as well as chronic diseases and conditions that are determined by the genetic makeup of the individual. Because the outcome of infection is governed by carefully coordinated innate and adaptive immune responses, and pathogens have evolved strategies to evade these defenses, use of animal models that recapitulate key features of human infection is critical. Successful nonhuman primate models closely emulate human immunity, inflammation, and disease sequelae. They can also provide a critical pathway to clinical testing of risky prevention or treatment strategies for serious human diseases.

Some past successes of infectious diseases research in nonhuman primates are described. However, the primary objective of the paper is to identify conditions that either support or limit use of these animals for the study of human viral, bacterial, or parasitic infections. A survey of the published literature reveals that the common chimpanzee (Pan troglodytes) is the only great ape used in infectious disease research. With few exceptions there is usually no alternative, because lower species are not permissive for infection or fail to replicate key features of disease. Most studies involve very small numbers of chimpanzees to ensure safe translation of vaccines or therapeutics to humans, or provide incontrovertible evidence for basic mechanisms of immune control and evasion that cannot be obtained in human subjects. Various monkey species, primarily the Asian macaques (Macaca species), have served as models for infection with human viruses and microbes. Alternatively, monkey pathogens like the simian immunodeficiency viruses (SIV) provide a reliable model of human infection with closely related viruses like human immunodeficiency virus (HIV). Infection studies with human and monkey viruses have facilitated advances in vaccine development and studies of immunity and pathogenesis relevant to humans.

Sequencing of the human, chimpanzee, and macaque genomes has provided unprecedented insight into the evolutionary relationship between these species, especially for genes that regulate host defense and susceptibility to infection. Here we also provide examples of gene families involved in immunity that have been largely conserved since speciation,



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