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INSIGHTS INTO HIV PREVENTION, PATHOGENESIS AND TREATMENT FROM NONHUMAN PRIMATE MODELS
Jeffrey D. Lifson
Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Infection of Asian macaques with Simian Immunodeficiency Viruses (SIV) endemic in African nonhuman primates (NHP) can lead to progressive pathogenesis/immunodeficiency that recapitulates key aspects of human HIV infection and AIDS. Different NHP models, employing different naturally occurring or engineered SIVs or related chimeric viruses, used to infect different macaque species, can be used to authentically model relevant features of human HIV infection. Experimental flexibility and control, and opportunities for extensive tissue sampling afforded by NHP models provide advantages for studying virus/host interactions. NHP models have yielded key insights into AIDS virus transmission, allowing characterization of the earliest stages of infection, pathways of early viral spread, and initial host responses, and permit the preclinical safety and activity evaluation of prophylactic vaccines and other prevention approaches. When matched to conditions of clinical vaccine evaluation, results from NHP vaccine studies have been largely congruent. NHP models have also informed our understanding of the pathogenesis of AIDS virus infection, including processes such as early, extensive depletion of intestinal CD4+ T cells, mucosal disruption, microbial translocation and persisting systemic immune activation, along with inflammation related fibrotic disruption of secondary lymphoid tissues. Comparison of SIV infections in Asian macaques and African 'natural host' species, where infection can result in extensive viral replication but does not typically lead to progressive disease, highlight the role of host responses in pathogenesis. NHP models have also shed light on mechanisms of viral persistence despite apparently effective viral suppression by antiretroviral drug treatment or potent immune responses, through viral sequestration in relatively immune privileged sanctuary sites such as B cell follicles in secondary lymphoid tissues, establishment and expansion of T cell clones bearing clonally integrated proviruses, and other mechanisms, and provide the basis for experiments to evaluate the safety and in vivo activity of strategies to target residual viral reservoirs. Contributions of NHP studies to our understanding in these areas and recent developments will be reviewed, underscoring the key role that NHP models have played and will continue to play in our efforts to develop more definitive approaches for preventing, treating, and attempting to cure HIV infection.