Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Beatrice H. Hahn

Abstract

Simian immunodeficiency virus of chimpanzees (SIVcpz) is widespread in wild-living chimpanzees and can cause mortality and AIDS-like immunopathology. However, due to limited access to naturally infected chimpanzees, little is known about SIVcpz pathogenesis and potential intervention strategies that might be effective in captivity or in the wild. Given the central role of the intestinal microbiome in mammalian health, I asked whether gut microbial constituents could reveal any insights into SIVcpz-associated pathogenicity. I characterized the gut microbiome and virome of SIVcpz infected and uninfected chimpanzees in Gombe National Park, Tanzania. I found that SIVcpz infected chimpanzees retain a stable gut microbiome throughout much of their natural infection course, with a significant destabilization of bacterial communities observed only in individuals with known immunodeficiency within the last several months before their death. I also explored potential interventions that could be effective in both wild-living and captive chimpanzees. Broadly cross-reactive neutralizing antibodies (bNabs) represent powerful new tools to combat human immunodeficiency virus type 1 (HIV-1) infection. I found that some antibodies and antibody-like inhibitors developed to combat HIV-1 infection are capable of neutralizing genetically diverse SIVcpz and SIVgor strains with considerable breadth and potency, including in primary chimpanzee CD4+ T cells. Identification of these reagents provides an important first step toward translating potential intervention strategies currently developed to treat and prevent AIDS in humans to SIV infected apes. I also report a first case of clinical immunodeficiency in an experimentally SIVcpz infected captive chimpanzee, which improved markedly following antiretroviral treatment. These findings provide new insight into SIVcpz pathogenicity and identify promising new approaches to combat SIVcpz infection.

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