In most human immunodeficiency virus type 1 (HIV−1) infected individuals, highly active antiretroviral therapy (HAART) suppresses viremia to levels below standard clinical detection limits and delays the progression to AIDS. More sensitive assays have demonstrated that low−level residual viremia is present during HAART. Furthermore, viremia rebounds upon cessation of therapy and thus, life−long treatment is required to prevent the progression to AIDS. This is presumably due to viral persistence within anatomical and cellular viral reservoirs that are not eliminated during long−term HAART. During HAART, viral persistence has been principally attributed to a latent viral reservoir; however, instances of complete viral replication cycles, termed residual replication, may occur. Human studies have provided evidence for and against the hypothesis that residual replication occurs in tissues and contributes to residual viremia.
To address questions regarding viral persistence, this dissertation research utilized a rhesus macaque model of HIV−1 HAART. This model uses RT−SHIV, a chimeric simian immunodeficiency virus (SIV) with the HIV−1 reverse transcriptase (RT) replacing the native SIV RT gene. This modification renders RT−SHIV susceptible to non−nucleoside RT inhibitors, which are an important component of frontline therapies. Chapter 2 describes a longitudinal phylogenetic analysis of residual viremia during 42 weeks of therapy in five macaques that initiated HAART eight weeks after infection. This is the first non−human primate phylogenetic study to characterize residual viremia for a period greater than five weeks. The results did not provide substantial evidence that residual replication contributed to residual viremia. Additionally, one of the five macaques maintained a predominant plasma clone (PPC) population, which is an enigmatic feature of human residual viremia. Chapter 3 describes viral DNA diversification in lymphoid and gastrointestinal tissues relative to pre−HAART viremia. Similar to many human studies, there was no discernible evidence of residual replication or selection of resistance mutations. The origins of PPC populations were also not identified. Importantly, this dissertation advances the relevancy of HAART in RT−SHIV infected macaques as a model of human HAART. Thus, this model may be ideal in studies designed to improve human health, investigate the nature of viral persistence, and potentially develop a cure for HIV−1.
|Advisor:||North, Thomas W.|
|Commitee:||Barry, Peter A., Schinazi, Raymond F., Sparger, Ellen E.|
|School:||University of California, Davis|
|School Location:||United States -- California|
|Source:||DAI-B 75/11(E), Dissertation Abstracts International|
|Subjects:||Genetics, Microbiology, Virology|
|Keywords:||Animal model, HIV, Highly active antiretroviral therapy, Residual replication, Residual viremia, Viral reservoirs|
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