Human Immunodeficiency Virus Type-1 Mutations and Associated Fitness Costs for Viral Replication
- Author(s): De La Cruz, Justin
- Advisor(s): Yang, Otto O
- et al.
The CD8+ cytotoxic T lymphocyte (CTL) is a critical component in the antiviral immune response to Human Immunodeficiency Virus type-1 (HIV-1). However, the efficacy of immune containment is limited due the high viral turnover, rapid rate of mutation, and remarkable sequence plasticity of HIV-1. Studies have shown that immune selection pressure exerted by CTL can also readily produce epitope escape variants. Although these virions have the capacity to elude immune detection, escape events occur only if the benefit of immune evasion outweighs the fitness cost of the mutation. The dynamics of escape and the effect of such mutations on viral replication, however, have been generally poorly understood.
Here, we measured the fitness costs of HIV-1 mutations across different viral proteins and evaluated their overall impact on replication. We examined the effect of specific mutations in the Envelope gp41 membrane-proximal tyrosine-based sorting signal on the susceptibility to CTL and developed a potential model for in vivo attenuation of Simian Immunodeficiency Virus (SIV) containing analogous mutations that confer subsequent protection from wild type challenge. We investigated pairing-disruptive synonymous mutations within a novel RNA secondary structure identified in the pol gene and their impact on HIV-1 reproductive success while, in parallel, used chemically-based procedures to confirm RNA structure modification. Finally, we analyzed the differential fitness costs of immune-mediated escape mutations identified in gag-pol in persons with acute or chronic HIV-1 infection and assessed the breadth of escape mutations with associated fitness impairments across individuals expressing class I human leukocyte antigen (HLA-I) types not implicated with superior control of viral replication.