Investigation of the adaptation of HIV-1C to the host CTL immune response
By: by Christian Lane Boutwell
Published: 2008
Language: eng
Number of pages: 149
Description: The human immunodeficiency virus (HIV) exhibits the capacity to adapt to host cytotoxic T lymphocyte (CTL) immune responses resulting in CTL escape. Such CTL escape not only plays a role in the pathogenesis of HIV infection, but also poses a challenge to the durability of CTL immunity induced by an eventual HIV vaccine. In this dissertation, we investigated two aspects of the adaptation of HIV to the CTL immune response: the extent to which CTL escape occurs and the cost to viral relative fitness that is associated with CTL escape. We focused our attention on HIV-1 subtype C (HIV-1C), the strain of HIV-1 that accounts for the majority of current and new infections globally and is responsible for the particularly devastating HIV epidemic in southern Africa. We undertook a comprehensive analysis of the HIV-1C proteome for HLA class I-associated amino acid polymorphisms which are suggestive of CTL escape. We identified 94 such associations that were distributed throughout the viral proteome including in all but one of the regions in HIV-1C considered to be CTL immunodominant. Our results suggest that HIV-1C retains the capacity for CTL escape in all viral proteins and in regions that are most immunogenic for CTL.

To allow future studies of the in vivo dynamics of such CTL escape mutations, we developed a modification of the allele-specific quantitative PCR (ASPCR) technique to address problems arising from the extensive genetic variation of HIV. Finally, to investigate the fitness cost of CTL escape, we developed a sensitive dual infection assay and used it to quantify the decrease in relative replication capacity (RRC) associated with three HLA-B*57/B*5801 escape mutations in capsid: CA A146P, CA A163G, and CA T242N. The relative replication capacities associated with the escape mutations were comparable to, or when expressed in combination exceeded, that associated with the HIV reverse transcriptase antiretroviral drug resistance mutation RT M184V. These results suggest that the cost associated with these mutations may be sufficient to cause a clinically relevant impact on viral load during infection. These studies extend our understanding of HIV CTL escape and provide useful tools for further investigation of this topic.
Notes: "May 2008."

Thesis (Ph.D., Division of Medical Sciences (Virology))--Harvard University, 2008.

Includes bibliographical references.