Comparative Studies of HTLV-1 Particle Assembly and Morphology

Abstract

Human T-cell leukemia virus type 1 (HTLV-1; deltaretrovirus genus; Retroviridae) was the first human retrovirus discovered. As the etiological agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis, HTLV-1 is responsible for a considerable amount of morbidity and mortality worldwide. Between 5 and 10 million people are infected with HTLV-1, and approximately 500,000 suffer from HTLV-1-related pathologies. Previous observations have implicated HTLV-1 assembly having unique attributes compared with other retroviruses, including human immunodeficiency virus type 1 (HIV-1). The overarching hypothesis under investigation in this dissertation was that the HTLV-1 capsid (CA) domain of Gag encodes the primary determinants that impact immature particle morphology and the process of Gag-Gag oligomerization. To test this hypothesis, experiments were conducted utilizing virus-like particle (VLP) model systems, which demonstrated: 1) HTLV-1 immature particle morphology is unique among retroviral genera, particularly with flat regions of electron density that did not follow viral membrane curvature; 2) the HTLV-1 CA amino-terminal domain (NTD) can functionally replace the HIV-1 CA carboxy-terminal domain (CTD), but the HIV-1 CA NTD cannot replace the HTLV-1 CA CTD, indicating that the HTLV-1 CA subdomains provide distinct contributions to Gag-Gag oligomerization, particle morphology, and particle biogenesis; 3) the discovery of HTLV-1 CA amino acid residues identified by alanine-scanning mutagenesis (i.e., M17, Q47/F48, and Y61) that are important for Gag oligomerization and particle assembly. Taken together, these observations provide new insights into HTLV-1 particle assembly and contributes information that will aid efforts directed towards the discovery of therapeutic targets for intervention in order to prevent the HTLV-1 transmission and pathology in endemic populations.