Early Spatial and Temporal Events of Human T-Lymphotropic Virus Type 1 Spread following Blood-Borne Transmission in a Rabbit Model of Infection

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia/lymphoma (ATL) and is associated with a variety of lymphocyte-mediated disorders. HTLV-1 transmission occurs by transmission of infected cells via breast-feeding by infected mothers, sexual intercourse, and contaminated blood products. The route of exposure and early virus replication events are believed to be key determinants of virus-associated spread, antiviral immune responses, and ultimately disease outcomes. The lack of knowledge of early events of HTLV-1 spread following blood-borne transmission of the virus in vivo hinders a more complete understanding of the immunopathogenesis of HTLV-1 infections. Herein, we have used an established animal model of HTLV-1 infection to study early spatial and temporal events of the viral infection. Twelve-week-old rabbits were injected intravenously with cell-associated HTLV-1 (ACH-transformed R49). Blood and tissues were collected at defined intervals throughout the study to test the early spread of the infection. Antibody and hematologic responses were monitored throughout the infection. HTLV-1 intracellular Tax and soluble p19 matrix were tested from ex vivo cultured lymphocytes. Proviral copy numbers were measured by real-time PCR from blood and tissue mononuclear leukocytes. Our data indicate that intravenous infection with cell-associated HTLV-1 targets lymphocytes located in both primary lymphoid and gut-associated lymphoid compartments. A transient lymphocytosis that correlated with peak virus detection parameters was observed by 1 week postinfection before returning to baseline levels. Our data support emerging evidence that HTLV-1 promotes lymphocyte proliferation preceding early viral spread in lymphoid compartments to establish and maintain persistent infection.

Animal Models of Bovine Leukemia Virus and Human T-Lymphotrophic Virus Type-1: Insights in Transmission and Pathogenesis

“…HTLV-1 was found to accumulate in primary lymphoid and gut-associated lymphoid compartments in rabbits and was associated with an early lymphocytosis (99). These data are consistent with emerging evidence that HTLV-1 promotes lymphocyte proliferation, thereby enhancing early viral spread.…”

“…Infectious molecular clones of HTLV-1 were instrumental to identify viral determinants that control infection and demonstrated the requirement of accessory and regulatory proteins of the virus in the maintenance of proviral loads (69,74,(94)(95)(96)(97)(98)(99). HTLV-1 was found to accumulate in primary lymphoid and gut-associated lymphoid compartments in rabbits and was associated with an early lymphocytosis (99).…”

Molecular Determinants of Human T-lymphotropic Virus Type 1 Transmission and Spread

“…Example showing inoculation of HTLV-1-transformed cell line (R49) with ACH proviral clone [204]. Determinants of viral transmission and spread can be measured in context of the complete viral genome with the ability to test mutant viral clones concurrent with positive controls that demonstrate infectivity with parameters (e.g., proviral loads).…”

“…The roles of Rex and HBZ in viral transmission and spread have been tested using the ACH clone in rabbits [ 116 , 154 ]. Using ACH wild type virus immortalized rabbit T-cells in an intravenous infection model, HTLV-1 was found to accumulate in primary lymphoid and gut-associated lymphoid compartments in rabbits and was associated with an early lymphocytosis [ 204 ]. These data are consistent with a variety of human studies that support emerging evidence that HTLV-1 promotes lymphocyte proliferation preceding early viral spread in lymphoid compartments to establish and maintain persistent infection.…”

“… Rabbit model of HTLV-1 transmission demonstrates a reproducible system to produce persistent infections with widespread distribution of the virus similar to humans in an economical and easily monitored model. Example showing inoculation of HTLV-1-transformed cell line (R49) with ACH proviral clone [ 204 ]. Determinants of viral transmission and spread can be measured in context of the complete viral genome with the ability to test mutant viral clones concurrent with positive controls that demonstrate infectivity with parameters (e.g., proviral loads).…”