Lymphoid Organs as a Major Reservoir for Human T-Cell Leukemia Virus Type 1 in Experimentally Infected Squirrel Monkeys (Saimiri sciureus): Provirus Expression, Persistence, and Humoral and Cellular Immune Responses

Abstract

The aim of this study was to investigate the distribution of human T-cell leukemia virus type 1 (HTLV-1) in various organs of serially sacrificed squirrel monkeys (Saimiri sciureus) in order to localize the reservoir of the virus and to evaluate the relationship between viral expression and the humoral or cellular immune response during infection. Six squirrel monkeys infected with HTLV-1 were sacrificed 6, 12, and 35 days and 3, 6, and 26 months after inoculation, and 20 organs and tissues were collected from each animal. PCR and reverse transcription-PCR (RT-PCR) were performed with gag and tax primers. Proviral DNA was detected by PCR in peripheral blood mononuclear cells (PBMCs) of monkeys sacrificed 6 days after inoculation and in PBMCs, spleens, and lymph nodes of monkeys sacrificed 12 and 35 days and 3, 6, and 26 months after inoculation. Furthermore, tax/rex mRNA was detected by RT-PCR in the PBMCs of two monkeys 8 to 12 days after inoculation and in the spleens and lymph nodes of the monkey sacrificed on day 12. In this animal, scattered HTLV-1 tax/rex mRNA-positive lymphocytes were detected by in situ hybridization in frozen sections of the spleen, around the germinal centers and close to the arterial capillaries. Anti-HTLV-1 cell-mediated immunity was evaluated at various times after inoculation. Anti-p40Tax and anti-Env cytolytic T-cell responses were detected 2 months after infection and remained detectable thereafter. When Tax peptides were used, this response appeared to be directed against various Tax epitopes. Our results indicate that squirrel monkeys represent a promising animal model for studying the early events of HTLV-1 infection and for evaluating candidate vaccines against HTLV-1.

Molecular and cellular aspects of HTLV-1 associated leukemogenesis in vivo

“…Analyzing the HTLV-1 replication pattern over time in PBMCs and various organs from HTLV-1 experimentally infected monkeys revealed that PBMCs and lymphoid organs constitute the major reservoirs for HTLV-1. [50][51][52][53] A pattern of persistent clonal expansion of infected cells, identical to that observed in humans, was evidenced in the PBMCs of experimentally infected animals. 51 The dissemination of the virus throughout the different body compartments appeared to result from the cellular transport of the integrated provirus.…”

“…After experimental infection of squirrel monkeys (Saimiri sciureus) with HTLV-1 infected cells, the virus appeared to be transcribed only transiently into the animal circulating blood, spleen and lymph nodes. 50 A stable disappearance of the viral expression occured at 2-3 weeks from inoculation, coinciding with the development of the anti-HTLV-1 immune response and the persistent detection of the provirus in PBMCs. Analyzing the HTLV-1 replication pattern over time in PBMCs and various organs from HTLV-1 experimentally infected monkeys revealed that PBMCs and lymphoid organs constitute the major reservoirs for HTLV-1.…”

CRM1, an RNA transporter, is a major species-specific restriction factor of human T cell leukemia virus type 1 (HTLV-1) in rat cells

“…Monkeys and rabbits have been 4 used to examine HTLV-1 infection, replication, disease manifestations, immune response, and vaccine development [15][16][17][18][19][20]. However, rats and mice are more attractive models for HTLV-1 study because of the ease with which they can be genetically manipulated.…”

HTLV-1 tropism and envelope receptor

“…In this model, peripheral blood mononuclear cells were the main infected cell compartment, but other HTLV-1-infected tissues including salivary and thyroid glands, lung, liver, pancreas, intestine, muscle and spinal cord were sporadically detected in individual monkeys (Kazanji et al, 2000).…”

“…HTLV-1 infection and spreading has also been closely examined after intravenous inoculation of adult squirrel monkeys (Saimiri sciureus) (Kazanji et al, 1997(Kazanji et al, , 2000Mortreux et al, 2001). In this model, peripheral blood mononuclear cells were the main infected cell compartment, but other HTLV-1-infected tissues including salivary and thyroid glands, lung, liver, pancreas, intestine, muscle and spinal cord were sporadically detected in individual monkeys (Kazanji et al, 2000).…”