Molecular determinants of human T-lymphotropic virus type 1 transmission and spread

Abstract

Human T-lymphotrophic virus type-1 (HTLV-1) infects approximately 15 to 20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa. The virus is spread through contact with bodily fluids containing infected cells, most often from mother to child through breast milk or via blood transfusion. After prolonged latency periods, approximately 3 to 5% of HTLV-1 infected individuals will develop either adult T-cell leukemia/lymphoma (ATL), or other lymphocyte-mediated disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The genome of this complex retrovirus contains typical gag, pol, and env genes, but also unique nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo such as, p30, p12, p13 and the antisense encoded HBZ. While progress has been made in the understanding of viral determinants of cell transformation and host immune responses, host and viral determinants of HTLV-1 transmission and spread during the early phases of infection are unclear. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the early events of HTLV-1 infection. This review will focus on studies that test HTLV-1 determinants in context to full length infectious clones of the virus providing insights into the mechanisms of transmission and spread of HTLV-1.

Keywords: HTLV-1; animal models; determinants; human T-lymphotropic virus type-1; replication; transmission.

Figure 1

Human T-lymphotrophic virus type-1 (HTLV-1) genome, mRNA, and proteins. The HTLV-1 genome appears on top, the mRNA in the middle, and the protein species on the bottom. The numbers represent nucleotide positions of each exon splice acceptor and donor site.

Figure 2

HTLV-1 assembly and incorporation of viral components (left) and fully developed mature virion following budding from cell membrane (right).

Figure 3

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).