AUTHOR=de La-Roque Debora Glenda Lima , Santos Elaine Vieira , Rodrigues Evandra Strazza , da Costa Péricles Natan Mendes , Brauer Verônica Soares , Almeida Fausto , de Haes Tissiana Marques , Takayanagui Osvaldo Massaiti , Covas Dimas Tadeu , Kashima Simone 

TITLE=The Expression of Tax and HBZ Genes in Serum-Derived Extracellular Vesicles From HTLV-1 Carriers Correlates to Proviral Load and Inflammatory Markers

JOURNAL=Frontiers in Microbiology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.881634

DOI=10.3389/fmicb.2022.881634

ISSN=1664-302X

ABSTRACT=Human T-lymphotropic virus 1 (HTLV-1) is the etiologic agent of adult cell leukemia/lymphoma
(ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). One of the
major questions in HTLV-1 studies is related to the understanding of causes that lead to different
clinical manifestations. However, it is well known that the viral genes tax and HTLV-1 basic leucine
zipper factor (HBZ) are related to viral infectivity and the development of neurological and
hematological diseases. Currently, there is evidence that HTLV-1 infected cells can release small
extracellular vesicles (sEV) involved in mechanisms of viral particles spreading. Therefore, we
evaluated the expression levels of tax and HBZ viral transcripts in serum-derived sEV from HTLV-1
carriers, as well as the role of these vesicles in the modulation of the immune response. Three
HAM/TSP carriers presented detectable levels of tax and HBZ transcripts in sEV and were positively
correlated to the PVL in peripheral blood mononuclear cells (PBMC). The viral transcripts were only
detectable in individuals with PVL higher than 6,000/10^5 PBMC. It was also observed that HBZ
presented a 2 to 12 fold increase over tax expression units. Gene expression and secretory protein
analysis indicated that PBMC from blood donors and HTLV-1 carriers exposed to increasing doses
of tax+ HBZ+ sEV showed a dose-dependent increase in IFN-γ and IL-8 transcripts and proteins.
Interestingly, the increase in IL-8 levels were close to those seen in HTLV-1-infected PBMC with
high PVL. Taken together, these findings indicate that the expression of viral transcripts in serum-
derived sEV of HTLV-1 carriers is related to the PVL presented by the infected individual.
Additionally, tax+ HBZ+ sEV can induce the production of inflammatory cytokines in patients with
low PVL, which may be related to the development of symptoms in HTLV-1 infection.