J Biosci Vol. 43, No. 4, September 2018, pp. 785–795 Ó Indian Academy of Sciences DOI: 10.1007/s12038-018-9787-9 Review HTLV-1: A real pathogen or a runaway guest of a diseased cell? LIBKANZAKI Laboratory of Bioprospection, Department of Pharmacy, University of Brasilia, Brası´lia, DF CEP 70.910-900, Brazil (Email, [email protected]) MS received 9 October 2017; accepted 31 May 2018; published online 4 August 2018 The human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus claimed to be aetiologically linked to the adult T-cell leukaemia/lymphoma (ATLL) and associated myelopathy/tropical spastic paraparesis (HAM/TSP) besides other minor pathologies. HTLV-1 infection is worldwide distributed, despite its heterogeneous prevalence. Environmental factors and host-genetic background are very likely to determine the epidemiological profile of HTLV-1 prevalence and related disease confinement in distinct human ethnic populations and geographical coordinates, which raises the question if the virus is a real pathogen or a runaway well-organized packed genome of a burden host cell near death process. New methodological approaches need to be proposed and applied in order to prove or discard the hypotheses emerged in the present review. Keywords. Deltaretrovirus; environment; HTLV; ionizing radiation 1. Introduction lymphoma (mycosis fungoides) (Poiesz et al. 1980; Gallo 2005). Previously, in 1977, Takatsuki and coworkers, in The factors that determine the incidence and prevalence of Kyoto, Japan, described a new haematological disease, the certain infectious diseases seem to be well established, such adult T-cell leukaemia (ATL) that later on was aetiologically as the host-genetic background with special focus on the linked to human T-cell lymphotropic virus (HTLV) (Takat- major histocompatibility complex and the innate immunity. suki 2005). After reviewing the patient records from whom But also, climate conditions and environmental contamina- HTLV was first isolated, it was concluded to be also ATL. In tion associated with geographical coordinates and geological 1998, the International Committee on Taxonomy of Virus profiles have a profound effect on both host health and established the seven genera (Alpharetrovirus, Betaretro- parasite success in the established relationship. Infectious virus, Deltaretrovirus, Epsilonretrovirus, Gammaretrovirus, diseases are particularly distinct, as the interactions between Lentivirus and Spumavirus) of the retroviridae family, the pathogen and the host immune system play a crucial role including the Deltaretrovirus genus enclosing the HTLV in the outcome of host health and parasite survival and species (http://www.ictvonline.org/taxonomyReleases.asp). evolution. The pathogen and host interrelationship, mainly administered by the immune system, is not solely circum- scribed by these players, but also influenced by a plethora of 2. The Deltaretrovirus genus factors, with extraordinary emphasis on the environment settings, including toxic metal content of foods, mainly of The Deltaretrovirus genus comprises the HTLV types 1, 2, 3 botanical origin and meat of animals (Anche et al. 2015; and 4 (HTLV-1/2/3/4), the simian T-cell lymphotropic virus Bickler et al. 2016; de la Pen˜a-Lo´pez and Remolina-Bonilla types 1, 2, 3 and 4 (STLV-1/2/3/4) and the bovine leukaemia 2016; Pitchappan 2016; Sochorova´ et al. 2016; Maria John virus (BLV) (Gessain et al. 2013; Lairmore 2014; LeBreton et al. 2017; Padayachee et al. 2017). et al. 2014). Among the human deltaretroviruses, only The first human retrovirus was isolated and characterized HTLV-1 has been aetiologically linked to human diseases as in Gallo’s laboratory in 1979, in Bethesda, MD, USA ATL/lymphoma (ATLL) and the tropical spastic paraparesis (Coffin 2015). Initially, the virus was named human cuta- (TSP), also known in Japan as HTLV-1-associated neous T-cell lymphoma virus, strain CR, HTLVcr, referring myelopathy (HAM), besides other pathologies related to the to the patient’s name (CR) diagnosed with a cutaneous T-cell abnormal lymphocytic proliferation induced by the http://www.ias.ac.in/jbiosci 785 786 LIB Kanzaki interaction of viral proteins with the host cell biochemical The retrovirus long-terminal repeat, LTR, controls virus machinery. The other members of the HTLV group were not expression through their cis acting elements, U3, R and U5. yet aetiologically linked to any disease, their role in human The HTLV-1 accessory proteins, p30, p12 and p13, play pathologies is not clear, even though some researchers claim auxiliary roles in viral oncogenesis as latency also. The that HTLV-2 would also be a causative agent of neurological HTLV-1 infected subjects could behave just as virus carriers disorders (Biglione et al. 2003; Montanheiro et al. 2008; without any visible pathological abnormality and symp- Biswas et al. 2009). The HTLV types 3 and 4 were also not tomless, or present any related disease in progression which, related to any disease, and solely found among indigenous in both cases, represent a fine and delicate intrinsic virus– people in Central Africa (LeBreton et al. 2014). host cellular and molecular orchestration that still needs Closely related to the human deltaretroviruses, the STLV- more insights to completely understand, unravelling the role 1/2/3/4 were transmitted to humans by non-human primates, played by the cellular and viral gene products (Boxus and very probably in Africa, in an apparently long-term adap- Willems 2009). tation. Altogether, HTLVs and STLVs compose of the group of the primate T-lymphotropic viruses (PTLVs) due to their intimate phylogenetic relationship (Slattery et al. 1999; 4. Human Deltaretrovirus and the host immune system Filippone et al. 2015; Richard et al. 2016). Inferred from molecular analysis with paleobiogeographical and ecological T as well as B lymphocytes and dendritic cells are the main data, Reid et al.(2016) concluded that it was very likely that targets of deltaretroviruses, even though monocytes and STLV-1 transmission from a macaque (Macaca sp.) to an macrophages are also susceptible to HTLV-1 infection. The orangutan (Pongo sp.) occurred around 207.5–17.2 kya (late cell receptor for the virion envelope (ENV) glycoprotein, the Pleistocene) and to humans between 125.9 and 10.4 kya. glucose transporter type 1 (GLUT1), mediates the host cell Recently, two individuals in Gabon, Central Africa, were membrane fusion to the virion surface and transmembrane found to be infected by HTLV-4/STLV-4 after being bitten ENV glycoproteins and therefore infection, assisted by other by a gorilla, as both deltaretrovirus, from human and gorilla, cellular factors as the heparan sulphate proteoglycans showed more than 99.4% nucleotide identity. The geo- (HSPG) and the vascular endothelial growth factor (VEGF)- graphical origin of the PTLV group is still on debate, but 165 receptor neuropilin 1 (NRP-1) (Jones et al. 2011; confined to the limits of Africa and Asia among their non- Kannian et al. 2013; Maeda et al. 2015). human primate hosts (Slattery et al. 1999; LeBreton et al. HTLV-1 preferentially presents tropism for CD4? T-cells, 2014; Filippone et al. 2015; Reid et al. 2016; Richard et al. so the highest proviral load is detected among these cells, 2016). and in much less amount in CD8? T-cells, therefore ATL cells are mainly represented by CD4? T-cells. On the other hand, HTLV-2 mainly infects CD8? T-cells (Bangham et al. 3. Deltaretrovirus genome composition and disease 2014; Maeda et al. 2015). Scarce information is available for implications HTLV-3 and 4, as studies are still restricted to the genome of these viruses, as few subjects were found to be infected by Retroviral genomes are organized in the 50-LTR-gag-pro- them in Central Africa. Apparently, both viruses share the pol-env-LTR-30 structure, enclosing sequences that code for same host cell receptors as HTLV-1 and 2 (Gessain et al. proteins that build-up the virion architecture (gag and pol 2013; Mahieux and Gessain 2013). Infection of monocytes genes), and enzymes necessary for molecular plasticity in the by HTLV-1 is likely a prerequisite for viral persistence in virus assembly (pro and pol genes). Also, regulatory/acces- humans, as also the viral load would determine the disease sory factors are coded by the retroviral genome, in attempts onset and progression (Bellon and Nicot 2015; de Castro- to circumvent the host immune response through controlling Amarante et al. 2015; Hyun et al. 2015). gene function and host virus interaction, usually deleterious In vitro studies have demonstrated that the HTLV-1 Tax for the host (Skalka 2014). oncoprotein interacts with the Toll-dependent TIR-domain- The HTLV-1 9 kb genome, besides the classical organi- containing adapter-inducing interferon-b (TRIF), which zation of all retroviruses, possesses gene sequence coding suppresses the innate immune response (Mahieux and Ges- for the regulatory proteins Tax, Rex and HTLV-1 bZIP factor sain 2011). Both Tax and HBZ expressions induce, through (HBZ). The Tax and HBZ proteins, coded in the plus and multiple pathways, telomerase activity in HTLV-1 infected minus strands, respectively, in the pX region, play a major cells, preventing them to enter a senescence state (Bellon role in viral pathogenesis, HTLV-1-associated inflammatory and Nicot 2015), but the infected cells concomitantly diseases and ATLL. Despite this, in some pathways, Tax and expressing Tax and the cell adhesion molecule 1 (CADM1/ HBZ act antagonically, as the Tax protein is important for TSLC1) are efficiently eliminated by TCD8? cytotoxic cells, the initiation of viral oncogenesis but HBZ balances Tax during MHC presentation (Manivannan et al. 2016). activity, maintaining the neoplastic state (Philip et al. 2014). Therefore in someway, HBZ and Tax play complementary, HTLV-1 escape 787 opposite and replacing roles during the fate of infected cells, highest prevalence of HTLV-1 infection in the world has deciding the asymptomatic or disease state of HTLV-1 car- been recently found among indigenous Australians (Ein- rier hosts.