HTLV-3/STLV-3 and HTLV-4 viruses: discovery, epidemiology, serology and molecular aspects

Abstract

Human T cell leukemia/lymphoma virus Type 1 and 2 (HTLV-1 and HTLV-2), together with their simian counterparts (STLV-1, STLV-2), belong to the Primate T lymphotropic viruses group (PTLV). The high percentage of homologies between HTLV-1 and STLV-1 strains, led to the demonstration that most HTLV-1 subtypes arose from interspecies transmission between monkeys and humans. STLV-3 viruses belong to the third PTLV type and are equally divergent from both HTLV-1 and HTLV-2. They are endemic in several monkey species that live in West, Central and East Africa. In 2005, we, and others reported the discovery of the human homolog (HTLV-3) of STLV-3 in two asymptomatic inhabitants from South Cameroon whose sera exhibited HTLV indeterminate serologies. More recently, two other cases of HTLV-3 infection in persons living in Cameroon were reported suggesting that this virus is not extremely rare in the human population living in Central Africa. Together with STLV-3, these human viral strains belong to the PTLV-3 group. A fourth HTLV type (HTLV-4) was also discovered in the same geographical area. The overall PTLV-3 and PTLV-4 genomic organization is similar to that of HTLV-1 and HTLV-2 with the exception of their long terminal repeats (LTRs) that contain only two 21 bp repeats. As in HTLV-1, HTLV-3 Tax contains a PDZ binding motif while HTLV-4 does not. An antisense transcript was also described in HTLV-3 transfected cells. PTLV-3 molecular clones are now available and will allow scientists to study the viral cycle, the tropism and the possible pathogenicity in vivo. Current studies are also aimed at determining the prevalence, distribution, and modes of transmission of these viruses, as well as their possible association with human diseases. Here we will review the characteristics of these new simian and human retroviruses, whose discovery has opened new avenues of research in the retrovirology field.

Keywords: HTLV-3; HTLV-4; STLV-3; Tax; emerging virus; interspecies transmission; retrovirus; transformation.

Figure 1

Current known geographical distribution of STLV-3, HTLV-3 and HTLV-4 viruses in the African continent. HTLV-3 and HTLV-4 are designated in bold.

Figure 2

Phylogenetic tree showing the relationship between PTLV-1, PTLV-2, PTLV3, and HTLV-4. Unrooted tree generated with the neighbor-joining method, performed with the PAUP program using the 7075 bp of the concatanated gag-pol-env-tax genes with all the complete sequences of PTLVs available in GenBank. Branch lengths are drawn to scale. The human HTLV-3 and HTLV-4 strains are indicated in bold. Recent data based on shorter fragments of more STLV-3 strains confirmed that PTLV-3s are separated according to their geographical origin with four main distinct lineages (A, B, C, D). Mac B43 strain is a highly divergent STLV-1 originating from Macaca arctoides. It is considered as an STLV-5 by some authors due to its great genetic diversity compared to STLV-1/HTLV-1 strains.

Figure 3

Geographical distribution of the four HTLV-3 and the unique HTLV-4 viruses reported in Cameroon. These viruses originated from individuals (either Pygmies or Bantus) living in villages or settlements of the rainforest of South Cameroon. This area is a region of high diversity for NHPs, many of them being infected by different STLV-1 and/or 3 viruses. The different human isolates are indicated with either a green circle (HTLV-3) or in blue (HTLV-4). The two shaded areas correspond to two nature reserves, the habitat of a large variety of non-human primates.

Figure 4

Serological pattern of HTLV-1, HTLV-2, STLV-3 and HTLV-3_Pyl43 strain. (A) Western blot from MP Biomedicals (HTLV Blot 2.4 version); (B) Line immunoassay from Immunogenetics (INNO-LIA HTLVI/II Score). Lane 1: HTLV-1 positive control. Lane 2: HTLV-2 positive control. Lanes 3 and 4: STLV-3 positive controls. Lane 5: negative control. Lane 6: HTLV-3/Pyl43 sample. Lanes 7 and 8: Two samples of HTLV-3/Lobak18 sampled a few months apart. Infection with the other two HTLV-3 strains (2026ND and CAM2031AB) led to different Western-blot patterns when compared to HTLV-3_pyl43 [3,17]. (Adapted from [15]).

Figure 5

HTLV-3 genomic organization. HTLV-3 ORFs and transcription map. A scheme of the HTLV-3 genome, alternatively spliced mRNAs, and putative proteins encoded by each mRNA is shown. ORFs are indicated by boxes. gag, pro, pol, env, tax/rex and APH-3 transcripts were amplified from 293T cells transfected with an HTLV-3 molecular clone or from STLV-3 infected cells [24,25]. Gray: LTR; blue: structural and enzymatic viral proteins; red: regulatory proteins; green: auxiliary protein. LTR: Long Terminal Repeat; (Blue color): gag: group specific antigen; pro: protease; pol: polymerase; env: envelope; (Red color): rex: regulator of expression; tax: transactivator and APH-3: antisense protein of HTLV-3; (Green color) RorfII. Note that RorfII shares its first exon with Rex.