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Review
. 2019 Dec 18;16(1):43.
doi: 10.1186/s12977-019-0502-1.

Role of HTLV-1 orf-I encoded proteins in viral transmission and persistence

Sarkis Sarkis  1 , Veronica Galli  1 , Ramona Moles  1 , David Yurick  2 , Georges Khoury  2 , Damian F J Purcell  2 , Genoveffa Franchini  3 , Cynthia A Pise-Masison  4
Affiliations
Review

Role of HTLV-1 orf-I encoded proteins in viral transmission and persistence

Sarkis Sarkis et al. Retrovirology. .

Abstract

The human T cell leukemia virus type 1 (HTVL-1), first reported in 1980 by Robert Gallo's group, is the etiologic agent of both cancer and inflammatory diseases. Despite approximately 40 years of investigation, the prognosis for afflicted patients remains poor with no effective treatments. The virus persists in the infected host by evading the host immune response and inducing proliferation of infected CD4+ T-cells. Here, we will review the role that viral orf-I protein products play in altering intracellular signaling, protein expression and cell-cell communication in order to escape immune recognition and promote T-cell proliferation. We will also review studies of orf-I mutations found in infected patients and their potential impact on viral load, transmission and persistence. Finally, we will compare the orf-I gene in HTLV-1 subtypes as well as related STLV-1.

Keywords: ATLL; Adult T-cell leukemia/lymphoma; HAM/TSP; HTLV-1; HTLV-1 associated myelopathy/tropical spastic paraparesis; Immune evasion; STLV-1; orf-I; p12/p8; rex-orf-I.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Structure of orf-I proteins p12 and p8. Amino acid sequence and putative functional domains of full length orf-I protein. The p12 protein is highly hydrophobic and contains an amino terminus noncanonical ER retention/retrieval motif (in bold), four putative proline-rich (PxxP) Src homology 3 (SH3)-binding domains, two putative leucine zipper (LZ) motifs, and an IL-2R β and γ chain binding motif (in blue boxes). The calcineurin-binding motif [70PSLP(I/L)T75] is indicated by a green box, and two transmembrane helices TM-1 and TM-2 domains are designated by black bars above the sequence. The black triangles indicate the two cleavage sites between amino acid positions 9 and 10, and 29 and 30, respectively. The asterisk denotes the position of cysteine 39. The proteolytic cleavage site G29/L30 leading to the production of p8 is indicated with a red arrow. The lysine-to-arginine variant is highlighted at position 88 by a red box. Arginine at this position increases the stability of the protein
Fig. 2
Fig. 2
p12/p8 protein trafficking and function. (1) In the endoplasmic reticulum (ER), p12 binds to and retains the immature forms of interleukin-2 receptor (IL-2R) β and γ subunits, decreasing their trafficking to the plasma membrane. However, accumulation of the p12/IL-2R γ and β chains in the ER results in signal transducer and activator of transcription 5 (STAT5) phosphorylation in the absence of IL-2, allowing STAT5 translocation to the nucleus to promote cellular proliferation. (2) In the ER, p12 interacts with the immature heavy chains of MHC-I (MHC-I-Hc), binding to its α chain and preventing their interaction with β2 microglobulin (β2m). This leads to its degradation by the proteasome and decreased MHC-I expression at the cell surface. (3) HTLV-1A p12 also mediates the release of calcium ions (Ca2+) from the ER by binding calreticulin and calnexin. The release of Ca2+ inhibits the binding of calcineurin to the nuclear factor of T-cells (NFAT), preventing its dephosphorylation, nuclear translocation, induction of IL-2 expression and T-cell activation. In addition, p12 can inhibit the NFAT pathway by binding to calcineurin. (4) The p12 protein is proteolytically cleaved in the ER, leading to the formation of p8 that traffics to the cell surface. There, p8 increases T-cell adhesion through lymphocyte function-associated antigen-1 (LFA-1) clustering and promotes the formation of cell-to-cell contacts. (5) Further, p8 enhances the number and length of cellular conduits between T-cells, thereby enhancing signal transduction and HTLV-1 transmission
Fig. 3
Fig. 3
Effect of p12/p8 on cytotoxic T-cells (CTLs). Cytotoxic CD8 T-cells (CTL) recognize target cells bearing an appropriate antigen-MHC I complex via the T-cell receptor (TCR). CTLs carry out target cell killing by releasing the cytotoxic proteins, granzyme B and perforin. Both p12 and p8 expression are important for HTLV-1 inhibition of CTL killing. By inducing the proteasome degradation of immature MHC I, p12 decreases MHC I surface expression, reducing antigen presentation to CTLs. In addition, the reduction of ICAM-1 expression in infected cells further reduces cell adhesion. The p8 protein enhances the number and length of cellular conduits between T-cells, allowing for the transfer of target cell proteins to other cells, including p8 itself. Transferred p8 could alter intracellular signaling and dampen TCR signaling to inhibit CTL killing. The p8 protein also promotes T-cell adhesion through lymphocyte function-associated antigen-1 (LFA-1) clustering and by enhancing the formation of cell-to-cell contacts promoting viral transmission
Fig. 4
Fig. 4
Impact of p12/p8 proteins on the host immune response. Summary of p12 and p8 influence on the host immune response to HTLV-1-infected cells. Expression of HTLV-1 p12/p8 results in decreased intercellular adhesion molecules (ICAM) and MHC-I expression, resulting in the inhibition of natural killer (NK) cell recognition and cytotoxic T-cell (CTL) killing. The p8 protein induces increased cell adhesion through increased lymphocyte function-associated antigen-1 (LFA-1) expression, increased virus transmission and cell signaling through tunneling nanotubes (TNTs) and virological synapse formation, and dampens T-cell receptor (TCR) signaling
Fig. 5
Fig. 5
Amino acid sequence analysis of HTLV and STLV orf-I proteins. Alignment of amino acid sequences of p12 from HTLV-1A prototype (NC-001436; J02029; AF033817), and other previously described p12 sequences for HTLV-1A, HTLV-1B, HTLV-1C and STLV-1 available on Genbank. A dash (–) indicates a gap in the amino acid alignment, an asterisk (*) represents a stop codon, and a period (.) represents amino acid similarity. Functional elements are indicated as follows: the proteolytic cleavage sites between positions 9 and 10, and between 29 and 30 are highlighted in blue. The calcineurin binding motif is highlighted in gray, the ubiquitylation site is highlighted in yellow, the four SH3 binding domains are outlined in red, and IL-2Rβ and γ binding domain is outlined in magenta. The multi-alignment was performed with the Mega7 program using default parameters
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