Functional comparison of antisense proteins of HTLV-1 and HTLV-2 in viral pathogenesis

Abstract

The production of antisense transcripts from the 3' long terminal repeat (LTR) in human T-lymphotropic retroviruses has now been clearly demonstrated. After the identification of the antisense strand-encoded human T-lymphotropic virus type 1 (HTLV-1) bZIP (HBZ) factor, we reported that HBZ could interact with CRE-binding protein (CREB) transcription factors and consequently turn off the important activating potential of the viral Tax protein on HTLV-1 5' LTR promoter activity. We have recently accumulated new results demonstrating that antisense transcripts also exist in HTLV-2, -3, and -4. Furthermore, our data have confirmed the existence of encoded proteins from these antisense transcripts (termed antisense proteins of HTLVs or APHs). APHs are also involved in the down-regulation of Tax-dependent viral transcription. In this review, we will focus on the different molecular mechanisms used by HBZ and APH-2 to control viral expression. While HBZ interacts with CREB through its basic zipper domain, APH-2 binds to this cellular factor through a five amino acid motif localized in its carboxyl terminus. Moreover, unlike APH-2, HBZ possesses an N-terminal activation domain that also contributes to the inhibition of the viral transcription by interacting with the KIX domain of p300/CBP. On the other hand, HBZ was found to induce T cell proliferation while APH-2 was unable to promote such proliferation. Interestingly, HTLV-2 has not been causally linked to human T cell leukemia, while HTLV-1 is responsible for the development of the adult T cell leukemia/lymphoma. We will further discuss the possible role played by antisense proteins in the establishment of pathologies induced by viral infection.

Keywords: APH-2; HBZ; HTLV-1; HTLV-2; antisense transcription.

FIGURE 1

HTLV-1 and HTLV-2 proviral DNA. Viral ORFs are depicted as either common retroviral proteins (blue), regulatory factors (red), or accessory proteins (yellow).Antisense strand-encoded ORFs are also indicated (green). Antisense transcripts are initiated from the 3′ LTR and spliced to produce the antisense proteins, HBZ and APH-2. In both cases, transcripts are initiated at a similar position in the 3′ LTR (which constitutes the first exon) and are spliced to the second exon, which contains the main ORF region as well as the 3′ untranslated region. Their polyA tail is positioned 1450 nucleotides from the ORF stop codon. In HTLV-1, an unspliced transcript initiating downstream of the 3′ LTR (not shown here) has also been described (Yoshida et al., 2008).

FIGURE 2

Schematic representations of HBZ and APH-2 functional domains. Both proteins contain basic domains (blue) involved in their nuclear localization. HBZ possesses an N-terminal activation domain (AD in red), a modulatory domain (MD in yellow) and a ZIP (green) controlling the transcriptional activity of Jun and ATF/CREB proteins. While APH-2 does not contain any activation domain, it can interact with c-Jun and JunB through a non-canonical ZIP region (ncZIP in green) and with CREB through a C-terminal CREB-binding motif (CBM in black). Unlike HBZ, APH-2 binds to Tax (+) and (-) respectively indicate an activating or inhibiting effect of viral proteins on targeted proteins.

FIGURE 3

HBZ and APH-2 differently impact T cell proliferation. Infection of T lymphocytes with HTLV-1 or HTLV-2 results in an increase in proviral loads, with a more pronounced effect for HTLV-1 proviral DNA load. An antibody response against Gag and Env and Tax-specific CTL responses induces killing of infected cells. HTLV-1 can evade the immune response by reducing Tax and stimulating HBZ expression. HBZ would subsequently promote the establishment of a chronic infection by inhibiting Tax-dependent viral transcription, stimulating its own expression, and inducing T cell proliferation. APH-2 also down-regulates Tax-dependent HTLV-2 transcription but is unable to induce cell proliferation. A low expression of Tax induced by APH-2 through its capacity to positively modulate c-Jun activation could be responsible for HTLV-2-stimulated lymphocytosis.