HTLV-2 APH-2 expression is correlated with proviral load but APH-2 does not promote lymphocytosis

Equipe Oncogenèse Rétrovirale, INSERM-U758 Virologie Humaine, France.
The Journal of Infectious Diseases (Impact Factor: 6). 11/2011; 205(1):82-6. DOI: 10.1093/infdis/jir708
Source: PubMed


We recently discovered the antisense protein of human T-cell leukemia virus (HTLV) type 2 (APH-2), whose messenger RNA is
encoded by the antisense strand of the HTLV-2 genome. We quantified proviral load, level of tax, and APH-2 in a series of blood samples obtained from a cohort of HTLV-2 carriers. We determined whether APH-2 promotes cell proliferation.
APH-2 was detectable in most samples tested and was correlated with proviral load. APH-2 levels were not correlated with lymphocyte count in vivo, consistent with the inability of APH-2 to promote cell proliferation
in vitro. APH-2 does not promote cell proliferation and does not cause lymphocytosis.

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Available from: Masao Matsuoka
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    • "During chronic HTLV-2 infection, the low viral replication would drive infected cells to proliferate and propagate the infection via clonal expansion with concomitant propagation of integrated proviral DNA [1]. The reported stable proviral load (pVL) over time would support a balance between virus-induced clonal proliferation and the immunologic control of HTLV infection [2] [3] [4] [5]. "
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    ABSTRACT: Numerous studies have analyzed the effects of raltegravir intensification on HIV-1 viral replication in infected individuals receiving suppressive combined antiretroviral treatment (cART). Nevertheless, there are only two studies on the effect of raltegravir in HTLV-1 infection, and none in HTLV-2. To study the effect of raltegravir on HTLV-2 infection in HIV-1-co-infected individuals. This retrospective longitudinal study included four HTLV-2-HIV-1-co-infected individuals who received raltegravir-based cART during 48 weeks and 11 HTLV-2-HIV-1-co-infected individuals under cART without raltegravir during 48 weeks. HTLV-2 proviral load, CD4 and CD8 count and frequency were analyzed. HTLV-2 proviral load significantly increased at week 24 compared to baseline among all the patients who received raltegravir (p=0.003), while no significant increases were found in the control group. No significant variation in either CD8 or CD4 counts was found during the follow up in both groups. Raltegravir induced a transient increment on total HTLV-2 DNA proviral load in HTLV-2/HIV-1-coinfected individuals on suppressive cART after 24 weeks.
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    • "HTLV-2, a type of retrovirus which is similar with HTLV-1, encodes an antisense protein (APH-2) using the minus strand of its genome. However, APH-2 does not seem to promote cell proliferation [9,10]. HBZ was reported to repress Tax-mediated transactivation of viral transcription from the HTLV-1 5’LTR [11]. "
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    ABSTRACT: Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus etiologically associated with adult T-cell leukemia (ATL). The HTLV-1 bZIP factor (HBZ), which is encoded by minus strand of provirus, is expressed in all ATL cases and supports the proliferation of ATL cells. However, the precise mechanism of growth promoting activity of HBZ is poorly understood. In this study, we showed that HBZ suppressed C/EBPalpha signaling activation induced by either Tax or C/EBPalpha. As mechanisms of HBZ-mediated C/EBPalpha inhibition, we found that HBZ physically interacted with C/EBPalpha and diminished its DNA binding capacity. Luciferase and immunoprecipitation assays revealed that HBZ repressed C/EBPalpha activation in a Smad3-dependent manner. In addition, C/EBPalpha was overexpressed in HTLV-1 infected cell lines and fresh ATL cases. HBZ was able to induce C/EBPalpha transcription by enhancing its promoter activity. Finally, HBZ selectively modulated the expression of C/EBPalpha target genes, leading to the impairment of C/EBPalpha-mediated cell growth suppression. HBZ, by suppressing C/EBPalpha signaling, supports the proliferation of HTLV-1 infected cells, which is thought to be critical for oncogenesis.
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    • "Furthermore, a typical nuclear sequestration of its mRNA was inferred in both patient cells and infected cell lines (Bender et al., 2012). However, unlike HBZ, APH-2 is not capable of leading to IL-2-independent growth of IL-2-dependent cell lines (Douceron et al., 2012). Moreover, the absence of an impact on proliferation was further suggested in a study demonstrating no impact on proliferation of infected cells lines in addition to no effect on the immortalization capacity of HTLV-2 on infected PBMCs (Yin et al., 2012). "
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    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.
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