HTLV-2 APH-2 Expression Is Correlated With Proviral Load but APH-2 Does Not Promote Lymphocytosis

Douceron, Estelle; Kaidarova, Zhanna; Miyazato, Paola; Matsuoka, Masao; Murphy, Edward L.; Mahieux, Renaud

doi:10.1093/infdis/jir708

Cited by 30 publications

(32 citation statements)

References 14 publications

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“…Aph-2 mRNA was detected previously in HTLV-2-infected cell lines and in 27% of HTLV-2 carriers (20). Aph-2 mRNA expression correlated with HTLV-2 proviral loads in HTLV-2-infected carriers, but APH-2 expression did not appear to promote lymphocytosis in vivo or cell proliferation in vitro (12). In the present study, we further determined the presence of the APH-2 transcript and protein in HTLV-2 stably transfected B-cell lines as well as in HTLV-2-immortalized T-cell lines.…”

Section: Discussionmentioning

confidence: 68%

“…However, similar to HBZ, APH-2 has been shown to downregulate Taxmediated viral transcription by interacting with cellular CREB (20). APH-2 expression was found to correlate with the proviral load in HTLV-2-infected carriers but did not appear to promote lymphocytosis (12). Since evidence suggests that HBZ likely contributes to HTLV-1 pathogenesis, we hypothesized that an understanding of the differences in APH-2 function would provide important insights into the distinct pathogeneses of HTLV-1 and HTLV-2.…”

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confidence: 98%

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Human T-Cell Leukemia Virus Type 2 Antisense Viral Protein 2 Is Dispensable for In Vitro Immortalization but Functions To Repress Early Virus Replication In Vivo

Yin

Kannian

Dissinger

et al. 2012

J Virol

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dHuman T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are closely related but pathogenically distinct human retroviruses. The antisense strand of the HTLV-1 genome encodes HTLV-1 basic leucine zipper (b-ZIP) protein (HBZ), a protein that inhibits Tax-mediated viral transcription, enhances T-cell proliferation, and promotes viral persistence. Recently, an HTLV-2 antisense viral protein (APH-2) was identified. Despite its lack of a typical b-ZIP domain, APH-2, like HBZ, interacts with cyclic AMP response element binding protein (CREB) and downregulates Tax-mediated viral transcription. Here, we provide evidence that the APH-2 C-terminal LXXLL motif is important for CREB binding and Tax repression. In order to investigate the functional role of APH-2 in the HTLV-2-mediated immortalization of primary T lymphocytes in vitro and in HTLV-2 infection in vivo, we generated APH-2 mutant viruses. In cell cultures, the immortalization capacities of APH-2 mutant viruses were indistinguishable from that of wild-type HTLV-2 (wtHTLV-2), indicating that, like HBZ, APH-2 is dispensable for viral infection and cellular transformation. In vivo, rabbits inoculated with either wtHTLV-2 or APH-2 mutant viruses established a persistent infection. However, the APH-2 knockout virus displayed an increased replication rate, as measured by an increased viral antibody response and a higher proviral load. In contrast to HTLV-1 HBZ, we show that APH-2 is dispensable for the establishment of an efficient infection and persistence in a rabbit animal model. Therefore, antisense proteins of HTLV-1 and HTLV-2 have evolved different functions in vivo, and further comparative studies will provide fundamental insights into the distinct pathobiologies of these two viruses.

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Section: Discussionmentioning

confidence: 68%

mentioning

confidence: 98%

Human T-Cell Leukemia Virus Type 2 Antisense Viral Protein 2 Is Dispensable for In Vitro Immortalization but Functions To Repress Early Virus Replication In Vivo

Yin

Kannian

Dissinger

et al. 2012

J Virol

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“…These studies and others have provided evidence that HBZ is a secondary oncogene that plays a key role in cell proliferation (25,26,28,29) and cell survival (29,30). The antisense-strand protein of HTLV-2 (APH-2) has been detected in most HTLV-2-infected samples (31,32). Like HBZ, APH-2 is a nuclear protein that represses Tax-2 transactivation through its interaction with CREB (32,33).…”

mentioning

confidence: 99%

Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis

Panfil

Dissinger

Howard

et al. 2016

J Virol

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Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that transform T cells in vitro but have distinct pathological outcomes in vivo. HTLV-1 encodes a protein from the antisense strand of its proviral genome, the HTLV-1 basic leucine zipper factor (HBZ), which inhibits Tax-1-mediated viral transcription and promotes cell proliferation, a high proviral load, and persistence in vivo. In adult T-cell leukemia/lymphoma (ATL) cell lines and patient T cells, hbz is often the only viral gene expressed. The antisense strand of the HTLV-2 proviral genome also encodes a protein termed APH-2. Like HBZ, APH-2 is able to inhibit Tax-2-mediated viral transcription and is detectable in most primary lymphocytes from HTLV-2-infected patients. However, unlike HBZ, the loss of APH-2 in vivo results in increased viral replication and proviral loads, suggesting that HBZ and APH-2 modulate the virus and cellular pathways differently. Herein, we examined the effect of APH-2 on several known HBZ-modulated pathways: NF-B (p65) transactivation, transforming growth factor ␤ (TGF-␤) signaling, and interferon regulatory factor 1 (IRF-1) transactivation. Like HBZ, APH-2 has the ability to inhibit p65 transactivation. Conversely, HBZ and APH-2 have divergent effects on TGF-␤ signaling and IRF-1 transactivation. Quantitative PCR and protein half-life experiments revealed a substantial disparity between HBZ and APH-2 transcript levels and protein stability, respectively. Taken together, our data further elucidate the functional differences between HBZ and APH-2 and how these differences can have profound effects on the survival of infected cells and, ultimately, pathogenesis. IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that have distinct pathological outcomes in infected hosts. Functional comparisons of HTLV-1 and HTLV-2 proteins provide a better understanding about how HTLV-1 infection is associated with disease and HTLV-2 infection is not. The HTLV genome antisense-strand genes hbz and aph-2 are often the only viral genes expressed in HTLV-infected T cells. Previously, our group found that HTLV-1 HBZ and HTLV-2 APH-2 had distinct effects in vivo and hypothesized that the differences in the interactions of HBZ and APH-2 with important cell signaling pathways dictate whether cells undergo proliferation, apoptosis, or senescence. Ultimately, these functional differences may affect how HTLV-1 causes disease but HTLV-2 generally does not. In the current study, we compared the effects of HBZ and APH-2 on several HTLV-relevant cellular pathways, including the TGF-␤ signaling, NF-B activation, and IRF-1 transactivation pathways. Human T-cell leukemia virus type 1 (HTLV-1) is a complex oncogenic deltaretrovirus that infects an estimated 15 million to 25 million people worldwide, with areas of endemic infection being found in southwestern Japan, Africa, South America, and the Caribbean Basin (1). Approximately 2 to 5% of HTLV-1-infected indi...

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“…Recent studies have compared the proliferation-inducing capacity of APH-2 to this functional characteristic of HBZ (Douceron et al, 2012). Although not associated with any forms of leukemia, HTLV-2 has nonetheless been linked to lymphocytosis in infected patients (Bartman et al, 2008).…”

Section: Hbz Induces Il-2-independent T Cell Proliferationmentioning

confidence: 99%

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

Barbeau¹,

Péloponèse²,

Mesnard³

2013

Front. Microbiol.

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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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HTLV-2 APH-2 Expression Is Correlated With Proviral Load but APH-2 Does Not Promote Lymphocytosis

Cited by 30 publications

References 14 publications

Human T-Cell Leukemia Virus Type 2 Antisense Viral Protein 2 Is Dispensable for In Vitro Immortalization but Functions To Repress Early Virus Replication In Vivo

Human T-Cell Leukemia Virus Type 2 Antisense Viral Protein 2 Is Dispensable for In Vitro Immortalization but Functions To Repress Early Virus Replication In Vivo

Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis

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

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