Vulnerability to APOBEC3G linked to the pathogenicity of deltaretroviruses.

in Proceedings of the National Academy of Sciences of the United States of America by Takafumi Shichijo, Jun-Ichirou Yasunaga, Kei Sato, Kisato Nosaka, Kosuke Toyoda, Miho Watanabe, Wenyi Zhang, Yoshio Koyanagi, Edward L Murphy, Roberta L Bruhn, Ki-Ryang Koh, Hirofumi Akari, Terumasa Ikeda, Reuben S Harris, Patrick L Green, Masao Matsuoka

TLDR

  • The study found that a protein called A3G generates mutations in the genetic material of a virus called HTLV-1. However, this mutation happens less often in another virus called HTLV-2. The study then investigated how HTLV-2 is able to resist the mutation caused by A3G. The study found that a protein called HBZ in HTLV-1 and a protein called APH-2 in HTLV-2 both inhibit the activity of A3G. However, HBZ only weakly inhibits hA3G, while APH-2 efficiently inhibits both hA3G and simian A3G. The study also found that hA3G activates a pathway called TGF-β/Smad, which promotes the growth of infected cells. In contrast, the combination of APH-2 and hA3G does not activate this pathway. Therefore, the study suggests that the way antisense factors in each virus control host cellular functions through A3G may dictate the pathogenesis.

Abstract

Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts, but in humans, HIV causes AIDS, and human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia-lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques () and found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, we investigated the mechanism of how HTLV-2 is resistant to human A3G (hA3G). HTLV-1, HTLV-2, and STLV-1 encode the so-called antisense proteins, HTLV-1 bZIP factor (HBZ), Antisense protein of HTLV-2 (APH-2), and STLV-1 bZIP factor (SBZ), respectively. APH-2 efficiently inhibits the deaminase activity of both hA3G and simian A3G (sA3G). HBZ and SBZ strongly suppress sA3G activity but only weakly inhibit hA3G, suggesting that HTLV-1 is incompletely adapted to humans. Unexpectedly, hA3G augments the activation of the transforming growth factor (TGF)-β/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulatingand. In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-β/Smad pathway. Thus, HTLV-1 is vulnerable to hA3G but utilizes it to promote the proliferation of infected cells via the activation of the TGF-β/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.

Overview

  • The study analyzed the proviral sequences of HTLV-1, HTLV-2, and STLV-1 from Japanese macaques to investigate the mechanism of how HTLV-2 is resistant to human A3G (hA3G).
  • The study found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, the study investigated the mechanism of how HTLV-2 is resistant to hA3G.

Comparative Analysis & Findings

  • The study found that A3G generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, the study investigated the mechanism of how HTLV-2 is resistant to hA3G.

Implications and Future Directions

  • The study found that hA3G augments the activation of the TGF-β/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating and. In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-β/Smad pathway. Therefore, the study suggests that antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis. Future research could investigate the role of antisense factors in other human retroviruses and their impact on host cellular functions.
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