Mechanism of HTLV-1 counteraction of APOBEC3

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Worldwide, 20-30 million people are infected with the delta-retrovirus Human T-lymphotropic virus type I (HTLV-1). Up to 5 % of all infections lead to adult T-cell leukemia and an additional 1-2 % develop myelopathy. HTLV-1, like HIV-1, primarily targets CD4+ T-lymphocytes. There is currently no cure for HTLV-1-infected patients and the lack of efficient antiviral drugs for HTLV-1 offers limited management options. The role of the innate immune system in the HTLV-1 infection is not well known. Part of it, the cytidine deaminase family of APOBEC3 (A3) proteins (A3A - A3D, A3F - A3H) can strongly inhibit retroviruses. HTLV-1 encounters A3 proteins in vivo as it targets the same CD4+ T cells as HIV-1, but HTLV-1 lacks a molecule like Vif, which allows HIV to escape the A3 restriction. We found that A3C - A3G did little to curb HTLV-1 infectivity, yet A3A, A3B and A3H haplotype II (hapII) potently decrease HTLV-1 infectivity. A3A and A3B require catalytic deaminase activity for restriction and induced severe mutations in the viral genome, whereas A3H hapII restricts HTLV-1 in a deaminase-independent manner. We propose to investigate the mechanisms by which HTLV-1 counteracts the human A3C - A3G, and to elucidate the antiviral mechanism of human A3H hapII that inhibit HTLV-1 without inducing cytidine deamination in the viral genome. The results will help us to better understand the human-HTLV-1 interaction and may open the window for new treatment options.