Et al., 2005; Ooms et al., 2012; Sasada et al., 2005; Strebel, 2005). The impact of these enzymes on HTLV-1 infectivity in primary lymphocytes has yet to be examined in part due to technical challenges of lower virus infectivity and strong preferences for cell-to-cell, rather than cell-free transmission. However, in contrast HIV-1 sequences derived from patient samples, characteristic G-to-A mutations are relatively rare in HTLV-1 sequences. An initial study of HTLV-1 in 10 patients found no evidence for hypermutation (Mahieux et al., 2005). A subsequent larger study analyzed the entire sequence of HTLV-1 proviruses from 60 adult T-cell leukemia (ATL) patients and 10 HTLV-1 carriers and found inactivating mutations in nearly 50 of cases with G-to-A changes in an A3G context accounting only for a small subset of nonsense changes (Fan et al., 2010). These observations are consistent with the fact thatVirology. Author manuscript; available in PMC 2016 May 01.Harris and DudleyPageHTLV-1 provokes strong cytotoxic T cell responses in vivo, which often select for mutational inactivation of dominant viral epitopes encoded by plus-strand genes such as Tax (Bangham et al., 2014). This manifests in ATL as oligoclonally expanded pools of T cells, with each pool characterized by a single replication-defective provirus insertion (Bangham et al., 2014). A3 counteraction mechanism of HTLV-1 As mentioned above, HTLV-1 is relatively resistant to restriction by A3G, in comparison to Vif-deficient HIV-1 (Derse et al., 2007; Navarro et al., 2005; Ooms et al., 2012). This resistance phenotype correlated with lower levels of encapsidated A3G. An elegant mutational analysis revealed that resistance was not due to a viral accessory protein, rather to a unique C-terminal extension of the viral nucleocapsid (NC) protein (Derse et al., 2007). If 20 residues of this extension were deleted or mutated, then HTLV-1 became exquisitely sensitive to A3G restriction through an encapsidation and hypermutation mechanism analogous to that described above for Vif-deficient HIV-1. This work was significant by its demonstration of a novel mechanism of A3 resistance by exclusion. Thus, other potentially susceptible DNA parasites may use a similar exclusion mechanism or possess a novel strategy for preventing A3 enzymes from attacking single-stranded DNA replication intermediates.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptRetrovirus restriction by murine A3 ?in vivo insights from animal modelsMMTV restriction The first direct evidence that APOBEC family members protect against retroviral infection in vivo was obtained by studying mouse mammary tumor virus (MMTV) infection of A3defective mice (Okeoma et al., 2007). A3 mRNA is detectable in a wide variety of wild-type mouse tissues with the highest levels occurring in the thymus and lymph nodes, suggesting preferential order Lixisenatide activity in lymphoid tissues (Okeoma et al., 2007). C57BL/6 (B6) mice were infected subcutaneously with MMTV and compared to infections of ML240 web A3-mutant mice created by gene trap technology. The mutant (designated A3-/-) expressed an in-frame fusion of the first four A3 exons to the -galactosidase gene and was confirmed to lack deaminase activity as well as inhibitory activity after packaging into HIV virions. Since MMTV must infect and activate B and T cells during transmission to target mammary epithelial cells (Golovkina et al., 1992; Golovkina et al., 1998; Held et al., 1993a; Held et al.Et al., 2005; Ooms et al., 2012; Sasada et al., 2005; Strebel, 2005). The impact of these enzymes on HTLV-1 infectivity in primary lymphocytes has yet to be examined in part due to technical challenges of lower virus infectivity and strong preferences for cell-to-cell, rather than cell-free transmission. However, in contrast HIV-1 sequences derived from patient samples, characteristic G-to-A mutations are relatively rare in HTLV-1 sequences. An initial study of HTLV-1 in 10 patients found no evidence for hypermutation (Mahieux et al., 2005). A subsequent larger study analyzed the entire sequence of HTLV-1 proviruses from 60 adult T-cell leukemia (ATL) patients and 10 HTLV-1 carriers and found inactivating mutations in nearly 50 of cases with G-to-A changes in an A3G context accounting only for a small subset of nonsense changes (Fan et al., 2010). These observations are consistent with the fact thatVirology. Author manuscript; available in PMC 2016 May 01.Harris and DudleyPageHTLV-1 provokes strong cytotoxic T cell responses in vivo, which often select for mutational inactivation of dominant viral epitopes encoded by plus-strand genes such as Tax (Bangham et al., 2014). This manifests in ATL as oligoclonally expanded pools of T cells, with each pool characterized by a single replication-defective provirus insertion (Bangham et al., 2014). A3 counteraction mechanism of HTLV-1 As mentioned above, HTLV-1 is relatively resistant to restriction by A3G, in comparison to Vif-deficient HIV-1 (Derse et al., 2007; Navarro et al., 2005; Ooms et al., 2012). This resistance phenotype correlated with lower levels of encapsidated A3G. An elegant mutational analysis revealed that resistance was not due to a viral accessory protein, rather to a unique C-terminal extension of the viral nucleocapsid (NC) protein (Derse et al., 2007). If 20 residues of this extension were deleted or mutated, then HTLV-1 became exquisitely sensitive to A3G restriction through an encapsidation and hypermutation mechanism analogous to that described above for Vif-deficient HIV-1. This work was significant by its demonstration of a novel mechanism of A3 resistance by exclusion. Thus, other potentially susceptible DNA parasites may use a similar exclusion mechanism or possess a novel strategy for preventing A3 enzymes from attacking single-stranded DNA replication intermediates.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptRetrovirus restriction by murine A3 ?in vivo insights from animal modelsMMTV restriction The first direct evidence that APOBEC family members protect against retroviral infection in vivo was obtained by studying mouse mammary tumor virus (MMTV) infection of A3defective mice (Okeoma et al., 2007). A3 mRNA is detectable in a wide variety of wild-type mouse tissues with the highest levels occurring in the thymus and lymph nodes, suggesting preferential activity in lymphoid tissues (Okeoma et al., 2007). C57BL/6 (B6) mice were infected subcutaneously with MMTV and compared to infections of A3-mutant mice created by gene trap technology. The mutant (designated A3-/-) expressed an in-frame fusion of the first four A3 exons to the -galactosidase gene and was confirmed to lack deaminase activity as well as inhibitory activity after packaging into HIV virions. Since MMTV must infect and activate B and T cells during transmission to target mammary epithelial cells (Golovkina et al., 1992; Golovkina et al., 1998; Held et al., 1993a; Held et al.
