Abstract
Human Ku70/Ku80 protein is known to influence HIV-1 replication. One of the possible reasons may be the protection of integrase from proteasomal degradation by Ku70 subunit. We demonstrated that recombinant HIV-1 integrase and Ku70 form a stable complex, while no interaction of Ku70 with integrase from prototype foamy virus was observed. By analyzing protein subdomains we determined two binding sites in the structure of both Ku70 and integrase: the 51–160 a.a. region of integrase interacts with residues 251–438 of Ku70, whereas Ku70 N-terminal domain (1–250 a.a.) contacts an α6-helix in the 200–220 a.a. integrase region. Single substitutions within integrase (E212A or L213A) block the interaction with Ku70 thus indicating that the binding site formed by the 200–220 a.a. integrase region is crucial for complex formation. E212A/L213A substitutions decreased the integrase capacity to bind Ku70 in HEK293T cells. A conjugate of 2′-ОMe-GGUUUUUGUGU oligonucleotide with eosin is shown by molecular modeling to shield integrase residues E212/L213 and is effective in blocking complex formation of Ku70 with integrase what makes the complex between α6-helix and Ku70(1–250) a possible target for drug development.
Highlights
Human immunodeficiency virus requires many cellular factors in order to successfully complete its replication[1]
At least two possible explanations were proposed for the impact that Ku has on viral integration: participation as a member of DNA-PK complex in the repair of gaps resulting from the viral DNA integration into the cell genome[18, 27, 28]; and protection of HIV-1 integrase (IN) against proteasomal degradation[29]
The mode of IN/LEDGF binding is well characterized, inhibitors of this binding, named LEDGINs, are developed and their potential as anti-HIV drugs is shown[34, 35]. The latter fact indicates that the study of the HIV-1 IN interactions with its cellular partners is promising in the context of new antiretroviral drug development
Summary
Human immunodeficiency virus requires many cellular factors in order to successfully complete its replication[1]. It has been found that DNA-PK triggers apoptosis in activated CD4+ T cells during early HIV infection[26] These data point to multiple roles of Ku in HIV-1 replication cycle and indicate the need for more detailed study of the effects of Ku that could confirm the significance of this protein as a novel probable target for antiretroviral therapy. The mode of IN/LEDGF binding is well characterized, inhibitors of this binding, named LEDGINs, are developed and their potential as anti-HIV drugs is shown[34, 35] The latter fact indicates that the study of the HIV-1 IN interactions with its cellular partners is promising in the context of new antiretroviral drug development. Depletion of Ku80, which decreased the intracellular level of Ku70, in transduced HCT 116 cells is not found to affect the efficiency of viral DNA integration into the cellular genome[23]
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