Abstract
Integration of retroviral DNA is an obligatory step of retrovirus replication because proviral DNA is the template for productive infection. Integrase, a retroviral enzyme, catalyses integration. The process of integration can be divided into two sequential reactions. The first one, named 3'-processing, corresponds to a specific endonucleolytic reaction which prepares the viral DNA extremities to be competent for the subsequent covalent insertion, named strand transfer, into the host cell genome by a trans-esterification reaction. Recently, a novel specific activity of the full length integrase was reported, in vitro, by our group for two retroviral integrases (HIV-1 and PFV-1). This activity of internal cleavage occurs at a specific palindromic sequence mimicking the LTR-LTR junction described into the 2-LTR circles which are peculiar viral DNA forms found during viral infection. Moreover, recent studies demonstrated the existence of a weak palindromic consensus found at the integration sites. Taken together, these data underline the propensity of retroviral integrases for binding symmetrical sequences and give perspectives for targeting specific sequences used for gene therapy.
Highlights
The human immunodeficiency virus is the causal agent of AIDS
Integrase possesses two major catalytic activities: an endonucleolytic cleavage at each 3'-OH extremities of the viral genome, named 3'processing, and a strand transfer reaction leading to the insertion of the processed viral DNA into the target DNA by a trans-esterification mechanism
Since the end of the 1990s, several inhibitors with genuine antiviral activity have been identified and developed. Two of these compounds – MK0518 or raltegravir and GS9137 or elvitegravir – have shown great promise and should ensure that integrase inhibitors rapidly become an important class in the arsenal of antiretroviral drugs (ARVs) available [1]
Summary
The human immunodeficiency virus is the causal agent of AIDS. AIDS morbidity and mortality have led to efforts to identify effective inhibitors of the replication of this virus. The presence either of the catechol or an another group on the SQLs able to form a complex of coordination with a divalent ion suggests that these compounds interact with the active site of the enzyme by a chelation with the metallic cofactor These compounds are mainly inhibitors of the 3'-processing reaction, and their mechanism of action in vitro can be assimilated to a competitive mechanism. Such internal cleavages are not observed using a mutant of the catalytic site (E152A) testifying that the DDE triad is implicated in this reaction This novel activity is stringent and highly specific as (i) it occurs with the physiological metallic cofactor (Mg2+) and Mn2+, (ii) only the full-length IN is competent for the internal cleavage of the palindrome, in contrast to the disintegration reaction that is efficiently catalysed by truncated proteins such as IN55–212, IN55–288, IN1–212 and (iii) it does not sustain any mutation in the sequence of the LTR-LTR junction. Dargemont and collaborators have found that integrase interacts with VBP1 (von Hippel-Lindau binding protein 1), a binding partner of Cul2/VHL ligase complex involved in the polyubiquitylation process [133]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
