With the increasing use of INSTIs in clinical

With the increasing use of INSTIs in clinical practice, drug resistance to this class in different HIV-1 subtypes should be carefully monitored and investigated. Studies on HIV-1 diversity and drug resistance would greatly help our understanding of viral transmission, pathogenesis and ART resistance for treatment of HIV-1 patients (Santoro and Perno, 2013). This review will summarize the latest findings on drug resistance to INSTIs in different HIV-1 subtypes in vitro and in vivo, the possible underlying mechanisms, as well as their implications for clinical practice.
Conclusions INSTIs, particularly DTG, have demonstrated high potency for the treatment of HIV patients. As INSTIs are widely used in clinical practice, drug resistance to this class in different HIV-1 subtypes should be carefully monitored and investigated. In the future, sequencing integrase before initiating any DTG-based regimen should be considered. More studies on development of resistance to INSTIs both in vitro and in vivo are needed to help us understand and manage INSTI-containing regimens and prevent the potential transmission of INSTI-resistant strains.
Disclosures
Introduction HIV-1 integrase (IN) is a pivotal enzyme of HIV that is responsible for integration of viral DNA into the host chromosome. HIV-1 IN catalyzes two of the three reaction steps of the integration process. In the first step, 3′-processing, IN removes two nucleotides from each 3′-end of the reverse transcribed viral DNA, and in the last step, strand transfer, IN inserts the processed viral DNA into the host DNA. The essential role of HIV-1 IN in the viral life Leflunomide has made it a prime target for anti-AIDS therapeutics. Although a number of HIV-1 IN inhibitors have been reported, only one of the currently FDA approved anti-HIV therapies, raltegravir, inhibits IN. Drug resistance has been observed with raltegravir, with two major mutation pathways identified in clinical studies.2, 3 With this in mind, there is still a significant need for additional strategies and inhibitors that target HIV-1 IN. HIV-1 IN is composed of three domains, including a catalytic core. The catalytic core has been shown to be a dimer in solution and in its crystal structure (Fig. 1),4, 5 whereas intact HIV IN exists as both a dimer and tetramer (dimer of dimers) in solution.6, 7 The dimeric nature of HIV IN provides the opportunity to develop inhibition strategies that target the dimerization interface of IN. Indeed, peptides derived from dimerization interface of the catalytic domain of HIV IN have been found to inhibit the enzyme,9, 10, 11, 12 with evidence for inhibiting dimerization.11, 12 In the latter case peptide fragments corresponding to α5 and α6 of the dimerization interface of HIV IN (Fig. 1) were found to be low μM inhibitors of HIV IN activity and dimerization. Recently small molecule inhibitors of HIV IN dimerization have also been reported, with mid to high micromolar potency.
Results and discussion
Conclusions In this study two low micromolar dimerization inhibitors of HIV-1 IN, α5 and α6, were crosslinked to mimic a larger area of the interfacial region of HIV-1 IN. The optimal flexible tether length was found to be seven methylene units; α5-7C-α6 has enhanced inhibitory activity over the compound containing the native loop sequence of HIV-1 IN. This agent, α5-7C-α6, was also found to function via a dissociative mechanism of inhibition. Crosslinked peptides with more rigid tethers were designed and synthesized as well. A number of these agents were found to be potent inhibitors of both the enzymatic activity and dimerization of HIV-1 IN, with IC50 values for the 3′-processing reaction in the mid-nM range. The most potent inhibitor, α5-Cmpi-α6, will be the focus of future investigations to minimize the inhibitor size through truncation.
Experimental procedures
Acknowledgments
Introduction Human immunodeficiency virus (HIV), the causative agent of AIDS, remains an urgent global challenge; more than 38 million people were infected by HIV as of 2015 [1]. Despite the introduction of highly active antiretroviral therapy (HAART), a complete cure remains elusive. Thus, the development of novel agents capable of complement existing treatment strategies remains one of the major goals of HIV drug discovery [2,3].