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J Biol Chem 2019 Oct 11 REVIEWS cro Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition Published, Papers in Press, August 29, 2019, DOI 10.1074/jbc.REV119.006901 X Alan N. Engelman1 From the Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215 and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 Edited by Karin Musier-Forsyth Antiretroviral inhibitors that are used to manage HIV infec- replication cycle (1)(Fig. 1). Unique among animal viruses is the tion/AIDS predominantly target three enzymes required for requirement for retroviruses to integrate their genetic informa- virus replication: reverse transcriptase, protease, and integrase. tion into the genome of the host cell that they infect. Integration Although integrase inhibitors were the last among this group to is mediated by the viral protein integrase (IN), which is incor- be approved for treating people living with HIV, they have since porated into fledgling viral particles alongside the other viral risen to the forefront of treatment options. Integrase strand enzymes reverse transcriptase (RT) and protease (PR). PR ini- transfer inhibitors (INSTIs) are now recommended components tiates virus particle maturation by cleaving viral Gag and Gag- Downloaded from of frontline and drug-switch antiretroviral therapy formula- Pol polyprotein precursors into separate viral structural pro- tions. Integrase catalyzes two successive magnesium-dependent teins and enzymes, which is required to form the viral core -polynucleotidyl transferase reactions, 3؅ processing and strand (reviewed in Ref. 2). The core consists of the viral ribonucleo transfer, and INSTIs tightly bind the divalent metal ions and protein (RNP) complex, which contains two copies of the RNA ؅ viral DNA end after 3 processing, displacing from the integrase genome bound by viral nucleocapsid, IN, and RT proteins, http://www.jbc.org/ active site the DNA 3؅-hydroxyl group that is required for strand encased within a fullerene shell composed of the viral capsid transfer activity. Although second-generation INSTIs present protein (reviewed in Ref. 3). RT converts retroviral RNA into a higher barriers to the development of viral drug resistance than single molecule of linear DNA containing a copy of the viral first-generation compounds, the mechanisms underlying these long terminal repeat (LTR) at each end (Figs. 1 and 2) (reviewed superior barrier profiles are incompletely understood. A sepa- in Ref. 4). The linear DNA, comprised of U3 and U5 terminal rate class of HIV-1 integrase inhibitors, the allosteric integrase sequences in respective upstream and downstream LTRs, is the by guest on October 11, 2019 inhibitors (ALLINIs), engage integrase distal from the enzyme substrate for IN-mediated viral DNA insertion into chromo- active site, namely at the binding site for the cellular cofactor somal DNA (5–7). lens epithelium-derived growth factor (LEDGF)/p75 that helps Four classes of antiretroviral drugs, nucleoside RT inhibitors to guide integration into host genes. ALLINIs inhibit HIV-1 rep- (NRTIs), nonnucleoside RT inhibitors (NNRTIs), PR inhibitors lication by inducing integrase hypermultimerization, which (PIs), and IN strand transfer inhibitors (INSTIs) have in recent precludes integrase binding to genomic RNA and perturbs the years comprised frontline cART formulations (8). Highlighting morphogenesis of new viral particles. Although not yet the success of the INSTI drug class, current guidelines recom- approved for human use, ALLINIs provide important probes mend the use of a second-generation INSTI (dolutegravir that can be used to investigate the link between HIV-1 integrase (DTG) or bictegravir (BIC)) co-formulated with two NRTIs to and viral particle morphogenesis. Herein, I review the mecha- treat most people living with HIV (PLHIV) who have not pre- nisms of retroviral integration as well as the promises and chal- viously failed an INSTI-containing regimen (9, 10). INSTIs lenges of using integrase inhibitors for HIV/AIDS management. inhibit IN strand transfer activity and thus specifically block the integration step within the HIV-1 life cycle (11)(Fig. 1). A sep- arate class of inhibitors, the allosteric IN inhibitors (ALLINIs), Combination antiretroviral therapy (cART)2 treats patients with a mixture of drugs to inhibit different steps of the HIV-1 genic EM; CTD, C-terminal domain; CSC, cleaved synaptic complex; DTG, dolutegravir; EVG, elvitegravir; FDA, Food and Drug Administration; IBD, integrase-binding domain; IN, integrase; INSTI, integrase strand transfer This work was supported by National Institutes of Health Grants R37 AI039394 inhibitor; KPN, karyopherin; LA, long-acting; LEDGF, lens epithelium-de- and R01 AI070042. The author has received fees from ViiV Healthcare Co. rived growth factor; LRA, latency reversal agent; LTR, long terminal repeat; within the past 12 months. The content is solely the responsibility of the MMTV, mouse mammary tumor virus; MVV, Maedi-visna virus; NNRTI; non- author and does not necessarily represent the official views of the National nucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse tran- Institutes of Health. scriptase inhibitor; NTD, N-terminal domain; PDB, Protein Data Bank; PFV, 1 To whom correspondence should be addressed: Dept. of Cancer Immunol- prototype foamy virus; PI, protease inhibitor; PIC, preintegration complex; ogy and Virology, Dana-Farber Cancer Institute, Boston, MA 02215. PLHIV, people living with HIV; PPT, polypurine tract; PR, protease; PrEP, Tel.: 617-632-4381; Fax: 617-632-4338; E-mail: alan_engelman@dfci. pre-exposure prophylaxis; RAL, raltegravir; RANBP, Ran-binding protein; harvard.edu. RNP, ribonucleoprotein; RT, reverse transcriptase; SHIV, simian-human 2 The abbreviations used are: cART, combination antiretroviral therapy; immunodeficiency virus; SSC, stable synaptic complex; t-BSF, tert-butylsul- ALLINI, allosteric integrase inhibitor; BIC, bictegravir; CAB, cabotegravir; fonamide; TCC, target capture complex; TNPO, transportin; SH3, Src homo- CCD, catalytic core domain; CIC, conserved intasome core; cryo-EM, cryo- logy 3. J. Biol. Chem. (2019) 294(41) 15137–15157 15137 © 2019 Engelman. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. JBC REVIEWS: HIV integrase mechanisms and inhibition Downloaded from http://www.jbc.org/ by guest on October 11, 2019 Figure 1. HIV replication cycle. After entry into a susceptible target cell, RT converts genomic RNA into linear DNA within the confines of the reverse transcription complex (RTC)(272). Processing of the viral DNA ends by IN yields the PIC (30), which can integrate the endogenous DNA made by reverse transcription into recombinant target DNA in vitro (5). Following nuclear import and integration, the provirus (flanked by composite cyan/yellow/magenta LTRs) serves as a transcriptional template to produce viral mRNAs for translation of viral proteins as well as nascent viral genomes that co-assemble with viral proteins to form immature virions that bud out from the infected cell (2). Shown is a generalized scheme that depicts the major steps of HIV-1 replication, although it is important to note that deviations from this plan exist throughout Retroviridae. Most notably, spumavirus reverse transcription occurs during the second half of the infectious cycle (after integration), and spumaviral particles accordingly predominantly contain dsDNA (104, 273). The primary steps in the HIV-1 replication cycle that are inhibited by the two major classes of IN inhibitors discussed herein are indicated. by contrast inhibit particle maturation (12, 13) (see below). To includes related enzymes such as transposase proteins and fully understand the nature of these different types of inhibi- RNase H (reviewed in Ref. 17). tors, it is important to appreciate the different steps of HIV-1 Two different IN activities, 3Ј processing and strand transfer, replication (Fig. 1) as well as the mechanistic and structural are required for integration (Fig. 2). During 3Ј processing, IN bases of retroviral DNA integration. prepares the linear reverse transcript for integration by hydro- lyzing the DNA ends 3Ј of conserved CA dinucleotides, which Mechanism of retroviral integration most often liberates a dinucleotide from each end (18–20). IN is a polynucleotidyl transferase composed of three con- However, symmetrical DNA processing is not required for inte- served protein domains: the N-terminal domain (NTD) with gration; the upstream terminus of spumaviral DNA is 5Ј-TG, conserved His and Cys residues (HHCC motif) that coordinate Zn2ϩ binding for 3-helix bundle formation; the catalytic core obfuscating the need for U3 end processing by IN (21), whereas domain (CCD), which adopts an RNase H fold and harbors the a trinucleotide is processed from the U5 end of some primate enzyme active site composed of invariant carboxylate residues lentiviruses (22, 23), including HIV-2 (24). During strand trans- Ј (DDE motif); and the C-terminal domain (CTD), which adopts fer, IN uses the CAOH-3 hydroxyl groups to cut chromosomal an SH3 fold (reviewed in Ref. 14). The role of the DDE residues DNA in a staggered fashion, which, due to the nature of SN2 in catalysis is to coordinate the positions of two divalent cat- chemistry, simultaneously joins the viral DNA ends to the ions, which under physiological conditions are almost certainly 5Ј-phosphate groups of the dsDNA
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