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AIDS Reviews.Rev. 2008;10:172-89 2008;10 HIV Type 1 Integrase Inhibitors: From Basic Research to Clinical Implications Oyebisi Jegede1, John Babu2, Roberto Di Santo3, Damian J. McColl4, Jan Weber5 and Miguel E. Quiñones-Mateu5 1Department of Cellular and Molecular Biology, Kent State University, Kent, Ohio, USA; 2Panvirex LLC, Cleveland, Ohio, USA; 3Pasteur Institute, Cenci Bolognetti Foundation, Department of Chemistry and Technology of Drug Pharmacology, Sapienza University of Rome, Rome, Italy; 4Gilead Sciences, Foster City, California, USA; 5Diagnostic HYBRIDS, Inc., Cleveland, Ohio, USA Abstract Similar to other retroviruses, productive infection with HIV-1 requires three key steps in the viral replication: (i) reverse transcription of viral genomic RNA into viral cDNA by the viral reverse transcriptase; (ii) integration of viral cDNA into host cell genome using the viral integrase; and (iii) cleavage of newly synthesized viral polypeptide by the viral protease into individual viral proteins during new virion assembly. Following their discovery, all three viral enzymes were considered as targets for antiretroviral drugs. However, while multiple reverse transcriptase and protease inhibitors have been used for more than 12 years to treat HIV-infected individuals, only recently has the viral integrase enzyme emerged as an alternative, clinically validated target to block HIV-1 replication. Here we review the biology of HIV-1 integration, the mechanisms of action and development of resistance to integrase inhibitors, and the latest data on the most recent clinical trials involving this promising, novel class of antiretroviral drugs. (AIDS Rev. 2008;10:172-89) Corresponding author: Miguel E. Quiñones-Mateu, [email protected] Key words HIV. Integrase inhibitors. Drug resistance. Replicative fitness. tinct mechanisms of action, and include nucleoside/ ovel targets for antiretroviral therapy N nucleotide reverse transcriptase inhibitors (NRTI) and nonnucleoside reverse transcriptase inhibitors (NNRTI). HIV/AIDS has evolved into an ongoing global pan- Several RTI have been combined into fixed-dose com- demic with significant socio-economic impact. Cur- bination tablets, which contain either two or more NRTI, rently, 23 antiretroviral drugs are approved for the or two NRTI and the NNRTI efavirenz. The protease treatment of HIV-1 infection, the majority of which tar- inhibitors (PI) comprise the third class of approved get two essential viral enzymes: reverse transcriptase antiretroviral drugs, all of which inhibit the essential and protease. Reverse transcriptase inhibitors (RTI) No part of this publicationproteolytic processing may ofbe viral proteins. Other classes can be subdivided into two classes, based their dis- of drugs act extracellularly to prevent the entry of the reproduced or photocopyingvirus into the host cell (fusion or entry inhibitors). Enfu- virtide (T-20, Fuzeon™, Roche Laboratories Inc. and Trimeris, Inc. USA), a fusion inhibitor, was introduced without the prior written permission Correspondence to: in 2003, and acts to mimic the viral gp41 polypeptide, Miguel E. Quiñones-Mateu thereby blocking the fusion of the viral and cellular Diagnostic HYBRIDS, Inc. of the publishermembranes. Maraviroc (UK-427857, Selzentry™, Pfizer 7100 Euclid Avenue, Suite 190 Inc. USA) a newly approved member of the entry in- Cleveland, Ohio 44106, USA hibitors class, targets coreceptor binding by HIV-1 E-mail: [email protected] © Permanyer Publications(CCR5 antagonist). 2010 172 Oyebisi Jegede, et al.: HIV Type 1 Integrase Inhibitors: From Basic Research to Clinical Implications For the last decade, combination therapy, known as host genome for its replication and propagation20. highly active antiretroviral therapy (HAART), has been Typical products of the HIV-1 integration process in- the gold standard of care for HIV-1 infected individu- clude linear and nonintegrated DNA, which are de- als in most developed countries. HAART has been graded in cells within 24 hours, plus 1- and 2-LTR credited with a highly significant reduction in HIV/ circles (formed by the ligation of the long terminal AIDS mortality by reducing plasma viremia, increas- repeat ends of the linear HIV-1 genome)21-23. Most ing CD4+ lymphocytes count, reducing immune acti- importantly, HIV-1 integrase has no known human vation, and restoring lymph node architecture1-7. On equivalent and offers the possibility of high drug the other hand, many currently available antiretroviral specificity with limited cellular toxicity. This review will drugs have also been associated with long-term side focus on the viral integrase and the development of effects8, inability to eradicate latent reservoirs of HIV- integrase inhibitors as new anti-HIV-1 therapeutic 19-11, development of drug resistance, and eventual agents. failure of therapy12,13. Moreover, new infections with HIV-1 strains exhibiting multiclass drug resistance, together with the continual evolution of drug-resistant Biology of HIV-1 integration virus strains9,14,15, highlights the urgent need to de- velop novel antiretroviral drugs, preferably against Structure and function new HIV-1 targets. of the integrase Several potential targets for the development of new antiretroviral drugs have been identified due to the HIV-1 integrase is an essential viral enzyme that is substantial increase in the knowledge of the struc- required to catalyze the specific and efficient splicing tural biology of HIV-1 and its interaction with host of the viral DNA product of reverse transcription into cells16. Among the viral targets being evaluated for the host cell genomic DNA24-26. The 32 KDa integrase new drug development, the most exciting opportuni- enzyme is a 288 amino acid protein encoded by the ties currently under consideration include (i) viral en- 3′-end of the pol gene and approximately 50-100 cop- try, with a major focus on blocking the interaction of ies of the integrase enzyme are packaged per virion the virus with its two major coreceptors, CCR5 and particle27. Like other viral proteins, the mature func- CXCR4, (ii) integration of viral DNA into the human tional integrase enzyme is generated by proteolysis genome, and (iii) maturation of the viral particle. The of the precursor Gag-Pol fusion protein by the viral use of different compounds to block the interaction of protease enzyme28. Integrase consists of three struc- the viral envelope with its major receptor (the CD4 tural and functional domains (i.e. an N-terminal do- protein) or coreceptors (CCR5 or CXCR4) is relative- main, a catalytic core domain, and a C-terminal do- ly advanced and, as a consequence, has been exten- main) and the functional integrase enzyme is sively reviewed17,18. Inhibition of virion maturation, that composed of integrase homodimers that are pro- is, the blockage of the cleavage of Gag (p55) and posed to further associate with each other to form a Gag/Pol (p160) precursor polyproteins into structural multimer complex in solution29,30 (Fig. 1). Crystal proteins and enzymes (i.e. protease, reverse tran- structures of several integrase catalytic core domains, scriptase, and integrase), represents another intrigu- obtained as dimers or trimers31-34, show that it con- ing opportunity to develop antiretroviral drugs. Al- sists of five β-sheets flanked by six α-helices that are though viral maturation inhibitors are less advanced connected by flexible loops. in clinical development thanNo protease, part ofreverse this tran publication- The N-terminal may domain be of the integrase (amino acids scriptase and entry inhibitors, the first member of this 1-50) is characterized by two pairs of highly con- drug class (PA-457, bevirimat)reproduced has been shown orto photocopyingserved histidine and cysteine residues (histidine res- reduce plasma viral RNA load by > 1 log10-fold in idues 12 and 16; cysteine residues 40 and 43) that phase IIa clinical trials19. form a “HH-CC” or zinc finger motif that involves the The HIV-1 integrase inhibitors without act at the a point prior in the writtenchelation of permission one zinc atom per integrase monomer35,36. viral lifecycle following classical antiretroviral drugs The N-terminal domain is required for high-order mul- such as NRTI, NNRTI and the most recently of developed the publisher timerization that is stimulated by zinc36. A zinc atom is entry inhibitors, but prior to the effect of PI. Viral inte- required to stabilize the folded structure of the N-ter- gration is a particularly desirable target because, like minal domain of HIV-1 integrase and is necessary for other retroviruses,© PermanyerHIV-1 requires integration into Publications the optimal enzymatic activity35,37 2010. 173 AIDS Reviews. 2008;10 vif rev nef tat LTR LTR gag vpr env pol vpu INTEGRASE NTD CCD CTD 1 50 51 212 213 288 NTD CCD Figure 1. HIV-1 integrase structure and functional domains. NTD: N-terminal HH-CC zinc finger domain (binds cellular factors); CCD: cen- tral catalytic domain (binds Mg2+, Mn2+); CTD: C-terminal domain (binds DNA non-specifically); LTR: long terminal repeat. The catalytic core domain includes amino acids 51- integrase enzymatic activity45. Each one of these ami- 212 of HIV-1 integrase. The catalytic core domain no acids is required for the catalysis of the three steps forms a dimer in solution and in the functional enzyme; of viral integration into host DNA; substitution of any of the monomer structure of the catalytic core is similar these residues significantly reduces the enzymatic ac- to the folds of RNaseH andNo the partcatalytic of domains this publicationof tivity of HIV-1 integrase may 46-48be. Interestingly, although the Holliday junction resolvase RuvC and MuA trans po- catalytic core domain can also catalyze the disintegra- sase38,39. These enzymes belongreproduced to the DNA process or- photocopyingtion reaction (the reverse of integration) by itself, the ing polynucleotide transferase superfamily that cut and N-terminal and C-terminal domains of integrase are join DNA by direct transesterification40-43. The catalytic also required for the 3′ processing and strand-transfer core domain is required for without the cleavage the and formationprior writtenreactions40,45,49 permission.