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      Enfuvirtide antiretroviral therapy in HIV-1 infection

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          Abstract

          It has been over 25 years since the first diagnosis of what would be known as AIDS. Although great strides in anti-HIV therapeutics have been made, there is still a great need for antiretrovirals that are effective against drug-resistant HIV. Enfuvirtide (ENF) is the first of a new class of fusion inhibitors to be approved by the US Food and Drug Administration for use in combination with other antiretroviral agents among HIV-1 infected patients with previous treatment experience. The inclusion of enfuvirtide in an optimized antiretroviral background regimen for the treatment of HIV-1 infected (treatment-experienced) patients followed the success of two critical clinical trials (TORO: T20 vs Optimized Regimen Only I and II). Even though injection-site reactions persisted in these trials, improved virological and immunological responses were observed among patients. Challenges associated with ENF treatment include the high cost of the drug, injection-site reactions, determining the optimal time to initiate treatment, and the potential for the selection of drug resistant mutants and viral evolution. ENF is a promising novel treatment for HIV infected individuals whose choices for effective treatment are limited by previous treatment and resistance. Understanding the implications of viral fitness and evolution in the presence of ENF treatment is crucial in determining effective and safe treatment regimens, particularly among treatment-experienced patients.

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          Most cited references 54

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          Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120.

          T-20 is a synthetic peptide that potently inhibits replication of human immunodeficiency virus type 1 by interfering with the transition of the transmembrane protein, gp41, to a fusion active state following interactions of the surface glycoprotein, gp120, with CD4 and coreceptor molecules displayed on the target cell surface. Although T-20 is postulated to interact with an N-terminal heptad repeat within gp41 in a trans-dominant manner, we show here that sensitivity to T-20 is strongly influenced by coreceptor specificity. When 14 T-20-naive primary isolates were analyzed for sensitivity to T-20, the mean 50% inhibitory concentration (IC(50)) for isolates that utilize CCR5 for entry (R5 viruses) was 0.8 log(10) higher than the mean IC(50) for CXCR4 (X4) isolates (P = 0. 0055). Using NL4.3-based envelope chimeras that contain combinations of envelope sequences derived from R5 and X4 viruses, we found that determinants of coreceptor specificity contained within the gp120 V3 loop modulate this sensitivity to T-20. The IC(50) for all chimeric envelope viruses containing R5 V3 sequences was 0.6 to 0.8 log(10) higher than that for viruses containing X4 V3 sequences. In addition, we confirmed that the N-terminal heptad repeat of gp41 determines the baseline sensitivity to T-20 and that the IC(50) for viruses containing GIV at amino acid residues 36 to 38 was 1.0 log(10) lower than the IC(50) for viruses containing a G-to-D substitution. The results of this study show that gp120-coreceptor interactions and the gp41 N-terminal heptad repeat independently contribute to sensitivity to T-20. These results have important implications for the therapeutic uses of T-20 as well as for unraveling the complex mechanisms of virus fusion and entry.
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            Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection.

            To define the role of the human immunodeficiency virus type 1 (HIV-1) envelope proteins in virus infection, a series of peptides were synthesized based on various regions of the HIV-1 transmembrane protein gp41. One of these peptides, DP-178, corresponding to a region predictive of alpha-helical secondary structure (residues 643-678 of the HIV-1LAI isolate), has been identified as a potent antiviral agent. This peptide consistently blocked 100% of virus-mediated cell-cell fusion at < 5 ng/ml (IC90 approximately 1.5 ng/ml) and gave an approximately 10 times reduction in infectious titer of cell-free virus at approximately 80 ng/ml. The inhibitory activity was observed at peptide concentrations approximately 10(4) to 10(5) times lower than those at which cytotoxicity and cytostasis were detected. Peptide-mediated inhibition is HIV-1 specific in that approximately 10(2) to 10(3) times more peptide was required for inhibition of a human immunodeficiency virus type 2 isolate. Further experiments showed that DP-178 exhibited antiviral activity against both prototypic and primary HIV-1 isolates. As shown by PCR analysis of newly synthesized proviral DNA, DP-178 blocks an early step in the virus life cycle prior to reverse transcription. Finally, we discuss possible mechanisms by which DP-178 may exert its inhibitory activity.
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              Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics.

              HIV entry inhibitors include coreceptor antagonists and the fusion inhibitor T-20. T-20 binds the first helical region (HR1) in the gp41 subunit of the viral envelope (Env) protein and prevents conformational changes required for membrane fusion. HR1 appears to become accessible to T-20 after Env binds CD4, whereas coreceptor binding is thought to induce the final conformational changes that lead to membrane fusion. Thus, T-20 binds to a structural intermediate of the fusion process. Primary viruses exhibit considerable variability in T-20 sensitivity, and determinants outside of HR1 can affect sensitivity by unknown mechanisms. We studied chimeric Env proteins containing different V3 loop sequences and found that gp120coreceptor affinity correlated with T-20 and coreceptor antagonist sensitivity, with greater affinity resulting in increased resistance to both classes of entry inhibitors. Enhanced affinity resulted in more rapid fusion kinetics, reducing the time during which Env is sensitive to T-20. Reduced coreceptor expression levels also delayed fusion kinetics and enhanced virus sensitivity to T-20, whereas increased coreceptor levels had the opposite effect. A single amino acid change (K421D) in the bridging sheet region of the primary virus strain YU2 reduced affinity for CCR5 and increased T-20 sensitivity by about 30-fold. Thus, mutations in Env that affect receptor engagement and membrane fusion rates can alter entry inhibitor sensitivity. Because coreceptor expression levels are typically limiting in vivo, individuals who express lower coreceptor levels may respond more favorably to entry inhibitors such as T-20, whose effectiveness we show depends in part on fusion kinetics.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                April 2008
                April 2008
                : 4
                : 2
                : 433-439
                Affiliations
                [1 ]Department of Biostatistics, UCLA School of Public Health Los Angeles, CA USA
                [2 ]Department of Hematology and Oncology, David Geffen School of Medicine at UCLA Los Angeles, CA USA
                [3 ]Departments of Pediatrics and Medical Molecular Pharmacology, David Geffen School of Medicine at UCLA Los Angeles, CA, USA
                Author notes
                Correspondence: Christina MR Kitchen UCLA School of Public Health, 650 Charles E. Young Drive, Los Angeles, CA 90095-1772, USA Tel +1 310 825 7332 Fax +1 310 276 2113 Email cr@ 123456ucla.edu
                Article
                2504070
                18728846
                © 2008 Dove Medical Press Limited. All rights reserved
                Categories
                Review

                Medicine

                evolution, hiv, salvage therapy, drug resistance, gp41, enfuvirtide

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