Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

  • Anti-viral drugs with activity against HIV (Human Immunodeficiency Virus)

    • Introduction:  Human Retroviruses continued:  Viral Replication

      • Viral DNA integrates with host cell chromosomes.

        • This integration step is catalyzed by the virally-encoded enzyme protein, integrase.

          • The HIV proviral DNA integrates into nuclear DNA preferentially within active gene introns and regional "hotspots."

            • The viral DNA integrated into host cell nuclear DNA may remain latent, i.e. transcriptionally inactive, or may exhibit gene expression to varying degrees, including that sufficient to support active viral production.

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              Domain structure of HIV integrase⁹

              Hopur3 "Schematic of the domain structure of HIV integrase" "Three structural and functional domains have been identified. The N-terminal domain (residues 1-50) contains a HHCC zinc finger motif and is required for dimerization and binding of cellular factors. The HHCC description refers to the fold group composed of cysteine and histidine, which represents a very well described mammalian zinc finger class. Cartoon representation of the zing-finger motif of proteins.11 Splettstoesser T Cartoon representation of the zing-finger motif of proteins. 17 November 2007. "The zinc ion (green) is coordinated with two histidine and two cysteine amino acid residues. http://commons.wikimedia.org/wiki/File:Zinc_finger_rendered.png The zinc finger is a small protein structural form (motif) that uses the coordination of one or more zinc ions to stabilize the structure.10 The catalytic core domain (residues 51-212) contains the conserved residues forming a catalytic triad (D64, D116 and E152) that are required to coordinate essential divalent metal ions Mn2+ or Mg2+). The C-terminal domain (residues 213-288) binds DNA non-specifically." http://commons.wikimedia.org/wiki/File:Structural_domains_of_the_HIV-1_integrase.jpg

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          "Interaction of HIV-DNA into a Host Chromosome"⁸ 

          Crenim, based on Mudrow S Falke D Truyen Molekulare Virologie, 2 Aufl. (engl:  Molecular Virology, 2nd ed), Spektr Akad Verrl. Heidelberg, Berlin, 2003. Uploaded version (latest) 2008-02-15. http://commons.wikimedia.org/wiki/File:HIV_genome_integration.png

           

      • Cellular Activation:

        • Cellular activation is an important part of the HIV replication cycle and plays an important role in development of HIV-related diseases.² 

          • After binding and virion internalization into the host, target cell reverse-transcribed DNA intermediates are relatively unstable, initially.

          • Efficiency of integration of viral-derived DNA into the host cell genome depends on cellular activation, which typically begins shortly after infection.

            • In addition, host cell activation is required for transcription of integrated proviral DNA into either genomic RNA or mRNA.

              • Activation of HIV expression from the latent state depends on both cellular and viral factors.

              • HIV mRNA is translated into proteins that are subsequently modified by glycosylation, phosphorylation, myristolylation, and cleavage.

            • The virion is formed as a result of HIV protein assembly, enzyme activities, and genomic RNA at the host cell plasma membrane with budding of the new virions occurring as special regions in the lipid bilayer (lipid rafts).

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                Lipid Raft Organization¹²

                Fijalkowski AJ Lipid raft organization scheme. http://commons.wikimedia.org/wiki/File:Lipid_raft_organisation_scheme.svg [A] above represents the intracellular space (cytosol) [B] above represents extracellular space or vesicle-Golgi lumen "1.  Non-raft membrane  2. Lipid raft  3. Lipid raft associated transmembrane protein  4. Non-raft membrane protein\  5. Glycosylation modifications (on glycoproteins and glycolipids)  6. GPI*-anchored protein  7. Cholesterol  8. Glycolipid" * GPI:  Glycophosphatidylinositol

              • At these specialized lipid bilayer regions, the core obtained its external envelope.

                • Lipid rafts are also important in HIV-1 entry into the host cell.

                • HIV Assembly¹³

                  Campbell SM Crowe SM Mak J Lipid rafts and HIV-1:  from viral entry to assembly of progeny virions.13 HIV-1 Assembly: 1.  "HIV-1 enters the target cell through binding to receptors located in lipid rafts. 2.  The viral structural protein, Env, is produced in the ER (endoplasmic reticulum) and transported through the trans-Golgi network (TGN). 3. HIV-1 Gag/Gal-Pol is produced in the cytoplasm. 4.  Formation of a putative intracellular assembly complex. 5. Progeny viruses are released from the cholesterol-rich plasma membrane lipid rafts." Attribution:  This figure corresponds to Fig. 3 in reference 13. (red circles added)

              • Virally-encoded protease enzyme catalyzes the cleavage of the gag-pol precursor, yielding mature virion.² 

            • The viral replication cycle is affected by many viral regulatory gene products.

        • Therapeutically, each point in the HIV replication cycle represents a possible or probable target for intervention.²  

          • At this point (2014) reverse transcriptase, protease and integrase enzymes in addition to viral-target cell binding and fusion represent sites shown susceptible to anti-HIV viral agents.²