Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

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

    • Introduction:  Human Retroviruses continued:  Viral Replication

      •  

        Diagram of the HIV Virion⁸

        US National Institute of Health (redrawn by Henderson C) Diagram of the HIV Virus http://commons.wikimedia.org/wiki/File:HIV_Virion-en.png

      • The HIV replication cycle begins with the association of the viral gp120 protein with the host cell surface receptor, the CD4 molecule.² 

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          H9 T-Cell:  HIV Infected¹⁰

          National Institute of Allergy and Infectious Diseases (NIAID) HIV-infected H9 T Cell Scanning electron microscope image of an HIV-infected H9 T cell. https://www.flickr.com/photos/niaid/6813314147/in/set-72157629102967679

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          H9 T-Cell:  HIV Infected¹¹

          National Institute of Allergy and Infectious Diseases (NIAID) HIV-infected H9 T Cell Scanning electron microscope image of an HIV-infected H9 T cell. https://www.flickr.com/photos/niaid/6813403685/in/set-72157625994990013

        • The CD4 protein is mainly associated with a T lymphocyte subset responsible for immunological helper function.

        • In addition to the T cell lymphocytes, CD4 molecules are also expressed on monocyte/macrophage and dendritic/Langerhans cell surfaces.

      • Following gp120 binding to CD4, a conformational change in gp120 facilitates additional association with one of two major co-receptors.²  

        • The two major co-receptors for HIV-1 are CCR5 and CXCR4.

          • These receptors belong to the well-known seven-transmembrane-domain G protein-coupled cellular receptor family.

          • Furthermore, viral cellular tropism is determined to a significant extent by the viral use of one or the other or both co-receptors.

      • Some dendritic cells express various C-type lectin receptors on their surface.²  

        • One such receptor, DC-SIGN, exhibits high affinity for the HIV gp120 envelope protein.

        • This association enhances HIV viral binding to the CD4⁺ T cell (following DC_SIGN interaction with dendritic cells).

      • After binding of the envelope protein to the CD4 molecule and subsequent viral envelope gp120 conformational change, host cell membrane-viral fusion proceeds, utilizing the newly exposed gp41 molecule.²  

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          HIV Viral Entry:  Membrane Fusion¹²

          Jones M Mechanism of Viral Entry/Membrane Fusion "1.  Inital interaction between gp120 and CD4. 2.  Conformational change in gp120 allows for secondary interaction with CCR5. 3.  The distal tips of gp41 are inserted into the cellular membrane. 4. gp41 undergoes significant conformational change; folding in half and forming coiled-coils. This process pulls the viral and cellular membranes together, fusing them. The diagram above suggests that it is a T helper cell; however, the co-receptor on a T helper cell for this mechanism is CXCR4 not CCR5. If it contains a CCR5 receptor is is more likely to be a macrophage." Early in HIV infection, viruses tend to be macrophage-trophic, using the CCR5 co-receptor.7   Syncytial-forming viral variants, using the CXCR4 co-receptor, exhibit T-lymphotrophic preference, likely associated with rapid advancement to AIDS.7

        • The gp41 protein penetrates the target cell plasma membrane and undergoes a structural change that brings the virion and target cell in close approximation.

        • Following fusion, the preintegration complex, composed of viral DNA and viral enzyme, all surrounded by a capsid protein coat, is released into the target cell cytoplasm.

      • The preintegration complex translocates through the cytoplasm, reaching the nucleus and at that point the viral reverse transcriptase catalyzed reaction promotes transcription of genomic RNA into DNA with the protein coat opening and thus releasing the new double stranded proviral HIV-DNA.² 

        • "Reverse Transcription"¹³

          Crenim (Modrow S Falke D Truyen Molekulare Virologie 2 Aufl (engl.  Molecular Virology, 2nd ed)< Spekr Akad Verl. Heldelberg Berlin, 12 February 2008 http://commons.wikimedia.org/wiki/File:Reverse_Transcription.png

        • In this stage of replication cycle, the viral genome may be susceptible to cellular constituents which may block infection progression.² 

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        HIV Replication Cycle⁹

        National Institute of Allergy and Infectious Diseases (NIAID) "Produced by the National Institute of Allergy and Infectious Diseases (NIAID), this illustration depicts the human immunodeficiency virus (HIV) replication cycle involving the host cell within the human body, Beginning with a HIV virion attaching to the host cell wall, Dumping its contents into the matrix of the host cell, Conversion of the viral RNA to viral DNA, Which combines with the host cell DNA, Leading to the creation of new viral RNA, Which migrates to the host cell periphery, and forms of vacuole around the new viral RNA using the host cell wall, Thereafter,budding off is a newly-created mature HIV virion." CDC:  ID#:  18162