Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

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

    • Introduction:  Human Retroviruses continued

      • In 1983 HIV (human immunodeficiency virus) was isolated from a patient exhibiting lymphadenopathy.² 

        • The following year HIV was identified as the causative agent in acquired immunodeficiency syndrome (AIDS).

        • The year after that, in 1985, a sensitive test was developed for HIV: the enzyme-linked immunosorbent assay (ELISA).

          • The availability of this test allowed a more comprehensive assessment of the HIV epidemic both in the United States and eventually worldwide.²  

      • The evolution of the HIV pandemic occurred concurrently with rapid expansion of understanding HIV biology.²  

        • Areas of interest include:

          • HIV virology

          • Pathogenesis

          • HIV disease treatment

          • Prophylaxis and treatment of AIDS infection-induced opportunistic disease

          • Infection prevention as well as

          • Efforts to develop a vaccine² 

      • The retroviruses (family: Retroviridae) exhibit tropism mainly for vertebrates.³ 

        • As suggested earlier, the term retrovirus indicates that information initially in the form of RNA undergoes in the host cell transcription into DNA.³  

          • This observation ran counter to the established molecular biology dogma that information moved in a unidirectional way from DNA→ RNA → protein.

          • The family Retroviridae is composed of seven subfamilies.

            • Retrovirus Classification:  Retroviridae³

              Genus	Example	Characteristic
              Alpharetrovirus	Rous Sarcoma Virus	Presence of src oncogene
              Betaretrovirus	Mouse Mammary Tumor Virus	May be Exogenous or Endogenous
              Gammaretrovirus	Abelson Mouse Leukemia Virus	Presence of abl oncogene
              Deltaretrovirus	HTLV-I	Causative in T Cell Lymphoma and some Neurologic Disorders
              Epsilonretrovius	Walleye Dermal Sarcoma Virus	--
              Lentivirus	HIV-1,2	Causative for AIDS
              Spumavirus	Simian Foamy Virus	Non-pathogenic in  Humans

            • Members of two of the families infects humans and cause pathologies.³  

              • The deltaretroviruses, include human T-cell lymphotropic virus (HTLV) type I which is the most important one for humans.

              • The lentiviruses of which human immunodeficiency virus (HIV) is the most important one in humans.³ 

      • Retroviral Structure:

        • Retroviruses are spherical with the envelope containing external surface protein (SU) which is associated with transmembrane protein (TM) extending across the lipid bilayer.⁵

          • The inner surface of the membrane is coded with viral matrix protein.

          • Capsid protein, CA, depending on the virus strain, describes an icosahedral or conical core.

            • Capsid structures are described as having icosahedral or helical symmetry.

              • The surface of an icosahedron is described by 60 identical subunits.¹⁰   

                • Accordingly, 60 structural units are required to create the viral shell that encapsulates its genome.

                • Despite the virus expressing icosahedral symmetry, viral shape in terms of physical appearance is spherical.¹⁰   

              • Icosahedral structures, although resembling spheres, exhibit 2-fold, 3-and 5-fold symmetry axes.

                •  

                  Icosahedral Viral Structure⁸  

                  "Structure of the icosahedral Cowpea mosaic virus (CPMV) based on PDB ID 2BFU."12

                •  

                  Icosahedral structure⁹ 

                  "Two adenoviruses with a cartoon to show their icosahedral structure."9

               

            • The virus core is associated with three important viral-encoded enzymes.

              • These are:

                • Reverse transcriptase (RT)

                • Protease (PR) and

                • Integrase (IN).⁵ 

          • Viral structural proteins are designated on the basis of both their glycosylation characteristics and molecular weights.⁵

            • For HIV:

              • External surface protein, SU is called gp120

              • Transmembrane protein, TM, is gp41 and

              • Capsid protein is p24.⁵

        • The virus genome is a positive-strand RNA along with the nucleocapsid protein (NC).⁵

          • Genomic RNAs are capped at the 5' terminal and polyadenylated at the 3' terminal.

          • Viral proteins are derived from three genes:

            • gag ("group-specific antigen)

            • pol (polymerase) and

            • env (envelope protein).⁵

          • gag codes for a polyprotein which is later processed, thus releasing major viral structural proteins.¹ 

          • pol overlaps gag and encodes for three enzyme proteins:¹ 

            • (a)  One with an RNA-dependent DNA polymerase or reverse transcriptase with RNAase activity.

            • (b)  A second with protease activity.

            • (c)  A third with viral integrase activity.¹ 

          • env encodes for the large transmembrane envelope protein that mediates viral-cell binding and viral entry.¹  

            • Additional small genes are involved in encoding regulatory proteins which promote virion production or inhibit host defenses.

            • These genes include:^1,6

              • tat (transactivator of transcription)

              • rev (Regulator of expression of virion proteins)

              • nef (Negative effector)

              • vpr  (Virion protein R [structural protein])

        •  

          Human Immunodeficiency Genome (HIV-Genome)¹¹

          Splettstoesser T " Structure of the HIV-1 genome" http://commons.wikimedia.org/wiki/File:HIV-genome.png "It has a size of roughly 10,000 base pairs and consists of nine genes, some of which are overlapping."