Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

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

    • "Global HIV/AIDS at the Crossroads:  Where do we go from here?"¹⁸

      Attribution:  "Panelists discuss what progress has been made in fighting this global epidemic, how research findings are being translated into improved clinical outcomes, and how the Bay Area research community is working to address the questions that remain. "Panelists:  Eran Bendavid, Assistant Professor, Medicine, Stanford; Stefano Bertozzi, Dean, School of Public Health, UC Berkeley; Diane Havlir, Professor and Chief of the HIV/AIDS Division & Positive Healthe Program, UCSF; Michael Lairmore, Dean, School of Veterinary Medicine, UC Davis.  "Paul Volberding, AIDS Research Institute and Director of Research, Global Health Sciences, UCSF, moderates Series:  "UC Global Health Institute." University of California Television (UCTV):  Global HIV/AIDS at the Crossroads:  Where do we go from here? https://www.youtube.com/watch?v=II03km_v4C0#t=16 (3/2014) University of California Television (UCTV) YouTube Channel:  https://www.youtube.com/channel/UCh6KFtW4a4Ozr81GI1cxaBQ

       

    • Introduction:  Human Retroviruses continued: HIV Genome

      • "Organization of the genome of the HIV provirus together with a summary description of its 9 genes encoding 15 proteins."2  Attribution:  Figure above corresponds to Figure 189-5 of reference 2 [Fauci AS Lane HC Chapter 189, Human Immunodeficiency Virus Disease:  AIDS and Related Disorders, in Harrison's Online   (Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds.),  Harrison's Principles of Internal Medicine, 18th edition, The McGraw-Hill Companies, Inc. 2012.] Figure is cited as an adaptation from reference 8 [ Green WC Peterlin BM HIV InSite Knowledge Base Chapter.:  Published February 2003; content reviewed February 2006. [http://hivinsite.ucsf.edu/InSite?page=kb-02-01-01]

  • HIV and AIDS  Etiology

    • "The History of HIV and Current Epidemic"¹⁷

      Attribution:  Gandi M Volberding PA The History of HIV and Current Epidemic https://www.youtube.com/watch?v=ph6_Z6NIx98 (5/2013) University of California Television (UCTV) https://www.youtube.com/channel/UCh6KFtW4a4Ozr81GI1cxaBQ

    • HIV is the viral, etiologic agent of Acquired Immune Deficiency Syndrome (AIDS).² 

      • This virus belongs to a family of human retroviruses (Retroviridae) and is categorized as belonging to the the subfamily of lentiviruses.² 

        • Nononcogenic lentiviruses cause disease in various animal species.

        • Four retroviruses are responsible for human disease and these retroviruses can be subdivided as belonging to two groups:

          • 1. Human T-Cell Lymphotropic Viruses (HTLV-I and HTLV-II).

            • These viruses are transforming retroviruses.

              • Transforming Retroviruses¹⁴

                Retroviruses transform cells by several mechanisms, three of which have been described.14 Animal retroviruses may contain oncogenes, capable of transforming cells. Over 30 oncogenes have been described since the initial one, Rous sarcoma virus (v-src), where v is an abbreviation for viral. Cells contain homologs of such genes and are called proto-oncogenes. In the Rous sarcoma viral example, the cellular homolog would be c-src, where c is the abbreviation for cellular. Transforming viruses carry cellular genes and accordingly may be described as "transducing retroviruses." Usually viral oncogenes exhibit at least one mutation which makes them distinct from cellular proto-oncogenes. Differences that occur as a result of this/these mutation(s) form the basis of cellular transformation. The resultant abnormal protein products may, possibly, interfere with normal cell signaling with inappropriate cell proliferation as a consequence. 14 Mechanism 1: 14 Tumor formation in vitro by retroviruses possessing an oncogene is typically rapid and efficient and because of this property can be described as "acute transforming viruses." The acute transforming viral mechanism has not been identified as a cause of human cancer but has been described in certain animal species.14 Mechanism 2: 14 The second mechanism is "insertional mutagenesis" and does not require continual viral gene product elaboration. Only the presence of the viral promoter/enhancer is needed to induce abnormal cellular gene expression. The cellular gene is located near the integrated provirus. This mechanism was initially described in avian B cell lymphoma, resulting from avian leukosis virus. The integrated provirus is located just next to a known proto-oncogene, c-myc. Oncogenesis occurs not due to a mutated c-myc gene but rather because the viral promoter next to the gene causes continual gene expression and overproduction of the gene product. Although human tumors have not been yet been shown  to result from such insertional mutagenesis due to retroviral infection, some human cancers such as Burkitt's lymphoma and chronic myelogenous leukemia result from placement, following chromosome translocation, of an active cellular promoter next to a cellular proto-oncogene.14   Chromosomal Translocation in Burkitt's Lymphoma16 "Burkitt's lymphoma, a B cell tumor characterized by a reciprocal translocation between chromosomes 8 and 14.16 "The segment of chromosome 8 that breaks off and moves to chromosome 14 contains c-myc.16 "The transposition places the previously inactive c-myc under the influence of the enhancer sequences of the genes coding for the heavy chains of immunoglobulins.  This juxtaposition results in activation of c-myc.16 "There is a greatly increased synthesis of c-myc coded DNA binding protein that acts to drive or force the cell towards becoming malignant, perhaps by an effect on the regulation of mitosis."16 Attribution:  Chhabra N Oncogenes-Lecture 3, Burkitt's Lymphoma, Mechanism 3: 14 The third mechanism followed from the discovery of human retrovirus. This virus, HTLV-1, results in adult T-cell leukemia. HTLV-1 and HIV-115 CDC: "This image revealed the presence of both the human T-cell leukemia type-1 virus (HTLV-1), (also known as the human T lymphotropic virus type-1 virus) and the human immunodeficiency virus (HIV).  "Human T-cell leukemia virus type-1 (HTLV-1), a human oncoretrovirus, is the etiologic agent of adult T-cell leukemia, and of tropical spastic paraparesis/HTLV-1-associated myelopathy.  "Two closely related retroviruses, HIV-1 and HIV-2, have been identified as causing AIDS in different geographic regions.  HIV-1 causes most cases of AIDS in the U.S., with only a few cases of HIV-2 having been found in the U.S. Epidemiologically, HIV-2 has been found to be mostly an infection of persons from West Africa."15 Public Domain:  CDC http://commons.wikimedia.org/wiki/File:HTLV-1_and_HIV-1_EM_8241_lores.jpg The HTLV-I1 nucleotide base sequence become integrated in leukemic cell DNA. The integrated proviral DNA site in all tumor cells from a given patient is the same, suggesting that such a tumor consists of clonal cells, all derived from a single cell. HTLV-1 infection results in malignancy by introducing a viral gene, tax, which codes for a protein that not only maximizes proviral DNA transcription but also activates transcription of many cellular genes (trans activation). The array of cellular proteins caused by this effect induces malignant transformation with uncontrolled cell division. This mechanism is distinct from oncogenes of acute transforming retroviruses because a viral gene, as opposed to a cellular proto-oncogene derivative, is responsible. HTLV-I is typically described as a "transactivating retrovirus."14

                 

          • 2. Human immunodeficiency viruses (HSV-1 and HIV-2, both causing cytopathologies)

            • HIV-1 virus is most common cause of HIV disease and is characterized by several subtypes exhibiting varied geographic localizations.

            • HIV-2, first recognized in 1986 in West African patients, was originally limited to West Africa.

              • Subsequently, however, this virus can be now identified worldwide. The HIV-1 viral group (M, N, O, P) and HIV-2 group (A-G) are most probably due to distinct transfers to humans from nonhuman primate reservoirs.

                • For example, HIV-1 virus is most likely to have come from chimpanzees and/or gorillas.² 

                  • HIV-1 Transfer to Humans Most Likely Came from Chimpanzees and/or Gorillas²

                    Lersch T Common Chipanzee (Leipzig Zoon) August 2005.9	Fidenci P Gorilla, Congo, September 2008.10

                • By contrast, HIV-2 most likely came from sooty mangabeys.

                  • HIV-2 Transfer to Humans Most likely Came from the Sooty mangabey (Cerocebus atys)2

                    Sooty mangabey (Cerocebus atys)  Primate Info Net, Library and Information Service, National Primate Research Center, University of Wisconsin, Madison.  Photo Yerkes NPRC.11

          • The AIDS pandemic is mainly due to the HIV-1 M viral group.

            • More restricted epidemics, although occurring in various countries may be due to HIV-1 group O and HIV-2.

      • Phylogenetic Tree of the SIV and HIV viruses¹²

        Kuiken C et al.  Phylogenetic Tree of the SIV and HIV viruses. http://commons.wikimedia.org/wiki/File:HIV-SIV-phylogenetic-tree.svg

    • HIV-1 Molecular Variability²

      • Analysis of HIV isolates shows considerable sequence diversity generally affecting the viral genome.

        • Variability in coding sequences for the viral envelope protein, as an example, ranges from a few percent in isolates from the same infected patient to 50% among isolates from different HIV-1 groups (M,N,O, P, as noted above).²

          • Alterations are localized in "hypervariable regions".

          • HIV molecular evolution occurs by several methods including:

            • Base substitution

            • Recombination

            • Insertions and

            • Deletions, and by loss of

            • Gycosylation sites.²

          • HIV sequence diversity may be a direct consequence of the error-prone action of the enzyme reverse transcriptase.²  

          • Immune pressure and functional constraints on proteins are mutually balancing and influence variation within proteins.

            • One example, the envelope protein, is exposed on the virion surface and experiences immune selective pressure from cytolytic T lymphocytes and antibodies.

              • As a consequence, envelope protein shows considerable variability with mutation clusters at the hypervariable domain regions.

            • On the other hand, the critical viral enzyme, reverse transcriptase, is "relatively" conserved especially at the catalytic site (and surrounding regions).²

    • Important Molecules in HIV-1

      "Molecules of HIV-1:  What They Look Like and How They Can Be Inhibited"¹³

      Attribution:  Summers M: The molecules of HIV-1:  What they look like and how they can be inhibited.https://www.youtube.com/watch?v=lRW37XBlIqY (4/2011) ThelHMC YouTube Channel:  https://www.youtube.com/channel/UCUOJc_aRBt9eSspTOSklJfw