Nursing Pharmacology:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • HIV Life Cycle and Sites of Antiretroviral Drug Activity⁶

    Steps in HIV Viral Replication and Sites for Antiretroviral Drug Action (Red ellipses)  http://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle

  • There are four classes of antiretroviral agents targeting HIV-specific enzymes.⁷

    • These classes include:⁷

      • Nucleoside and nucleotide reverse-transcriptase inhibitors

      • Nonnucleoside reverse-transcriptase inhibitors

      • Protease inhibitors

      • Integrase inhibitors

    • Another class of anti-HIV drugs is are HIV cell entry inhibitors or CCR5 antagonists.

      • Here a specific, nonenzymatic protein is the pharmacological target.⁷

  • History and Review:¹

    • By review, the HIV virus targets cells based on the presence of the CD4 receptor.¹ 

      • The targeting is regulated by the viral envelope protein gp160 (env).

        • The CD4 receptor is present on both lymphocytes and macrophages.

        • HIV entry into host cells is also dependent on a chemokine receptor, either CCR5 or CXCR4.

          • This viral integrase enzyme is a pharmacological anti-HIV target site.¹

    • After host cell genomic integration, the viral genome may remain latent i.e. not directing RNA or protein synthesis yet the viral genome is replicated as the cell divides.¹ 

      • Cells containing the viral genome as part of its own genome may be activated and at that time viral RNA and proteins would be synthesized.

      • Genomic viral RNA is housed in a nucleocapsid with envelope and structural proteins concentrated at the cell surface, localized in cholesterol-rich "lipid rafts.".

      • Nucleocapsid cores concentrate at these sites and bud across the cell membrane, thus creating new envelope HIV virions with two complete single-stranded RNA genomes.

      • When these virions infect new cell, reverse transcriptase may initiate a new cycle of viral replication.¹

        • HIV Replication Cycle¹²

          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." http://phil.cdc.gov/phil/details.asp ID#:  18162

   

  • Viral Pathogenesis:¹

    • HIV Disease Pathogenesis¹⁴

      "Pathogenic events in HIV disease. 1. "On entry into the body, HIV probably encounters a dendritic cell, which is either infected or carries the virus to a CD4+ T cell in a lymphoid organ. 2. "Infection is then established in the lymphoid organ and a burst of viraemia seeds virus throughout the body. 3. "Viral replication is partially controlled, but the remaining replication almost invariably leads to escape from immune control, and establishment of chronic persistent infection in lymphoid tissue. "The net level of viral replication is regulated by a balance between factors that induce virus replication and factors that contain or suppress it. "In most patients, replication accelerates over a period of time, leading to destruction of the immune system. "The white dots in the lymphoid tissue represent individual cells expressing HIV viral RNA, as determined by in situ hybridization. Trapped virus (large clumps of white staining in the peripheral regions of the lymph node) is extracellular." Attribution:  This figure corresponds to Fig. 1 in reference 14 [Fauci AS Host factors and the pathogenesis of HIV-induced disease.  Nature 384 (6609):  529-534 Dec 12, 1996.]

    • HIV infection due to sexual activity may be initiated by one or only a few infectious virions.¹ 

      • After this event, a short, rapid replication phase occurs in the 2-4 week time frame.¹ 

        • During this brief period ≥ 10⁹ cells become infected.

          • This peak of infectious activity is accompanied by a temporary reduction in peripheral CD4⁺ (helper) T lymphocytes.

          • New host immune response combined with HIV-target cell depletion leads to an approximate steady-state level of infectious HIV virions.

          • This level is mirrored by plasma HIV RNA concentration, also reflecting "viral load".

          • This apparently relatively constant level of HIV virus activity results from a number of factors such as the host immune response, the pathogenicity of the particular HIV viral strain and defines a "set point".

            • This set point can be thought of as a balance between virion replication which increases the viral burden and clearance which reduces it.¹

    • The early burst of activity is associated with acute symptoms, significant viremia and large numbers of infected target cells (CD4⁺ T cells) in blood.¹³ 

      • The early antiviral immune response involves antibodies and cytotoxic T cells and reduces circulating virus by at least a factor of 100, initiating the clinically latent phase characterized by low, yet constant presence of HIV virions and infected cells in circulation.

        • During this latent phase the number of CD4+ T cells gradually decline.

          • Clinical latency may extend for about 10 years.

          • Eventually, the number of CD4 + T cells is reduced to extremely low values coinciding with the development of acquired immunodeficiency syndrome (AIDS).

          • The development of AIDS is also associated with rapidly increasing viral activity and increasing circulating infected cells.¹³

      • As noted earlier, most individuals progress to clinical AIDS in about a decade patients subsequent to sexual acquisition of CCR5-tropic HIV-1 disease (without antiretroviral treatment) .¹ 

        • However, a subset of patients, described as "long-term nonprogressors" have been identified as having HIV infection for over 20 years without exhibiting immunosuppression or notable reduction in CD4 T cell counts.^1,14   

          • Long-term nonprogression may occur as a consequence of an interplay of individual immunogenetics and immune responses.^1,14 

          • Some long-term nonprogressors (probably a small subset) exhibit mutations of the CCR5 coreceptors; these mutations reduce HIV infectivity.^14,15 

References

Flexner C Antiretroviral Agents and Treatment of HIV Infection, Chapter 59  in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition (Brunton LL Chabner BA Knollmann BC, eds; Brunton LL, ed; Blumenthal DK  Murri N Hilal-Dandan R, assoc eds, Knollmann BC, consulting ed, on-line edition) The McGraw-Hill Companies, 2011. 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. Longo DL Fauci AS  188, The Human Retroviruses, 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. Woster PM Chapter 43:  Antiviral Agents and Protease Inhibitors in Foye's Principles of Medicinal Chemistry 6e, Lemke, TL Williams DA, eds; Roche VG Zito SW, asst eds) Wolters Kluwer|Lippincott Williams & Wilkins 1214, 2008. Rosenthal PJ Chapter 52:  Antiprotozoal Drugs (in Basic & Clinical Pharmacology, Katzung BG, Trevor AJ) 13 edition,  McGraw-Hill Education, 2015. HIV Overview:  The HIV Life Cycle, Education Materials, AIDSinfo, NIH http://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle Tsibris AMN Hirsch MS Chapter 130 Antiretroviral Therapy for Human Immunodeficiency Virus Infection in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8e (Bennett JE Bolin R Blaser, eds) Elsevier, Inc/Saunders 2015, online version. Safrin S Chapter 49:  Antiviral Agents:  Antiretroviral Agents in Basic & Clinical Pharmacology 13e (Katzung BG Trevor AJ, eds) 2015, online edition. US National Institute of Health (redrawn by Henderson C) Diagram of the HIV Virus; http://commons.wikimedia.org/wiki/File:HIV_Virion-en.png Jones M Mechanism of Viral Entry/Membrane Fusion http://commons.wikimedia.org/wiki/File:HIV_Membrane_fusion_panel.svg 11 March 2013. Ryan KJ, Ray C. Chapter 18. Retroviruses: Human T-Lymphotropic Virus, Human Immunodeficiency Virus, and Acquired Immunodeficiency Syndrome. In: Ryan KJ, Ray C. eds. Sherris Medical Microbiology (Part editor, Ahmad N Ray CG Drew WL), 5e. New York, NY: McGraw-Hill; 2010. National Institute of Allergy and Infectious Diseases (NIAID) HIV Replication Cycle http://phil.cdc.gov/phil/details.asp ID#:  18162 Coffin JM HIV Population Dynamics in Vivo:  Implications for Genetic Variation, Pathogenesis and Therapy.  Science (New Series) 267 (5197) 483-489, Jan 27, 1995. (http://www.ncbi.nlm.nih.gov/pubmed/7824947) Fauci AS Host factors and the pathogenesis of HIV-induced disease.  Nature 384 (6609):  529-534 Dec 12, 1996. Liu R Paxton WA Choe S Ceradini D Martin SR Horuk R MacDonald ME Stuhlmann H Koup Landau NR Homozygous Defect in HIV-1 Coreceptor Accounts for Resistance of Some Multiply Exposed Individuals to HIV-1 Infection.  Cell 86:  367-377, August 9, 1996. (http://www.ncbi.nlm.nih.gov/pubmed/8756719) Hendrickson SL Hutcheson HB Ruiz-Pesini E Poole JC Lautenberger J Sezgin E Kingsley L Goedert JJ Vlahov D Donfield S Wallace DC O'Brien SJ Mitochondrial DNA haplogroups influence AIDS progression. AIDS 22:  2429-2439, 2008. (http://www.ncbi.nlm.nih.gov/pubmed/19005266)

 

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