Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

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

    • HIV Budding¹⁵

      Goldsmith C Feorino P Palmer EL McManus WR/CDC; Photo Credit:  Goldsmith C HIV Budding http://commons.wikimedia.org/wiki/File:HIV-budding-Color.jpg "Scanning electron micrograph of HIV-1 budding (in green) from cultured lymphocyte. "Multiple round bumps on cell surface represent sites of assembly and budding of virions."15

    • Introduction:  Human Retroviruses

      • An early member of the family of viruses described as retroviruses is Rous sarcoma virus, which causes tumors in chickens.⁵ 

        • This retrovirus was so described over 100 years ago.

        • Retroviruses utilize an enzyme, reverse transcriptase, first identified in retroviruses.

        • Retroviruses depend on reverse transcriptase associated with the virion to make a fully double-stranded DNA copy from their single-stranded RNA virion genome.

          • Later, this DNA copy is translocated to the nucleus where a viral enzyme, integrase, catalyzes insertion of viral DNA into the cellular chromosome at random locations.⁵ 

      • Reverse transcriptase was discovered by Howard Temin and David Baltimore in 1971.⁵ 

        •  

          The Howard Temin Path

          Howard Temin Path "The Howard Temin Path was given this name in 1998 as a tribute to the late UW-Madison professor of oncology and Nobel Prize winner. "Howard Temin often walked and bicycled along the path, finding opportunities for quiet reflection and contemplation along the shoreline." Lakeshare Nature Preserve University of Winconsin: http://lakeshorepreserve.wisc.edu/visit/lakeshorepath.htm

        • Studies indicated that retroviruses could integrate a DNA copy of their RNA genome into infected cellular chromosomes.⁸ 

        • Later, Michael Bishop and Harold Varmus demonstrated that Rous sarcoma virus infection could cause tumors secondary to alteration of the cellular gene (termed "oncogene") due to the virus.⁹

      • AIDS was first identified as a possible disease in 1981 when the CDC (Centers for Disease Control and Prevention) in the United States noted an unexpected occurrence of Pneumocystis jirovecii, a fungus,  (previously described as P. carinii) pneumonia in five previously healthy homosexual men in Los Angeles.² 

      • "HIV/AIDS in 2014:   Progress and Priorities"¹⁶

        Fauci A HIV/AIDS in 2014:  Progress and Priorities ("Anthony Fauci MD, Director of the National Institute on Allergy and Infectious Diseases, will discuss the present and future environment for battling HIV/AIDS. "The event was held in the Rayburn House Office Building on Capital Hill in Washington, DC" published on May 8, 2014. Introduction by Lynn Marquis. https://www.youtube.com/watch?v=ZqS-6Bwm99w

      •  

        Ending the HIV/AIDS Pandemic:  Follow the Science

        Fauci A Ending the HIV/AIDS Pandemic:  Follow the Science Keynote Address,  Einstein-Rockefeller-CUNY CFAR Symposium June 19, 2017 https://www.youtube.com/watch?v=YqZmE_38SbE

         

        • Pneumocystics jiroveci cysts¹⁰

          Ewing Jr EP/CDC Pneumocystics jirovecii cysts in tissue from an AIDS patient CDC Image http://commons.wikimedia.org/wiki/File:Pneumocystis_carinii_01.jpg

        •  

          Chest X-ray of bilateral pulmonary interstitial infiltrates due to Pneumocystis jirovecii infection

          "This anteroposterior (AP) chest x-ray revealed radiologic evidence of pneumocystosis in the form of bilateral pulmonary interstitial infiltrates. This infection was due to the presence of an opportunistic fungal infection by the fungal organism Pneumocystis jirovecii, formerly knows as Pneumocystis carinii. This image was provided by Jonathan W.M. Gold. M.D., Assoc. Dir. Special Microbiology Lab, Assist. Attending Physician, Memorial Sloan-Kettering Cancer Center and Assist. Prof. of Medicine, Cornell Univ. Med. College, New York." "Pneumocystis jirovecii is the causative agent of Pneumocystis pneumonia (PCP), one of the most frequent and severe opportunistic infections in immunocompromised patients. Pneumosystis organisms represent a large group of species of atypical fungi with universal distribution and pulmonary tropism, and each specials has a strong specificity for a given mammalian host species." http://phil.cdc.gov/phil/details.asp (ID#:  14372)

        •  

          Pneumocystis Pneumonia (Pneumocystis jiroveccii, formerly P. carinii)¹¹  

          Attribution:  Minarcik JR "Histopathology Lung--Pneumocystis pneumonia", https://www.youtube.com/watch?v=zSdK_yWe_S4 May 2007.

      • Also, Kaposi's sarcoma (KS) with or without P. jiroveci pneumonia in 26 previously healthy homosexual men in New York and Los Angeles.

        • Kaposi sarcoma (patient's right heel)¹²

          "Here we see the medial side of a Kaposi sarcoma patient's right heel displaying the familiar characteristic violaceous cutaneous plaques indicative of this disease." "Kaposi sarcoma, is a malignant tumor of the lymphatic endothelium caused by the Human herpesvirus 8 (HHV8), i.e. Kaposi's sarcoma-associated herpes virus (KSHV), and arises from a cancer of the lymphatic endothelial lining. "It is characterized by bluish-red cutaneous nodules.  "Kaposi's sarcoma is thought of  as an opportunistic infection, affecting patients whose immune systems have been compromised, as in the case of patients with HIV/AIDS." Content provider is the CDC, 1986, ID# 14430

        •  

          Kaposi Sarcoma Micrograph¹³

          "This micrograph depicts the histopathologic changes found in the case of Kaposi's sarcoma lesions. This skin biopsy of what turned out to be a Kaposi's sarcoma lesion at a high magnification depicts two characteristic findings found in such lesions, which includes remnants of extravasated erythrocytes (RBSs), and deposits of hemosiderin." Content provider: CDC/Dr. Steve Kraus, 1981, ID#:  6432.

           

        • Kaposi Sarcoma: The Disease ¹⁴

          Attribution:  Donald Ganem https://www.youtube.com/watch?v=D7J9dm1d3dQ (3/2010) iBiology YouTube Channel:  https://www.youtube.com/channel/UCsvqEZBO-kNmwuDBbKbfL6A "In 1872, Moritz Kaposi first described a disease that included pigmented skin tumors and in some cases tumors of the viscera. While KS has been endemic in some areas of the world for many years, a highly aggressive and deadly form of the disease emerged concurrently with the HIV/AIDS epidemic. "KS is a very unusual cancer including multiple cell types, including cells of a spindle morphology, in a single tumor. In this section of the talk, the atypical biology of this cancer it will be discussed. "Epidemiological studies suggested that HIV was not the causative agent of KS. "In the mid-1990s, a new human herpes virus, Kaposi sarcoma associated herpes virus (KSHV), was identified as the likely cause of KS. "Development of a serological test for the presence of KSHV in patients showed that KS seroprevalence strikingly mirrored KS risk and, additionally, KS was never found in KSHV negative patients. "This data strongly supported KSHV as the causative agent of KS. However, epidemiology also showed that additional cofactors are required for disease development and in the case of patients with AIDS, HIV is this cofactor

      • AIDS was also identified in:

        • Male and female injection drug users

        • Hemophiliacs in blood transfusion recipients

        • Among female sexual partners of men with AIDS.

      • In addition, the disease was also found in infants born to mothers with AIDS or with an injection drug use history.²