Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

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

    • HIV-1 Pathophysiology/Pathogenesis

      • The immunodeficiency at the heart of HIV-1 viral disease occurs as a result of targeting by the virus of a subset of T-cell lymphocytes described as helper T cells.² 

        • These helper T cells are described by CD4⁺ molecules present on its surface and it is these molecules which serve as the principal HIV-1 cellular receptor.² 

          • As described earlier, a coreceptor must also be present along with CD4⁺ in support of binding, fusion and HIV-1 entry into target cells.

            • Two major co-receptors, CCR5 and CXCR4, are utilized by HIV.

              • Furthermore these co-receptors act as primary receptors for some chemoattractant cytokines (chemokines).

              • These co-receptors are classified as belonging to the family of seven-transmembrane domain G protein-coupled receptors.² 

        • Destructive effects of HIV-1 are mediated both by direct interaction as well as by indirect effects, including, immunological clearance of infected cells and activation-induced cell death, such as pyroptosis.

          • Associated with declining CD4⁺ T cells is the development of a category of diseases manifested as opportunistic infections and neoplasms.² 

            • These are "AIDS-defining" illnesses.

              • However, some manifestation of AIDS, including Kaposi's sarcoma and some neurological effects may be incompletely explained by HIV-1-mediated immunodeficiency, given that these complications appear to occur prior to severe immunological impairment.

            • The timeframe depicting the relationship between declining CD4⁺ T cell count, clinical latency, and opportunistic disease is described below.²

              •  

                Typical Progression of Untreated HIV Infection⁸

                "During the early period after primary infection there is a widespread dissemination of virus and a sharp decrease in the number of CD4 T cell in peripheral blood.8 "An immune response to HIV ensues, with a decrease in detectable viremia followed by a prolonged period of clinical latency.8 "The CD4 T-cell count continues to decrease during the following years, until it reaches a critial level below which there is a substantial risk of opportunistic infection."8 Figure Attribution:  The figure above corresponds to Fig. 1 in reference 8 (Panteleo G Graziosi Fauci AS The Immunopathogenesis of Human Immunodeficiency Virus Infection (Mechanism of Disease, Epstein FD ed)  The New England Journal of Medicine 328(5) 327-335, 1993).

        • Initial Events in HIV-1 Infection:

          • Entry of HIV-1 through the intact or degraded mucosal barrier or by dendritic cell transport is followed by viral association with target cells.²  

            •  

              HIV Infection Stages¹⁷

              Stages of HIV Infection https://www.aids.gov/hiv-aids-basics/just-diagnosed-with-hiv-aids/hiv-in-your-body/stages-of-hiv/index.html17

            •  

              HIV (or Simian Immunodeficiency Virus):  Stages of Infection¹⁸

              Key cells and molecules as well as events characterizing the interaction between HIV-1 and viral host cells.  Attribution:  Figure 1 from reference 18 (Haase AT Perils at Mucosal Front Lines for HIV and SIV and their Hosts. Nature Reviews|Immunology 5: 783-792 October 2005.)

            • The major HIV target is typically CD4⁺ T cells.²

              •  

                Human T Lymphocyte⁹

                NIH/HIAID:  "Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor." A T-cell expressing the CD4 surface protein, i.e. a helper T cell, important in the adaptive immune system is the primary target for HIV-1. This cell type is described as a CD4+ T cell.

              • "Partially" resting CD4⁺ T cells as well as activated CD4⁺ T cells amplify early infection.

                • Although resting CD4⁺ T cells are greater in number compared to activated CD4⁺ T cells, the latter subset is able to produce more virus.

                  • During the initial days to weeks following infection, HIV-1 virus is found initially in draining lymph nodes before proceeding to other lymphoid compartments, there gaining access to elevated concentration of CD4⁺ T cell targets.

                  • Access to this enriched CD4⁺ T cell environment accounts for an early burst of high-level viremia.²

                    • Gut-associated lymphoid tissue (GALT) is an important HIV-1 viral target and development of HIV-1 infection in GALT infection depletes memory-cell enriched CD4⁺ T cell subpopulations.

                    • Depletion of these cells occurs both by direct virus infection and virus-induced apoptosis (including possibly pyroptosis).²

                  • At this point, with the infection established, continued HIV replication and dissemination appear irreversible.²

                    •  Some characteristics of initial target cell infection may be dependent on the route of infection.

                      • For example, virus entering the bloodstream directly (e.g. via blood/blood products) may be cleared by normal physiological processes to the spleen and other lymphoid organs.

                      • At these sites primary focal infections begin and wider spread to other lymphoid tissues follow.²

        • HIV-1 Resistance to Antibody Neutralization:

          • HIV sexual transmission has been described as a single infectious event.² 

            • Features of the HIV envelope glycoprotein appear to influence significantly HIV transmission (for subtype A and C viruses, at least).² 

              • The viral isolate most active in transmission has been designated "founder viruses," and are less common in the viral population of the transmitting partner and also appear less divergent with respect to certain specific sequences.

              • Founder viruses have shorter V1-V2 loop sequences and fewer N-linked glycosylation sites compared to the major variants.

                • Generally HIV viruses are substantially glycosylated through post-translational modification. 

                  • The patterns of glycosylation enable evasion(s) of otherwise effective neutralizing antibodies.¹³

            • The V1-V2 loops (hypervariable loops) are part of the HIV-1 envelope glycoprotein (Env) trimer which contains both receptor binding sites and membrane fusion systems needed for viral genome transmission into the host cell.¹⁰ 

              • Env components include not only V1/V2 but also V3, HR1 and HR2 [HR1 and HR2 are helices forming the gp41 pedestal at the trimer base] domains in addition to "shielding glycans." ¹⁰ 

                • More specifically, Env spike consists of three gp120 subunits containing the CD4 receptor and co-receptor binding sites and three gp41 subunits responsible for membrane fusion.¹⁰ 

          • The HIV-1 viral spike represents the sole viral target for neutralizing antibodies and has evolved to counteract antibody-mediated neutralization.¹¹ 

            • The variable regions 1 and 2 (V1/V2) of HIV-1 gp120 envelope glycoprotein are especially vital for HIV "evasion" of antibody neutralization and are protected by sequence diversity and N-linked glycosylation.¹¹ 

              •  

                V1/V2 gp120 Variable Loop Structure¹⁰

                V1/V2 domain from the cryo-electronmicroscopic model. A more detailed description is available to and recommended to the reader (reference 10)

              •  

                Core gp120 Structure¹²

                Core gp120 structure (highly conserved simian model) Image attribution: Chen et al. (reference 12)

            • As replication proceeds in the newly infected individual, the founder virus diverges, variation in glycosylation sites results in increasing resistance to antibody neutralization.^2,13

          •  

            Progressive Changes in N-Linked Env Glycosylation Sites²

            "As HIV diverges from founder to chronically replicating virus, it accumulates N-linked glycosylation sites." Figure attribution: reference 2 and Chohan B Lang D Sangar M Korber B Lavreys L Richardson B Overbaugh J Selection for Human Immunodeficiency Virus Type 1 Envelope Glycosylation Variants with Shorter V1-V2 Loop Sequences Occurs during Transmission of Certain Genetic Subtypes and May Impact Viral RNA Levels. Journal of Virology 79(10): 6528-6531, May 2005. (reference 14) Derdeyn CA Decker JM Bibollet-Ruche F Mokili JL Muldoon M Denham SA Heil ML Kasolo F Musonda R Hahn BH Shaw GM Korber BT Sallen S Hunter E Envelope-Constrained Neutralization-Sensitive HIV-1 after Heterosexual Transmission. Science, New Series, 303(5666) 2019-2022, Mar. 26, 2004. (reference 15) Keele BF Giorgi EE Salazar-Gonzalez JF Decker JM Pham KT Salazar MG Sun C Grayson T Wang S Li H Wei X Jiang C Kirchherr JL Gao F Anderson JA Ping L-H Swanstrom R Tomaras GD Blattner WA Goepfert PA Kilby JM Saag MS Delwart EL Busch MP Cohen MS Montefiori DC Haynes BF Gaschen B Athreya GS Lee HY Wood N Seoighe C Perelson AS Bhattacharya T Korber BT Hahn B Shaw GM.  Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc. Natl. Acad. Sci. (US) 105(21) 7552-7557, May 27, 2008.