Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiviral Drugs

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

    • HIV-1 Pathophysiology/Pathogenesis

      • Long-term Infection:  Latency Phase

        • After the primary infection there is about a one week period before an initial viremia, which lasts 2-3 months.⁸ 

          • In many patients an acute mononucleosis-like presentation develops about a month following initial infection.

            • HIV Infection Progression¹⁴

              "The Progression of HIV Infection from Primary Infection through the Acute HIV Syndrome to the Stage of Clinical Latency"14 Attribution:  The above figure corresponds to Figure 2 in reference 14 [Panteleo G Graziosi Fauci AS The Immunopathogenesis of Human Immunodeficiency Virus Infection (Mechanism of Disease, Epstein FH, ed) The New England Journal of Medicine 328(5) 327-335, 1993.]

               

              • About 50-70% of individuals with HIV infection progress through an acute clinical syndrome about a month following primary infection. (See figure above).²

                • Despite variability in clinical severity during this period, no correlation between initial viremia level in the acute HIV infection stage and subsequent evolution of disease has been found.

                • Symptoms of acute HIV syndrome include:

                  • Fever

                  • Skin rash

                  • Myalgia and

                  • Pharyngitis.

                • These symptoms may occur less frequently in those infected via drug injection compared to those infected due to sexual contact.²

                • Opportunistic infections may occur during this early stage of HIV infection and may be due to both diminished CD4⁺ T cells and dysfunctional CD4⁺ T cells, secondary to viral protein and cytokine-mediated cell effects.

                • Immunological abnormalities are associated with acute HIV syndrome.²

                  • These abnormalities include various anomalies in circulating lymphocyte subsets with reduction in total lymphocytes as well as CD4⁺ and CD8⁺ both noted.

                  • Lymphadenopathy is documented in about 70% of individuals with primary acute HIV infection with most patients recovering spontaneously with many exhibiting only slightly depressed but initially stable CD4⁺ T cell count, prior to a progressive CD4⁺ T cell level decline.

                  • Absent treatment some patients may exhibit a rapid immunologic and clinical deterioration; however, most patients exhibit clinical latency (smoldering disease).

                    • Following acute HIV infection, several disease courses may be described (absent treatment):⁶

                      • Rapid progressors (10-15%); these patients develop "late stage" symptoms in about 2-3 years.

                      • Slow progressors (70-80%); these patients develop "late stage" symptoms in about 8-10 years.

                      • Long-term non-progressors (5%); these patients show no decline in CD4⁺ T-cell counts.⁶

            • In this early phase a notable decline in circulating CD4⁺ T cells is observed.

            • An immune response to HIV-1, developing one week to three months following infection, results in a reduction of HIV-1 viral load (reduce viremia) with an increase in previously suppressed CD4⁺ cell number.²

          • For reasons discussed earlier, the immune response is insufficient to resolve the infection and persistent presence of HIV-1 in infected cells (latent) has been documented.⁸  

          • Clinical latency itself may extend to 10 years, while viral replication continues at a high level.⁸  

            •  

              HIV Infection Stages⁹

              Stages of HIV Infection https://www.aids.gov/hiv-aids-basics/just-diagnosed-with-hiv-aids/hiv-in-your-body/stages-of-hiv/index.html9

            • In this circumstance about 10 billion HIV virions are produced and destroyed each day.

            • The viral plasma half-life is about six hours with a complete virus lifecycle lasting about 2.5 days.

              •  

                Steps in the HIV Lifecycle¹⁰

                AIDSinfo (NIH): HIV Overview, The HIV Life Cycle (last reviewed, 9/23/2014)

              • A similar high turnover rate for CD4⁺ T lymphocytes, targeted by HIV-1, has also been described, with a half-life of an infected CD4⁺ lymphocyte estimated at 1.5 days.⁸ 

            • The uniqueness of HIV infection, compared to other human viral infections, rests in its indefinite persistence in the body, despite a cellular and humoral immune response, and its ability to emerge from a period of latency.²

              • (Note that herpes simplex viral infections, HSV infections, also persist but enter both a clinical and microbiological latent state).

              • For HIV, as noted earlier, a chronic infection is established that exhibits varying degrees of viral replication with a latent period of about 10 years prior to the untreated patient exhibiting signs of clinical disease.² 

                • In untreated, infected patients viral replication is detectable both by direct assays for plasma HIV RNA and by identification of cell-associated HIV RNA in CD4+ T cells and macrophages both in lymphoid tissue and in the circulation.

                • In HIV patients undergoing treatment with cART ("effective combination AntiRetroviral Therapy"), also known as HAART ("Highly Active AntiRetroviral Therapy), although plasma viremia may be suppressed to <50 HIV/ml copies, viral replication persists.²

      • HIV-Latency:  CD4⁺ T Cell Reservoir:

        • After the HIV virus has integrated into host cell DNA, postintegration latency results in some cells causing a stable, proviral reservoir.¹¹ 

          • This reservoir is localized within resting memory CD4⁺ T cells.

            • Within a few days following the initial infection, within the acute phase, latency develops.^11,13 

              • Although the latent, integrated viral genome is not transcriptionally active, activation of the host cell allows transition of the transcriptionally inactive viral genome to a transcriptionally active viral genome fully capable of producing infectious virions.

              • This transition may be induced by "recall" antigens or cytokines or upon discontinuation of anti-retroviral drugs.¹¹ 

          • Normally, naïve CD4⁺ T cells remain in a resting state prior to encountering an antigen.¹¹  

            • After that, the CD4⁺ T cells become activated, proliferate and thus generate effector cells that remove the associated pathogen from the body.¹¹  

              • Most of these activated cells remain alive only a few weeks.

              • However, some of the same cells revert back to a resting state, continuing to exist as a "memory T cell" which are capable of responding at a later time to the same antigen.

                • The longevity of the memory T cell and their daughter cells allow these cells, if they have been infected by HIV-1, to serve as a primary reservoir for the latent HIV provirus.

                  • Accordingly, memory T cells may be viewed as an ideal cellular HIV reservoir with the proviral genome remaining inactive and hidden.¹¹  

              • As stated above, activation of these memory T cells by reexposure to antigen or through cytokine activation (e.g. NF-κB, NFAT) , both leading to transcription factor induction, result in reactivation of latent HIV provirus.

                • NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex controlling DNA transcription.

                  •  

                    Mechanism of NF-κB Action¹²

                    "BogHog" NFKB mechanism of action http://commons.wikimedia.org/wiki/File:NFKB_mechanism_of_action.png "In this figure, the NF-κB heterodimer between Rel and p50 proteins is used as an example. "While in an inactivated state, NF-κB is located in the cytosol complexed with the inhibior protein IκBα.  "Through the intermediacy of integral membrane receptors, a variety of extracellular signals can activate the enzyme IκB kinase (IKK). "IKK, in turn, phosphorylates the IκBα protein, which results in ubiquitination, dissociation of IκBα from NF-κB and eventual degradation of IκBα by the proteosome. "The activated NF-κB is then translocated into the nucleus where it binds to specific sequences of DNA called response elements (RE). "The DNA/NF-κB complex then recruits other proteins such as coactivators and RNA polymerase, which transcribe downstream DNA into mRNA, which, in turn, is translated into protein which result sin a change of cell function. Attribution: 1.  http://en.wikipedia.org/wiki/NF-%CE%BAB 2.  Gilmore TD (2006). "Introduction to NF-κB: players, pathways, perspectives". Oncogene 25 (51): 6680–4. (second sourced from reference 1 above) 3.  Brasier AR (2006). "The NF-κB regulatory network". Cardiovasc. Toxicol. 6(2): 111–30. (second sourced from reference 1 above) 4.  Perkins ND (January 2007). "Integrating cell-signalling pathways with NF-κB and IKK function". Nat. Rev. Mol. Cell Biol. 8 (1): 49–62. (second sourced from reference 1 above)

                • After activation, cytopathic effects or immune responses result in death of most HIV-infected cells.¹¹