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HIV-Disease Overview, Targets for Therapy and Open Issues

Christoph Stephan

Internal Medicine & Infectious Diseases, Medical Center/Infectious Diseases Unit, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany

Nearly 40 years have passed since the first patients were discovered to have the previously unknown "acquired immunodeficiency syndrome" (AIDS) [1] and 38 years, since the causative virus was discovered [2]. The time since, has been characterized by a dynamically evolving body of epidemiological and basic science that is unique in medical history. Preliminary result is the development of antiretroviral treatments and social medicine progress, accompanied and catalyzed by the predominantly affected risk groups' emancipation, with reintegration into the society.

1.1 HIV-Disease Overview

There has not been a significant change in the natural history of HIV-infection; however, today in industrialized countries, disease manifestation in the form of AIDS can only be observed in undiagnosed, late presenting patients, who already show manifestations of immunological deterioration. Figure 1.1 demonstrates the course of the disease, according to the two most important measurable surrogate markers-CD4-cell count and HIV-RNA (viral load).

After initial HIV transmission, the retrovirus spreads throughout the human body and infects potentially all CD4-receptor positive cells. Consequently, during the first weeks of infection, there is a substantial fall in CD4-positive T-lymphocyte count and a rise in viral load-up to a turning point. Thereafter, CD4-cells rise again and viral load decreases, due to regain of a partial immunological control. At this time, anti-HIV antibodies can be found in plasma, and the patient will now respond positively to serological HIV-tests. Elimination of HIV, however, will not occur due to the rapid variation of viral surface receptors which may hide infected cells from the immune system and lead to divergent virus populations, including in a single patient [3, 4, 5, 6]. This continuous change of HIV stems from proofreading failures which lead to the evolution of many HIV quasispecies. Another reason for the inability to eliminate HIV is the infection of durable reservoir and "archive" cells, e.g. edaphic CD4-receptor-positive macrophage and monocyte cells, leading to the chronic phase of the infection. For approximately 3-10 years, the patient will experience a relatively stable period, marked by individually solid CD4-cell count- and HIV-RNA viral load- "setpoints" [7]. However, after months or years, an immunological exhaustion will occur. Then, the CD4-cell count is substantially decreasing and viral load is rising again. The result may be AIDS, as defined by the emergence of at least one of 26 opportunistic infections and/or tumors, including pneumocystis pneumonia, cerebral toxoplasmosis, tuberculosis, cytomegalovirus retinitis, Kaposi's sarcoma, or B-cell non-Hodgkin lymphoma.

Figure 1.1 Shows the course of both most important measurable surrogate markers from blood count, i.e. CD4-cell count and HIV-RNA (viral load), during untreated HIV infection.

1.2 Targets for Antiretroviral Therapy

The replication of the retrovirus in the human host cell is well described and offers targeted treatment options, in order to prevent viral replication. Figure 1.2 shows the passage of HIV through the human host CD4-receptor positive T-cell. Antiretroviral drugs are able to address specific points in the HIV replication cycle and used in combination antiretroviral therapy (cART) aims to completely suppress HIV-1 replication long term. This will give the immune system a chance to recover and overcome opportunistic infections and tumors and/or to avoid significant deterioration from the beginning, when applied early after infection.

During the retrovirus replication in the human cell, specific cART-drug classes offer to interfere with different therapeutic intervention targets (see Table 1.1, presently favored drugs are printed in bold and Figure 1.2). Such interventions comprise: inhibition of first contact of HIV with the CD4-positive cell (attachment), the cell entry, intracellular reverse transcriptase-enzyme and -activity, DNA-integration, virus assembling by proteases, and virus maturation; the latter leaves immature, noninfectious virus particles. The chemical structures of the different HIV drugs can be found in Table 1.2.

Figure 1.2 Shows the viral replication cycle for HIV in the human target cell, i.e. the CD4-receptor positive cell, and six treatment targets for antiretroviral therapy classes (for numbers in red, see Table 1.1/row 1).

Table 1.1 Explains the mode of action for available cART options, according to the target area in HIV cell passage (for numbers: see Figure 1.2).

a) In clinical study development-also refer to public study registry online-resource, available at: https://www.clinicaltrials.gov.

b) Modern, recommended first-line combination antiretroviral therapy components: printed in bold. For treatment guidelines from the European AIDS Clinical Society (EACS), version 10, from November 2019, please refer to online-resource, available at: https://www.eacsociety.org/files/2019_guidelines-10.0_final.pdf.

Table 1.2 Illustrates chemical formula details and CAS registry numbers for available cART-drugs.