By Marina Artemiou
Human Immunodeficiency Virus, commonly known as HIV, is a pathogen which destroys the immune system by attacking CD4 white blood cells and interfering with the body’s ability to fight off infection. Transmission of the virus occurs through contact between broken skin, wounds and other bodily fluids of an HIV-positive person and an HIV-negative person, i.e. sharing injection equipment.
There is currently no cure for HIV, however, existing treatments involve the use of antiretroviral drugs, which stop viral particles from replicating by inhibiting key processes at different stages of the HIV life cycle. Patients are required to take a cocktail of multiple different antiretroviral drugs, between 1 and 4 different pills daily, which work to lower the viral load and allow the immune system to repair itself. Successful treatment has been shown to lower the viral load to an undetectable amount within six months, however the Coronavirus pandemic has severely impacted the global HIV/AIDS response and is threatening to undo the progress globally made so far.
Upon HIV entry into the bloodstream, the viral envelope comprised of gp120 and gp41 subunits, attaches to CD4 receptors on target cells. CD4 binding results in the viral envelope undergoing conformational changes, facilitating coreceptor binding, which is mediated partly by Variable loop 3 (V3) of the envelope. This initiates fusion between the membrane of CD4 cells and the viral envelope, whereby the fusion peptide of gp41 becomes embedded into the target membrane. Six-helix bundle formation ensues as an amino-terminal helical region and a carboxy-terminal helical region from either gp41 subunit are brought together resulting in fusion between the two membranes and delivery of the viral contents to the cytoplasm (Wilen et al., 2012).
Once inside the cell cytoplasm, the HIV reverse transcriptase converts HIV RNA to double-stranded DNA. Subsequently, HIV DNA enters the CD4 cell nucleus through nuclear pores where HIV integrase is used to insert viral DNA into the DNA of the host cell. This DNA is transcribed and then translated to form viral peptides, using CD4 cell transcription and translation machinery. Finally, the new HIV proteins move towards the cell surface and assemble into non-infectious virions which bud from the cell surface. Protease enzymes within non-infectious virions break up long peptides to create a mature viral particle which can go on to infect other CD4 cells, spreading throughout the bloodstream (AIDSinfo, 2020).
Knowledge of how HIV infects cells and replicates has made the development of antiretroviral therapy possible. Entry inhibitors, such as CCR5 Antagonists, prevent attachment of the viral envelope onto the CD4 plasma membrane. CCR5 is used as a coreceptor by HIV-1 to enter CD4 cells. Maraviroc, a human chemokine receptor (CCR5) antagonist interferes with the interaction between the viral envelope and CCR5 and is used for the treatment of CCR5-tropic HIV infection. Specifically, Maraviroc is a selective, small molecule antagonist that binds allosterically into a cavity within the transmembrane CCR5 helix and disrupts the geometry of the multi-point interaction between CCR5 and gp120 trimers (Ray, 2008). This prevents membrane fusion and infection of CD4 cells.
Similarly to entry inhibitors, fusion inhibitors also prevent the entry of virions into CD4 cells. Popular fusion inhibitor, Enfuvirtide prevents fusion between the viral envelope and cell membrane of CD4 cells. Enfuvirtide binds to the first heptad repeat domain of the gp41 heterodimer, which mediates the conformational change required for membrane fusion between the virus and host cell, by bringing the two membranes within close proximity of one another. Binding of the molecule prevents this change from occurring and as a result the two membranes are not in close enough vicinity for the virus to successfully bind to and enter the cell (Patel et al., 2005).
Nucleoside reverse transcriptase inhibitors or NRTIs, such as Zidovudine, belong to a class of reverse transcriptase inhibitors. Such drugs are nucleotide base analogues and function as chain-terminators during the extension of viral DNA by reverse transcriptase. NRTIs become incorporated into the growing DNA chain by complementary base pairing, however they lack the 3’ – hydroxyl group, which is substituted by another inert chemical group. The 3’–5’ phosphodiester bond needed to elongate the DNA chain is prevented from forming, hence new viral particles cannot be produced from the infected host cell. However, such drugs require 5’ – phosphorylation by host cell kinases in order to be activated and exert their terminating effect on the growing HIV DNA chain (Immunopaedia.org).
Another class of reverse transcriptase inhibitors are non-nucleoside reverse transcriptase inhibitors or NNRTIs, such as Delavirdine. HIV reverse transcriptase is a heterodimer comprised of 2 subunits and NNRTIs bind the p66 subunit at a hydrophobic pocket on the allosteric side of the enzyme. This non-competitive binding induces a conformational change in the enzyme that alters the active site, decreasing the binding affinity between the enzyme and nucleosides, thus preventing substrate binding and halting HIV DNA polymerization (Immonopaedia.org).
Other antiretrovirals include Integrase strand transfer inhibitors, such as Raltegravir, Protease inhibitors, such as Atazanavir and the gp120 attachment inhibitor, fostemsavir. Combinations of the different antiretrovirals mentioned are used in drug cocktails to treat HIV infections and prevent the development of drug-resistant strains.
Despite all the progress made in treating HIV, according to a WHO survey seventy-three countries have warned that they are at risk of stock-outs of antiretroviral medicines as a result of the COVID-19 pandemic (WHO, 2020). Failure of suppliers to provide antiretrovirals due to COVID-19 restrictions could lead to an increase in the number AIDS-related deaths in 2020. Global resources have been shifted away from the research and development of an HIV cure, stalling the progress made so far and effectively “silencing” the need to provide appropriate treatment to HIV-positive individuals.
References:
Wilen, CB., Tilton, CJ., Doms, RW. (2012) Cold Spring Harbor Perspectives in Medicine. HIV Cell Binding and Entry. 2(8). Available from: doi: 10.1101/cshperspect.a006866
AIDSinfo. (2020) HIV Overview: The HIV Life Cycle. Available from: https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/73/the-hiv-life-cycle
Ray N. (2008) Dove Medical Press. Maraviroc in the Treatment of HIV infection. 2: 151–161. Available from: doi: 10.2147/dddt.s3474
Patel, IH., Zhang, X., Nieforth, K., Salgo, M., Buss, N. (2005) Clinical Pharmacokinetics. Pharmacokinetics, pharmacodynamics and drug interaction potential of enfuvirtide. 44(2):175-86. Available from: doi: 10.2165/00003088-200544020-00003
Immunopedia.org. ARV Mode of Action. Available from: https://www.immunopaedia.org.za/treatment-diagnostics/hiv-infection-treatment/arv-mode-of-action/
World Health Organization. (2020) WHO: access to HIV medicines severely impacted by COVID-19 as AIDS response stalls. Available from: https://www.who.int/news-room/detail/06-07-2020-who-access-to-hiv-medicines-severely-impacted-by-covid-19-as-aids-response-stalls
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