An introduction to HIV treatments

By Allis Lai

Human immunodeficiency virus, or HIV, is one of the leading causes of morbidity and mortality across the globe. The retrovirus attacks the immune system, leading to loss of functional T cells and causing an increased risk of infections, bone disease, kidney and liver dysfunction, and other complications. The virus is transmitted via contact of body fluids of infected individuals with other’s mucosal tissue, blood, or broken skin. It is estimated that there are currently 37 million individuals living with HIV, and there is a high prevalence in “men who have sex with men, intravenous drug users, people in prisons and other closed settings, sex workers and transgender people”. Patients with HIV tend to lead a lower quality of life, due to a variety of reasons including effects of drug toxicity, co-morbidities of HIV, social isolation, and stigma surrounding the condition.1

The pathway by which HIV infects T cells is relatively well established. Upon entry to the body, the virion envelope glycoprotein gp120 binds to the CD4 molecule on T cells, assisted by the main co-receptors CXCR4 and CCR5.2 CCR5 is expressed in high levels on memory T cells but not on naïve T cells, whereas CXCR4 is expressed on both.1 Mutations that result in these coreceptors not being expressed therefore provide immunity: the only people known to be fully cured from HIV are patients who underwent bone marrow stem cell transplants that lacked CCR5 receptors.3 After binding to the T lymphocyte, the viral genome and enzymes in the nucleocapsids enter the cell, where the viral reverse transcriptase enzyme transcribes ssRNA and forms RNA-DNA hybrids. The viral RNA is then partly degraded by ribonuclease H, and the second DNA strand is made to synthesize HIV dsDNA. This translocates to the nucleus, and viral integrase enzymes integrate it into the host genome, forming proviral DNA. Host enzymes are used to transcribe and translate the proviral DNA, leading to the formation of viral precursor proteins. Viral proteases cleave these precursors into viral poly-proteins, which assemble with HIV ssRNA to form virion buds. These bud from the host cell and the poly-proteins are cleaved into individual HIV proteins, after which it becomes mature virions capable of infecting more host cells2. HIV is difficult to eradicate, as the pathogen reservoir is maintained by T cell replication and cannot be eliminated. However, antiretroviral drugs can inhibit HIV replication, limit infection of new cells within the host, and lower the risk of HIV transmission.1

The currently available HIV treatments can be grouped into 7 categories based on which step of the HIV infection pathway they target: chemokine receptor antagonists, attachment inhibitors, post-attachment inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) fusion inhibitors, integrase strand transfer inhibitors (INSTIs), and protease inhibitors (PIs).4 Anyone with an HIV infection is recommended to start combination antiretroviral therapy (ART)1, which is typically a combination of three drugs: two nucleoside reverse transcriptase inhibitors and one integrase strand transfer inhibitor.5 By combining drugs that target different mechanisms, viral suppression effectiveness is increased as the chance of the virus being resistant to all three drugs at the same time. Those who are at a high risk of being infected, such as partners of HIV-positive patients, are also recommended to take ART drugs in what is known as pre-exposure prophylaxis (PrEP): combination therapy of typically two nucleoside analogues to inhibit viral replication.1 Studies have shown that the use of PrEP leads to a 67-75% reduction in HIV infection risk, as the low HIV viral load when just infected can be suppressed with the two-drug combination. However, the lack of adherence to PrEP by patients has led to concerns for the emergence of drug-resistant strains.6

NRTIs and NNRTIs both inhibit the viral reverse transcriptase enzyme. NRTIs are nucleosides that lack the 3’-hydroxyl group, leading to the termination of the DNA chain. They are taken as prodrugs and require phosphorylation by cellular kinases to become active. There are however side effects including myopathy, neuropathy, and lipoatrophy (the loss of body fat from the face and limbs).6 Commonly used NRTIs include Tenofovir and Emtricitabine.1 NNRTIs work by binding to reverse transcriptase, creating a hydrophobic pocket near the active site and changing its conformation, hence decreasing polymerase activity. There are fewer adverse effects compared to NRTIs, and common side effects are rashes and dermatitis complications.6

On the other hand, INSTIs inhibits the integrase enzyme to prevent the formation of proviral DNA. Integrase works by first removing a GT dinucleotide from the 3’ end of viral DNA, leaving the complementary CA dinucleotide. The hydroxyl groups of the conserved adenine nucleotide act as nucleophiles when catalysed by integrase, inserting 3’ end of viral DNA into the host genome to form the provirus. Different types of INSTIs inhibit integrase via different mechanisms. Raltegravir for example acts by chelating magnesium ion cofactors in the integrase active site, which ultimately leads to displacement of the conserved adenine in viral DNA, preventing binding to host DNA.5

Another major class of HIV drugs is protease inhibitors. Protease enzymes are essential to the formation of mature virion by cleaving long polypeptide chains. Side effects of protease inhibitors include mild gastrointestinal symptoms and dyslipidaemia.1 Studies have shown that PIs have a “high genetic barrier to resistance”, giving them the potential to be used as monotherapy in the long run after the viral load has been suppressed with combination ART.7

Despite so, the high mutation rate of HIV at one mutation every few replications leads to the extensive variation of the virus1, and its “error-prone reverse transcriptase”8 alongside other factors contribute to the growing HIV drug resistance. In 2021 WHO reported that “up to 10% of adults starting HIV treatment can have drug resistance to the NNRTI drug class”9, demonstrating the need for the development of new HIV drugs. Recently, Lenacapavir, a new HIV drug showed promising antiviral activity in a phase 3 trial.10 This drug targets the HIV-1 capsid, and by modifying its stability suppresses its roles in reverse transcription and integration of HIV4. In the trial, Lenacapavir was reported to be safe with no serious adverse effects.11

Advances in HIV treatment in recent decades have led to HIV becoming a chronic condition and no longer a fatal disease. Yet, the emergence of drug resistance strains highlights the importance of continuing that progress to develop new drugs and preventive measures to truly end the HIV epidemic.

References:

  1. Deeks SG, Overbaugh J, Phillips A, Buchbinder S. HIV infection. Nature Reviews Disease Primers. 2015;1(1). https://doi.org/10.1038/nrdp.2015.35.
  2. Makvandi-Nejad S. Human Immunodeficiency Virus (HIV) | British Society for Immunology. https://www.immunology.org/public-information/bitesized-immunology/pathogens-and-disease/human-immunodeficiency-virus-hiv [Accessed 16th May 2022].
  3. First case of HIV cure in a woman after stem cell transplantation reported at CROI-2022. Error! Hyperlink reference not valid.. https://www.who.int/news/item/24-03-2022-first-case-of-hiv-cure-in-a-woman-after-stem-cell-transplantation-reported-at-croi-2022 [Accessed 16th May 2022].
  4. McFadden WM, Snyder AA, Kirby KA, Tedbury PR, Raj M, Wang Z, et al. Rotten to the core: antivirals targeting the HIV-1 capsid core. Retrovirology. 2021;18(1). https://doi.org/10.1186/s12977-021-00583-z.
  5. Smith SJ, Zhao XZ, Passos DO, Lyumkis D, Burke TR, Hughes SH. Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs. Viruses. 2021;13(2): 205. https://doi.org/10.3390/v13020205.
  6. Patel PH, Zulfiqar H. Reverse Transcriptase Inhibitors. 2022; https://www.ncbi.nlm.nih.gov/books/NBK551504/
  7. Paton NI, Stöhr W, Arenas-Pinto A, Fisher M, Williams I, Johnson M, et al. Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial. The Lancet HIV. 2015;2(10): e417–e426. https://doi.org/10.1016/s2352-3018(15)00176-9.
  8. Naif HM. Pathogenesis of HIV infection. Infectious Disease Reports. 2013;5(1S): 6. https://doi.org/10.4081/idr.2013.s1.e6.
  9. HIV Drug Resistance. World Health Organization. 2020. https://www.who.int/news-room/fact-sheets/detail/hiv-drug-resistance [Accessed 16th May 2022].
  10. Segal-Maurer S, DeJesus E, Stellbrink H-J, Castagna A, Richmond GJ, Sinclair GI, et al. Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. New England Journal of Medicine. 2022;386(19): 1793–1803. https://doi.org/10.1056/nejmoa2115542.
  11. Highleyman L. Lenacapavir Shows Promise for Long-Acting HIV Treatment and Prevention. POZ. https://www.poz.com/article/lenacapavir-shows-promise-longacting-hiv-treatment-prevention [Accessed 16th May 2022].

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