An Understanding of Protease Mechanisms Lead to New Treatments of HIV Infection

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In time with the HIV Awareness Month, I am glad to share one of my reaction papers in my graduate study program.

I hope that this can somewaht add information about human immunodeficiency virus or HIV.

 An Understanding of Protease Mechanisms Lead to New Treatments of HIV Infection

“…I would raise awareness to certain causes like HIV awareness that is timely and relevant to my country, which is the Philippines…” This is one part of Pia Wurztbach’s response to the final Q&A of Miss Universe 2015 where she hooked the crown.

What is the real status of HIV in the Philippines?

The case of HIV in the Philippines increased up to 207% from 2010 to 2019 with a death toll increase of 338%. This is considered the fastest rising in the Asia and Pacific region. In 2019, there are about 97,000 persons living with HIV or PLHIV. The majority of these PLHIV are persons who injected drugs, men who have sex with men, sex workers, and transgender (Nguyen).

The virus can be transmitted through body fluids like blood, breastmilk, semen, and vaginal secretions but does not pass by kissing, hugging, sharing food, or drinks (“HIV/AIDS”).

Human immunodeficiency virus or HIV is the main causative agent of acquired immune deficiency syndrome or AIDS, which emerges in the 80s and is considered an epidemic worldwide.

HIV is a retrovirus having its genetic information is in the form of RNA and has a reverse transcriptase enabling the virus to use the RNA in the synthesis of complementary DNA (Nelson, 587).

How do HIV infection proceeds?

The infection occurs when the viral and cellular membrane fused with the facilitation of viral envelope glycoprotein and the receptors CD4 of the target cells.

When the virus enters the cell, its RNA is reversed-transcribed to DNA by the reverse transcriptase. The HIV genetic material will combine with the host’s cell using the integrase enzyme followed by transcription into the messenger RNA and replicated into viral polyproteins. The HIV protease will incise these polyproteins to form new virions and become ready to infect another host’s cell. With the destruction of the host’s genetic materials and continuous production of virions results in the death of infected cells (Brik and Wong 5–14).

Figure 1. The life cycle of HIV (“Life Cycle | NIH”)

 

Based on the mechanism, there are 3 major enzymes of the HIV used in the cycle – reverse transcriptase, integrase, and HIV protease. With these three enzymes, the HIV protease is the most studied in the development of treatments against HIV.

Proteases are classified into two huge groups according to their ability to catalyze the mechanism. The first class uses a nucleophilic atom, either hydroxyl or thiol of the amino acid side chain to start the amide hydrolysis (Brik and Wong 5–14).

The second classification requires two aspartyl β-carboxyl groups in the enzymatic sites to activate a water molecule for nucleophilic reaction on a peptide bond. It is referred to as aspartyl protease where HIV protease belongs (Windsor et al. 1465).

One way to inhibit the proliferation of HIV is by disturbance of the HIV protease enzyme responsible for the breakdown of polyprotein virus using protease inhibitors called anti-retroviral or ARVs. Here are several USFDA-approved ARVs given to PLHIV (Brik and Wong 5–14).

Figure 2. Structures of different HIV protease inhibitors or antiretrovirals.

The different HIV protease inhibitors vary in their structures but have similarities in terms of the main chain with a hydroxyl group in the β-position from the benzyl group (Nelson, 589).

Refer to the figure below regarding one of the accepted mechanisms for the aspartyl protease (HIV protease) mechanism.

 

Figure 3. One of the acceptable mechanisms of HIV protease.

Studying the mechanisms for HIV protease enzyme, and other enzymes is a good starting point in the discovery of new drugs that can cure (or at least control its progress) not only HIV but also other chronic illnesses. The available ARVs help extend the lifespan of the PLHIV.

Recently, there is a reported case of PLHIV cured of the said retrovirus. The patient undergoes stem cell treatment using cord blood with the mutation that prevents the entrance of HIV into the cell. Thirty-seven (37) months after the transplant, the patient chooses to top the use of ARVs. After 14 months, the patient did not show any signs of HIV in the blood tests as well as detectable antibodies to the virus (Mandavilli).

With this information, it can be a great breakthrough for researchers to further study the mechanism on how the stem cell procedure works in killing the HIV in the body which will lead to the right medicine or drug in the cure of this incurable disease.

References:

Brik, Ashraf, and Chi-Huey Wong. “HIV-1 Protease: Mechanism and Drug Discovery.” Organic & Biomolecular Chemistry, vol. 1, no. 1, 2002, pp. 5–14. Crossref, https://doi.org/10.1039/b208248a.

 

“HIV/AIDS.” WHO, 30 Nov. 2021, www.who.int/news-room/fact-sheets/detail/hiv-aids.

 

“Life Cycle | NIH.” CLINICAL INFO.HIV.GOV, clinicalinfo.hiv.gov/en/glossary/life-cycle. Accessed 21 Mar. 2022.

 

Mandavilli, Apoorva. “A Woman Is Cured of H.I.V. Using a Novel Treatment.” The New York Times, 22 Feb. 2022, www.nytimes.com/2022/02/15/health/hiv-cure-cord-blood.html.

 

Nelson, David. Lehninger Principles of Biochemistry. 7th ed., W.H. Freeman, 2017.

 

Nguyen, Alice. “The HIV Epidemic in the Philippines: Affected Populations.” The Borgen Project, 26 Jan. 2021, borgenproject.org/hiv-epidemic-in-the-philippines.

 

Windsor, Ian W., et al. “An N→π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole.” ACS Catalysis, vol. 9, no. 2, 2018, pp. 1464–71. Crossref, https://doi.org/10.1021/acscatal.8b04142.