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This Sandbox is Reserved from August 30, 2022 through May 31, 2023 for use in the course Biochemistry I taught by Kimberly Lane at the Radford University, Radford, VA, USA. This reservation includes Sandbox Reserved 1730 through Sandbox Reserved 1749.

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HIV Protease

1 Introduction
2 Structural Highlights of HIV-1 protease
3 Structural Highlights of HIV-2 protease
4 HIV-1 Protease in Humans
5 HIV-2 Protease in Humans
6 The role of CD4+ T cell
7 Protease Inhibitors for HIV-1 Treatment
8 Protease Inhibitors for HIV-2 Treatment
9 Evolution's Role
10 HIV Prevention
11 References
12 Authors

Introduction

HIV stands for Human Immunodeficiency Virus. HIV is a retrovirus, meaning that it inserts itself into a cell, then, inserts itself into the DNA of that cell. When the cell is replicated, it will create more infected cells, spreading HIV throughout the body. There are different types of monkeys, apes, and animal species that can be affected by HIV, but humans are also affected by HIV. There are two categories of HIV: HIV-1 and HIV-2. A person can be infected with either form of HIV or both forms of HIV [1]. There are also two categories of HIV proteases: HIV-1 protease and HIV-2 protease. HIV-1 protease is highly researched, while HIV-2 protease is lacking research. This is likely due to the fact that HIV-1 is more transmissible and more likely to lead to AIDS [2]. AIDS stands for Acquired Immune Deficiency Syndrome [4]. HIV can cause AIDS. Moreover, HIV-1 and HIV-2 proteases are targets for drug treatments of HIV. Proteases are enzymes that break down proteins into amino acids [4]. Proteases evolved early in protein evolution playing a role in amino acid creation and catabolism [4]. HIV-1 and HIV-2 proteases are aspartic proteases. Aspartic proteases are proteolytic enzymes in the pepsin family [5].

Structural Highlights of HIV-1 protease

There are hundreds of forms of HIV-1 proteases. The basic HIV-1 protease contains two subunits that are homodimers [10]. These subunits contain beta sheets running antiparallel to each other, and random coils. The beta sheets are in a jelly roll fold conformation. In the middle of the homodimer is the active site. Below the active site are the catalytic aspartates. At the bottom of the molecule is the . This structure highlighted to the right is a wild type of HIV-1 protease, PDB code 1d4s. Notice in this wild type, there are molecules bound to the active site. This HIV-1 protease, 1d4s, is a wild type with catalytic aspartates, a flap domain, an elbow, and a core domain [10]. In other mutant forms, molecules are bound to other regions. In the mutant molecules are not bound at the active site. Different mutants and wild types have different molecules bound to the active site, making different versions of HIV-1 protease. Some versions are more easily controlled by drugs, such as protease inhibitors, while other versions are more drug-resistant. It is difficult to determine which form of HIV-1 protease a person has, and each case of HIV-1 has to be treated on a case basis because there are so many mutants and wild types [10]. Immunodeficiency virus protease

Structural Highlights of HIV-2 protease

HIV-2 protease is similar to HIV-1 protease because it has the beta sheets in the jelly fold conformation, the alpha helix, and the random coils.

HIV-1 Protease in Humans

HIV-1 is more transmissible than HIV-2 and is more likely to lead to AIDS in a patient. HIV-1 protease is a GagPol polyprotein [2]. HIV-1 protease belongs to Clan AA, family A2 of the aspartic proteases. Aspartic proteases are the smallest group of proteases found in humans [2].

HIV-2 Protease in Humans

As it is less transmissible, there are not as many complete crystal structures of HIV-2 protease. Research suggests that HIV-1 protease and HIV-2 protease are not vastly different in amino acid makeup, however, the small differences between the two make for large differences in treatment. There are four main amino acid positions that are different between HIV-1 protease and HIV-2 protease: 32, 47, 76, and 82 [6]. The research concludes that replacing these four amino acid active sites with amino acids in HIV-1, I32V, V47I, M76L, and I82V, will result in a protease that functions as HIV-1 protease [6].

The role of CD4+ T cell

The CD4+ T cell is a lymphocyte, also known as a white blood cell, that fights infection. HIV attacks the CD+ T cell by binding and replicating through the CD4 + T cell. HIV-1 and HIV-2 protease kills CD4+ T cells which results in low immunity. An HIV-infected person with very low CD4+ T cells can develop AIDS. AIDS stands for acquired immune deficiency syndrome. HIV can remain latent in the body through memory T cells. Because HIV can remain latent in the body, patients with HIV can experience periods without symptoms. Patients who do die from HIV/AIDS die from secondary infections because of their compromised immunity from low CD4+ T cells. Most infections that kill HIV/AID patients are opportunistic infections. Research suggests that HIV-1 is better at killing CD4+ T cells than HIV-2. This is one reason why HIV-1 is more likely to progress into AIDS than HIV-2 [7].

Protease Inhibitors for HIV-1 Treatment

For HIV-1, protease inhibition is one method of five methods for controlling HIV-1. The HIV-1 protease protein is encoded within the pol gene. This gene holds the information for the replication of HIV. This means that the gene holds HIV-1 protease, as well as reverse transcriptase and integrase proteins [8]. HIV-1 protease inhibitors are a method of treatment for HIV-1. However, HIV-1 protease inhibitors can lead to mutations within an individual and this is why they are classified as a treatment, but not a control. It is a constant chase to find which PR inhibitor works for a patient, and for how long it will work[8]. HIV-1 protease inhibitors work by binding to the protease to prevent the protease from breaking down proteins [4]. Molecular Playground/HIV Protease Inhibitor

Protease Inhibitors for HIV-2 Treatment

HIV-2 is less pathogenic, meaning it has a lower transmittance rate, so there tends to be less research and less money put into HIV-2 treatments. This also means that there is less research on HIV-2 protease compared to HIV-1 protease. Research states [9]. Effective protease inhibitors stop HIV-2 from replicating itself. There are four residues in the protease that lead to protease inhibitor resistance in HIV-2 [6]. There are only three out of nine approved protease inhibitors (PIs) that are effective against HIV-2 [6].

Evolution's Role

Due to the nature of HIV, many drug-resistant variants occur. Every time a new patient is infected with HIV, there is a chance that a new HIV protease mutation will arise. It is important that society and scientists remain vigilant in the fight against HIV. Mutations in the HIV-1 and HIV-2 proteases lead to drug resistance to HIV. [11].

HIV Prevention

Prevention plays an important role in public health in limiting HIV infection rates [3]. Even with partners who both have HIV, safe sex is important because it is difficult to determine HIV-1 infections, and HIV-2 infections, from dual infections [1]. Furthermore, a partner of a patient with HIV is suggested to take preventative medicine.

References

1. Blassel, L.; Zhukova, A.; Villabona-Arenas, C. J.; Atkins, K. E.; Hué, S.; Gascuel, O. Drug Resistance Mutations in HIV: New Bioinformatics Approaches and Challenges. Current Opinion in Virology 2021, 51, 56–64.

2. Huang, L.; Chen, C. Understanding HIV-1 Protease Autoprocessing for Novel Therapeutic Development. Future Medicinal Chemistry 2013, 5 (11), 1215–1229.

3. Hønge, B. L.; Jespersen, S.; Medina, C.; Té, D. S.; da Silva, Z. J.; Christiansen, M.; Kjerulff, B.; Laursen, A. L.; Wejse, C.; Krarup, H.; Erikstrup, C. The Challenge of Discriminating between HIV-1, HIV-2 and HIV-1/2 Dual Infections. HIV Medicine 2018, 19 (6), 403–410.

4. López-Otín, C.; Bond, J. S. Proteases: Multifunctional Enzymes in Life and Disease. Journal of Biological Chemistry 2008, 283 (45), 30433–30437

5. Mahdi, M.; Szojka, Z.; Mótyán, J.; Tőzsér, J. Inhibition Profiling of Retroviral Protease Inhibitors Using an HIV-2 Modular System. Viruses 2015, 7 (12), 6152–6162.

6. Tang, J.; Wong, R. N. Evolution in the Structure and Function of Aspartic Proteases. Journal of Cellular Biochemistry 1987, 33 (1), 53–63.

7. Raugi, D. N.; Smith, R. A.; Gottlieb, G. S. Four Amino Acid Changes in HIV-2 Protease Confer Class-Wide Sensitivity to Protease Inhibitors. Journal of Virology 2016, 90 (2), 1062–1069.

8. Tie, Y.; Wang, Y.-F.; Boross, P. I.; Chiu, T.-Y.; Ghosh, A. K.; Tozser, J.; Louis, J. M.; Harrison, R. W.; Weber, I. T. Critical Differences in HIV-1 and HIV-2 Protease Specificity for Clinical Inhibitors. Protein Science 2012, 21 (3), 339–350.

9. Vidya Vijayan, K. K.; Karthigeyan, K. P.; Tripathi, S. P.; Hanna, L. E. Pathophysiology of CD4+ T-Cell Depletion in HIV-1 and HIV-2 Infections. Frontiers in Immunology 2017, 8.

10. Venkatakrishnan, B.; Palii, M.-L.; Agbandje-McKenna, M. Mining the protein data bank to differentiate error from structural variation in clustered static structures: An examination of HIV protease. Viruses 2012, 4(3), 348-362.

11. Weber, I. T.; Wang, Y.-F.; Harrison, R. W. HIV Protease: Historical Perspective and Current Research. Viruses 2021, 13 (5), 839.

Authors

Meg Burrows and Jynna Harrell

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1735"

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 == Structural Highlights of HIV-1 protease==
-There are hundreds of forms of HIV-1 proteases. The basic HIV-1 protease contains two subunits that are homodimers [10]. These subunits contain beta sheets running antiparallel to each other, and random coils. The beta sheets are in a jelly roll fold conformation. In the middle of the homodimer is the active site. Below the active site are the catalytic aspartates. At the bottom of the molecule is the <scene name='91/919044/Dimerization_regions/1'>dimerization region</scene>. This structure highlighted to the right is a wild type of HIV-1 protease, PDB code 1d4s. Notice in this wild type, there are molecules bound to the active site. This HIV-1 protease, 1d4s, is a wild type with catalytic aspartates, a flap domain, an elbow, and a core domain [10]. In other mutant forms, molecules are bound to other regions. In the mutant 3hvp molecules are not bound at the active site.
+There are hundreds of forms of HIV-1 proteases. The basic HIV-1 protease contains two subunits that are homodimers [10]. These subunits contain beta sheets running antiparallel to each other, and random coils. The beta sheets are in a jelly roll fold conformation. In the middle of the homodimer is the active site. Below the active site are the catalytic aspartates. At the bottom of the molecule is the <scene name='91/919044/Dimerization_regions/1'>dimerization region</scene>. This structure highlighted to the right is a wild type of HIV-1 protease, PDB code 1d4s. Notice in this wild type, there are molecules bound to the active site. This HIV-1 protease, 1d4s, is a wild type with catalytic aspartates, a flap domain, an elbow, and a core domain [10]. In other mutant forms, molecules are bound to other regions. In the mutant <scene name='91/919044/Mutant/1'>3hvp</scene> <scene name='91/919044/Mutant/1'> 3hvp</scene> molecules are not bound at the active site. Different mutants and wild types have different molecules bound to the active site, making different versions of HIV-1 protease. Some versions are more easily controlled by drugs, such as protease inhibitors, while other versions are more drug-resistant. It is difficult to determine which form of HIV-1 protease a person has, and each case of HIV-1 has to be treated on a case basis because there are so many mutants and wild types [10]. [[Immunodeficiency virus protease]]
-<Structure load='3hvp' size='250' frame='true' align='right' caption='HIV-1 PR mutant' scene='3hvp mutant' />
-Different mutants and wild types have different molecules bound to the active site, making different versions of HIV-1 protease. Some versions are more easily controlled by drugs, such as protease inhibitors, while other versions are more drug-resistant. It is difficult to determine which form of HIV-1 protease a person has, and each case of HIV-1 has to be treated on a case basis because there are so many mutants and wild types [10]. [[Immunodeficiency virus protease]]
 ==Structural Highlights of HIV-2 protease==