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 (Hønge et. al, 2018). 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 (Huang et. al, 2013). AIDS stands for Acquired Immune Deficiency Syndrome. 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 (López-Otín et. al, 2008). “Proteases likely arose at the earliest stages of protein evolution as simple destructive enzymes necessary for protein catabolism and the generation of amino acids in primitive organisms” (López-Otín et. al, 2008). HIV-1 and HIV-2 proteases are aspartic proteases. “Aspartic proteases (EC3.4.23) are a group of proteolytic enzymes of the pepsin family that share the same catalytic apparatus and usually function in acid solutions” (Tang et. al, 1987).
Structural Highlights of HIV-1 protease
There are hundreds of forms of HIV-1 protease. The basic HIV-1 protease contains two subunits that are dimers. These subunits contain an alpha helix, 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 dimer is the active site. The full image of the PDB 3hvp represents the dimer of HIV-1 protease. Mutants have different molecules bound to the active site, making different mutants of HIV-1 protease. Some mutants are more easily controlled by drugs, such as protease inhibitors, while other mutations 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. This particular mutant, PBD 3hvp, is bound drug resistant.
Structural Highlights of HIV-2 protease
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 (PR) is a virus-encoded proteolytic enzyme that is initially systemized as part of the GagPol polyprotein” (Huang et. al, 2013). HIV-1 protease belongs to Clan AA, family A2 of the aspartic proteases. Aspartic proteases are the smallest group of proteases found in humans (Huang et. al, 2013).
HIV-2 Protease in Humans
As it is less transmittable, 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. “The determinants of intrinsic PI resistance in HIV-2 are unknown, but previous studies have identified just four residues in the protease binding cleft, at amino acid positions 32, 47, 76, and 82, that differ between HIV-1 and HIV-2” (Raugi et. al, 2016). The research concludes, “We report, for the first time, that replacing four active-site amino acid residues in HIV-2 protease with the corresponding amino acids from HIV-1 (I32V, V47I, M76L, and I82V) results in a replication-competent virus which exhibits a pattern of class-wide PI sensitivity comparable to that of HIV-1” (Raugi, et. al, 2016).
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 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 (Vijayan et. al, 2017).
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 (Blassel et. al, 2021). 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 (Blassel et. al, 2021). HIV-1 protease inhibitors work by binding to the protease to prevent the protease from breaking down proteins. (López-Otín et. al, 2008).
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, “Currently used PIs are designed against HIV-1, and their effect on HIV-2 is understudied” (Mahdi et. al, 2015). Effective protease inhibitors stop HIV-2 from replicating itself. A research study concludes, “Our findings show that four residues in the protease binding pocket are the primary determinants of intrinsic PI resistance in HIV-2”(Raugi, et. al, 2016). There are only three out of nine approved protease inhibitors (PIs) that are effective against HIV-2 ((Raugi, et. al, 2016).
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. Research concludes, “Resistance to PR inhibitors arises primarily by mutations in PR, although other mutations also occur in its Gag and Gag-Pol substrates [69]. Major mutations associated with resistance are often deleterious for viral replication [70]; however, viral fitness can be restored by additional, compensatory mutations” (Weber et. al, 2021).
HIV Prevention
Prevention plays an important role in public health in limiting HIV infection rates. Even with partners who both have HIV, safe sex is important because it is difficult to determine HIV-1 infections, from HIV-2 infections, from dual infections. (Hønge et. al, 2018). Furthermore, a partner of a patient with HIV is suggested to take preventative medicine.
References
Authors
Meg Burrows and Jynna Harrell
