Human Immunodeficiency Virus
Extended Research Project by Jaein Kho
Chinese International School Manila
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Introduction
The study of Molecular Medicine tackles the fundamentals of pathophysiology in disease and how certain treatments are developed to counteract these diseases. The word “molecular” refers to the combination or production of molecules, particularly in the human body. This showcases the importance of studying even the slightest shifts at a molecular level in order to understand the pathogenesis of diseases. As broad as the field of molecular medicine is, the studies of different areas of knowledge within the field itself contributes to a larger understanding of innovative technology within the biological sciences.
In Immunology, Molecular Medicine is important in several diseases including those of an infectious nature. Diseases such as HIV, COVID-19 and SARS-CoV rely on the consistent developments of molecular medicine in order to be regulated and/or eliminated. Although Molecular Medicine plays a large role in immunological diseases, the prevalence of Molecular Medicine in other medical diseases of an oncological nature or hereditary nature is significant.
Molecular Medicine focuses particularly on the molecular basis of diseases altogether, bringing in topics such as Biochemistry, Genetics and Clinics into play. It's important to note that the best outcome in Molecular Medicine focuses on high prevention of disease in the first place, therefore risk factors and prevention procedures are greatly advocated in the field itself.
Review of Molecular Medicine in HIV/AIDS
Review of Molecular Medicine in HIV/AIDS
Molecular Medicine contributes, if not, to the most significant part of HIV/AIDS treatment. Antiretroviral Therapy (ART) is groundbreaking in the ability for drugs to maintain a high quality of life in HIV patients, essentially providing as an effective treatment for the virus as a whole. HIV patients under the treatment of ART therapy takes a standard combination of drugs developed specifically catered to a patient's characteristics in HIV, much like the Hallmarks of Cancer. This combination aids in increasing resistance and mutation of the HIV within the patient. This does not cure the virus however, and patients of HIV regularly have to take ART therapy in order to continue their daily lives with little to no disturbance from HIV. Currently, there are five drug classifications in ART:
Nucleoside Reverse Transcriptase Inhibitors
Integrase Strand Transfer Inhibitors
Non-Nucleoside Reverse Transcriptase Inhibitors
Protease Inhibitors
Chemokine Receptor Antagonists (CCR5 antagonists)
Figure 1; ART therapy corresponding to the stages of HIV infection, Volberding, Paul A, and Steven G Deeks. “Antiretroviral Therapy and Management of HIV Infection.” The Lancet, Elsevier, 3 July 2010, https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2960676-9/fulltext.
However, even as effective as ART therapy can be, new modifications in biotechnology have paved the way for more radical solutions in maintaining HIV. CAR-T cells, also known as modified T-cells are involved in the treatment of cell therapy in which cells may be engineered and modified to insert into a patient through allogenic or autologous means. This therapy in use of CAR-T cells include the treatment of various types of cancer including: Acute lymphoblastic leukemia, and non-Hodgkin lymphoma. In cancer patients, CAR-T cell therapy makes use of T-cell signaling to produce chimeric antigen receptors (CARS) in order to eliminate tumors, preventing metastasis within the body.
Figure 2; HIV infection with CCR5 gene and CCR5 delta32 gene, Xu, MengMeng. “CCR5-Δ32 Biology, Gene Editing, and Warnings for the Future of CRISPR-Cas9 as a Human and Humane Gene Editing Tool - Cell & Bioscience.” BioMed Central, BioMed Central, 30 Mar. 2020, https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-020-00410-6.
Thus, the investigation of CAR-T cells and the involvement of the treatment in HIV patients has led to the discovery of the CCR5 delta32 gene. The CCR5 delta32 gene and it's properties are found to be integral to the recent case studies regarding a cured HIV patient. The CCR5 delta32 gene was transferred through an umbilical cord stem cell to bone marrow transplantation, in which the patient had gradually developed a high resistance to the HIV. This suggests that the CCR5 delta32 gene carries a property that brings a high resistance to HIV in humans. The patient in question was announced cured of HIV after 10 months of maintenance and regulation. The treatment of CCR5 delta32 stem cell transplantation is not a generalized therapy that can be used across populations, however it provides insight into the future of medicine for HIV.
Research and Development in Molecular Medicine
As stated, Molecular Medicine offers a wide range of in-depth disease pathologies in order to develop medicine and treatments. These processes often include the involvement of biological molecular techniques that aid in drug development, clinical trials, biomedical research etc. It’s important to take note that molecular techniques vary depending on the nature of the disease, hence molecular techniques are not applicable to every laboratory. Due to the broad range of molecular techniques used throughout the course of biomedical research, common techniques such as:
Genome Sequencing
Hybridization Methods
Polymerase Chain Reaction
Protein isolation & purification
Restriction Fragment Length polymorphism
Restriction Enzymes
Genome Sequencing - Genomic Sequencing tackles the splicing and rearrangement of DNA nucleotides in a genome. This is significant in understanding the functions of certain genes as well as other factors such as location, growth and development. In Genomic Sequencing, the DNA nucleotides are spliced by pieces in order to reconstruct the sequence using strategies such as the “clone-by-clone” strategy or the “whole-genome-shotgun” strategy. Essentially, genomic sequencing can also apply to techniques such as genetic engineering, which modifies and reassembles genes for treatment in modern biomedicine.
Hybridization Methods - Hybridizations Methods consist of the usage of DNA and RNA to detect, identify and compare nucleic acid sequences. The process of hybridization involves the melting and reannealing of single-stranded DNA strands. According to Chargaff’s rules in complementary base pairing, two strands of DNA interact with each other through hydrogen bonds between complementary base pairs. The purine-pyrimidine base pairing holds together both of the strands, so while adenine pairs with thymine, guanine and cytosine are always paired in opposite strands.
Polymerase Chain Reaction - PCR is the synthesis and amplification of DNA sequences, and this process allows for the numbers of specific DNA sequences to be amplified in little time. Applications of PCR include HLA typing or the detection of pathogens. Methods and specific enzymes are used in particular due to the large complexity of genomic expression. Each individual has minor genetic differences in base sequences, forming variations of genomes worldwide. Therefore, the significance of mutation detection is prevalent in humans as the specificity and variety complicate the identification processes.
Protein Isolation and Purification - Protein Purification is a process which involves the isolation of one or more proteins from a mixture. This is done through a technique called centrifugation, where mixtures are slotted and spun in an axis. The result of this process would have the mixture components according to their size, shape, density, medium viscosity and rotor speed.
Restriction Enzymes - Specific endonucleases detect sequences of DNA phosphodiester bonds and cleave them; this is called a restriction enzyme. These recognition sequences typically vary from 4 or 6 bases to 5 or 8. These aid in isolating genes and diagnosing DNA sequences in modern medicine, making restriction enzymes indispensable in the medical field.
Restriction Fragment Length Polymorphism - RFLP (restriction fragment length polymorphism) is an allele identified based on either the presence or absence of a restriction enzyme site. These polymorphisms affect how proteins interact and contribute to phenotypic differences among individuals. Therefore polymorphisms such as RFLPs or SNPs (single nucleotide polymorphism) acting as biological markers contribute to the location of genetic mutations in the body, playing an essential role in the medical field.
Therapies and Treatments in Molecular Medicine
Molecular Therapy handles treatments that utilize drugs, substances or molecular techniques to treat patients. This can be used in various kinds of diseases in accordance with a specific type of therapy. The types of therapies include: Gene Therapy, Cell therapy, Gene/Cell Therapy and Cancer Therapies.
In Gene Therapy, a gene that has been genetically modified to give therapeutic properties is transplanted into a patient’s cells to treat diseases such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS. Gene therapy is additionally used to replace mutated genes or strengthen the immune system’s signaling for faster processing of elimination of pathogens. The risks associated with gene therapy can include side effects from the host body itself. This can result in constant inflammation or unwanted reactions from the immune system such as targeting the wrong cells inside the body.
Similarly, Cell therapy refers to a cell with therapeutic properties being transplanted into a patient to treat diseases such as spinal cord injuries, type 1 diabetes, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, heart disease, stroke, burns, cancer and osteoarthritis. Cell Therapies used today can be seen through CAR T cell therapy and Stem Cell therapy in particular.
Conclusion
In understanding Molecular Medicine it is possible to grow more potential in developing newer and more innovative treatments for incurable diseases of today. The study of Molecular Medicine allows for the research of specific subfields and the development of drugs within the pharmaceutical industry itself. Cutting-edge technology and methods are being developed sooner rather than later due to this surge in innovation and knowledge of molecular medicine and biomedical engineering; Therefore, contributing to better healthcare in society.
Sources
Davis, UC. “Could CAR T Cells Offer Hope for an HIV Cure?” News, 6 June 2022, www.health.ucdavis.edu/news/headlines/could-car-t-cells-offer-hope-for-an-hiv-cure/2022/03.
“Antiretroviral Therapy - PAHO/WHO | Pan American Health Organization.” www.paho.org/en/topics/antiretroviral-therapy#:~:text=Antiretroviral%20therapy%20(ART)%20is%20treatment.
Hütter, Gero et al. “Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation.” The New England journal of medicine vol. 360,7 (2009): 692-8. doi:10.1056/NEJMoa0802905 https://pubmed.ncbi.nlm.nih.gov/19213682/
“What’s a Genome?” Genomenewsnetwork.org, 2019, www.genomenewsnetwork.org/resources/whats_a_genome/Chp2_1.shtml.
Study.com, 2022, www.study.com/learn/lesson/dna-hybridization-technique-examples.html.
“Centrifugation - an Overview | ScienceDirect Topics.” Www.sciencedirect.com, www.sciencedirect.com/topics/agricultural-and-biological-sciences/centrifugation#:~:text=Centrifugation%20is%20a%20method%20of.
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