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Research Papers
Research Papers
This page contains summaries of research papers reviewed and discussed during the course.
Basic Immunology and Immunotherapy - PAPER 1
The premise of Basic Immunology and Immunotherapy tackles the most basic concepts of Immunology, specifically, the two lines of defense in Immunology, referred to as innate immunity and adaptive immunity. These mechanisms are complementary in nature for providing an effective immune system, carrying out functions in which the other system lacks.
Innate immunity is the first, non-specific mechanism in which it functions as the first line of defense to a pathogen entering the body. The innate immune mechanism is antigen-independent, responding to infections based on pattern recognition receptors (PRR). Innate immunity response covers several cell types and processes to perform the elimination of pathogens in the body at a rapid pace. Innate immune cells, such as phagocytes, mast cells, basophils, and eosinophils use degranulation, phagocytosis and antigen presentation to inactivate the pathogens.
Adaptive Immunity is antigen-specific and responds based on the mechanism’s capacity for immunologic memory should the body be exposed to the same pathogen. Critical processes of adaptive immunity depend on the regulated reciprocation of T cells, B cells and APCs. These cells perform functions that develop the immunologic memory of the adaptive immune system, leading to effective immune responses upon recurring pathogens. As the relationship between adaptive and innate immune systems are not mutually exclusive, there is an essential synergy for the mechanisms to correlate. This means that defects or malfunction in either system could lead to disorders regarding immunopathology.
Link to Source Paper: Marshall, Jean S., et al. “An Introduction to Immunology and Immunopathology.” Allergy, Asthma & Clinical Immunology, vol. 14, no. S2, Sept. 2018, https://aacijournal.biomedcentral.com/counter/pdf/10.1186/s13223-018-0278-1
Update on the Epidemiology and Prevention of HIV/AIDS in the United States - PAPER 2
Over the past few decades, the Human immunodeficiency virus (HIV) has been occurring in the US population continuously. In the past, stigma and avoidance did not adequately prepare education on preventing the acquisition of HIV. However, in recent years, more understanding and contextual background of HIV is intended to protect the general public's safety. Education and access to accurate information can contribute to HIV epidemic control and prevention, ensuring society is informed of recent developments. Through the epidemiology analysis in HIV/AIDS, measuring surveillance data, incidence, prevalence, mortality, and disparities are essential in updating the latest information and data on HIV transmission. These factors account for the HIV prevalence rates, survival rates and mode of transmission in contextual backgrounds.
Furthermore, to completely understand the current contextual background of HIV/AIDS, the HIV continuum of care identifies the ability to diagnose, care for and treat HIV patients chronologically. This accounts for viral suppression as an ultimate result of treatment in HIV patients. The development of prevention in HIV is pivotal in decreasing HIV rates in the US population as well; this counts for behavioral, biomedical, and structural approaches to HIV prevention. The primary goal for these approaches historically is to reduce HIV-related risk behavior. The behavioral approach system does so through marketing campaigns, counseling and health application interventions. Studies on biomedical approaches to HIV prevention include concepts such as post-exposure prophylaxis and antiretroviral treatment. The structural approach system accounts for several aspects of HIV patients, including reducing stigma or offering HIV prevention services. Through these studies and approaches to the prevention and analysis of HIV/AIDS, communities can come together and contribute to developing the reduction of HIV rates nationally.
Link to Source Paper: Castel, Amanda D et al. “Update on the Epidemiology and Prevention of HIV/AIDS in the United States.” Current epidemiology reports vol. 2,2 (2015): 110-119. doi:10.1007/s40471-015-0042-8 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422075/
Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation - PAPER 3
HIV-1, also known as human immunodeficiency virus type 1, is an RNA disease in correlation to the immune system, specifically the binding of itself to CD4 receptors on helper T-cells, interacting with CCR5 and the CXC chemokine receptor (CXCR4) as a result. This leads to the deletion of CD4+ T cells, ultimately weakening the immune system and allowing for pathogens to invade the body. As of now, HIV-1 has not found an effective cure to apply onto the population. In principle, the CD4 receptor and chemokine receptor 5 (CCR5) are essential for HIV to infect helper T-cells. This indicates that homozygosity of a 32-bp deletion in the CCR5 results in increased resistance to HIV-1 infection. Through stem-cell transplantation with an HLA-identical donor, HIV patients can gain this 32-bp deletion and develop high resistance to HIV-1.
In a particular patient, the outcome of inactive HIV rebound has been studied from this stem-cell transplantation. Methodology in Stem-Cell Transplantation of the CCR5 delta 32 mutation tackles procedures such as CCR5 genotyping, Chimerism and Viral-Envelope genotyping. Such strategies include using DNA extraction for sequencing and engineering or the chimeric analysis of the stem-cell transplant to regulate engraftment within the patient.
Link to Source Paper: 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/
Cellular and Humoral Immune Response to HIV-1
HIV Replication - PAPER 4
In the advancements of understanding the relationship between HIV-1 and the innate sensing of HIV in the body, the HIV-1 reverse transcription process (RTIs) can be identified and detected by pattern recognition receptors (PRRs) in the innate immune system. The IFN system is activated upon detection of HIV, which stimulates an antiviral interferon response. PRRs are responsible in detecting specific pathogens through pathogen-associated molecular patterns (PAMPs); this includes the detection of HIV. The groups of PRRs are divided into two, both critical in identifying the HIV genome. Membrane-bound receptors such as toll-like receptors (TLRs) and cytoplasmic receptors such as cyclic GMP-AMP synthase (cGAS) stimulate the IFN system, eliciting an interferon response to specific pathogens. However, HIV suppresses these mechanisms by blocking TLR signaling pathways and cloaking nucleic acids in the cytoplasm. Although these interferences have evolved overtime to avoid HIV detection within the body, these inhibiting mechanisms are considered imperfect. The activation of the interferon regulatory 3 factors (IRF3), NF-kB and various other transcription factors in the immune system is induced through HIV counteractive mechanisms. The relationship between these components plays a significant role in causing chronic inflammation of HIV, leading to AIDS.
This elucidates that human innate systems can detect the HIV-1 reverse transcription process through certain receptors and induction of interferon responses, even as a stealth virus. HIV also uses accessory proteins as counteractive mechanisms to suppress these immunological responses. Therefore, through a thorough understanding of the potential advantages and disadvantages of the innate system against HIV-1, the road for further advancements into antiviral vaccines can be paved to improving AIDS treatment.
Link to Source Paper: Sauter, Daniel, and Frank Kirchhoff. “HIV replication: a game of hide and sense.” Current opinion in HIV and AIDS vol. 11,2 (2016): 173-81. doi:10.1097/COH.0000000000000233 https://pubmed.ncbi.nlm.nih.gov/26628325/
HIV Infection - PAPER 5
Human Immunodeficiency Virus (HIV) is an infection that causes the progressive loss of CD4+ T-cells, resulting in increased host immunodeficiency. HIV patients are, therefore more likely to acquire infectious and oncological pathogens, which can pose lethal threats to the body. During an HIV infection, the HIV binds to the surface of a CD4+ T-cell. HIV proteins are expressed from the infected host CD4+ cell as a result, which assemble into immature HIV at the cell's surface. Proteases in turn are released to induce the immature HIV to mature HIV, allowing more CD4+ T-cells to get infected and killed. The average CD4+ T-cell count on an adult ranges from 500 cells to 1200 cells. As the HIV infection progresses, cell count reduction to <350 cells per microlitre, the host's growing immunodeficiency increases the risk of acquiring several infectious complications as the cell count declines. As the progressive loss of CD4+ T-cells becomes chronic, the degree to which HIV infection spreads progresses into Acquired Immunodeficiency Syndrome (AIDS).
To HIV prevention, HIV vaccines are being tested through clinical trials to be effective. The production of HIV vaccines is considered challenging however, due to the varying immunological responses and stimuli that respond in diversity. Over the years, this allowed newer strategies to be evaluated, such as generating balanced cellular immune responses or inducing more neutralizing antibodies (NAb) as a defense mechanism for pathogens. Combination Antiretroviral Therapy (ART) has recently been used to regulate and manage HIV in patients. Approximately 25 antiretroviral drugs in variance have been approved for use in the US.
During prototypic HIV infection, the transmitted virus first infects target cells in mucosal tissues and then spreads through the lymphoid system
As effective as ART proves to be, the recent developments regarding a cure for HIV points to the CCR5 delta32 mutation stem cell transplantation, in which donors with this mutation attain a higher resistance to the HIV-1 infection. Therefore HLA-matched stem cell transplantation of the CCR5 delta32 mutation gives the possibility of HIV patients developing a high resistance to the HIV genome as well. In recent years, HIV prevention, treatment and education advancements have influenced the betterment of human life, and possibly a definite cure to HIV as a whole.
Link to Source Paper: Deeks, Steven G et al. “HIV infection.” Nature reviews. Disease primers vol. 1 15035. 1 Oct. 2015, doi:10.1038/nrdp.2015.35 https://pubmed.ncbi.nlm.nih.gov/27188527/
HIV reservoirs: What, Where and How to target them - PAPER 6
A viral reservoir is defined as either an anatomical site or cell type in which viruses continue to accumulate and persist in replication. HIV reservoirs are known to consist of long-lived memory CD4+ helper T cells as well as other T cell subsets and lymphocytes. These play a role in contributing to fueling the HIV reservoir in a host, however the discussion of differing cell types contributing to the constitution of the HIV reservoir may be considered controversial beyond CD4+ T cells. The memory CD4+ T cell population harbors nearly all replication-competent viruses during ART, this is in particular to the constitution of HIV reservoirs and the high cell count of latent infected cells despite long-term treatment. The question of whether differing cell types are able to persist as an infected state in long-term ART is unclear, therefore making the topic of HIV reservoirs consisting of other cell types controversial in nature.
Other discussions regarding HIV reservoirs not only argue through constitutions of these HIV reservoirs but the tissues that harbor these HIV reservoirs in the first place. Some tissues and organs such as the gut-associated lymphoid tissue (GALT) may consist of latently infected cells but whether cells of that type from other organs contribute to the reservoir is undetermined. A general agreement upon this discussion is in how CD4+ T cells can be expressed and contribute to the reservoir at any tissue of T cell abundance. These cells generally reside in the secondary lymph nodes, the gut mucosa and the spleen. However the degree to which these areas harbor replication-competent viruses is not distinct. Other key factors in terms of person-to-person variability also have to be accounted for. Factors such as: age, gender, ART duration and viral subtypes can influence the overall distribution and effect of latent cells in HIV reservoirs. As a result of these discussions, latent HIV-infected cells are prevalent in various areas of the body, but the degree to which the virus persists during ART remains uncertain for the time being.
The barrier of undetected latently infected CD4+ T cells in eradication is consistently prevalent throughout the search for an ending treatment to HIV. In latent infection, the most agreed strategy among experts (Churchill et al, 2016) is the supposed ‘kick and kill’ strategy, which is currently a leading study of treatment used to activate latent and undetected HIV infected cells for the immune system to identify. This is considered one of the more logical strategies in curing HIV, with the process of ‘kick and kill’ strategy directly confronting the latent cells. While HIV is in its latent state, it is essentially impossible for the immune system to detect the infected cells as there is no viral activity in its resting state. To counter this, drugs called latency-reversing agents are inserted to reactivate latent cells, allowing them to be detectable by the immune system and targeted to be eliminated by either the body’s immune system or anti-HIV drugs.
Link to Source Paper: Churchill, Melissa. “HIV Reservoirs: What, Where and How to Target Them.” Nature, 30 Nov. 2015, www.nature.com/articles/nrmicro.2015.5.
Past, Present and Future: 30 years of HIV research
In the current search for a cure in HIV research, it’s important to understand the natural history of HIV as a virus and the milestones that researchers achieved to get society this far with HIV. These milestones highlight a historical perspective as to how the studies accumulated in the past 30 years have affected the studies now, and the shift of HIV-1 as a lethal and incurable disease to a more manageable chronic disease serves as a reminder of the effect that biomedical research has on healthcare in society. During 1981, the first few cases of AIDS were observed epidemiologically. This was a part of HIV-1[‘s first strain in the epidemic that arose with MSM (men who have sex with men) initially, but traveled through the general population through drug usage or blood transfusions. This epidemic led investigators to attempt at isolating the retrovirus, succeeding in 1983 where they identified it as HIV-1. At that time, there was a new human retrovirus called lymphadenopathy-associated virus (LAV), which was isolated in Paris, France at the origin of a lymph node biopsy sample from a patient with general lymphadenopathy. Within the same year, other similar viruses were isolated from patients with AIDS and later confirmed that HIV indeed causes AIDS. This is the first diagnosis of the HIV infection and served as a basis for HIV research. In 1984, after the isolation of HIV-1, the CD4 cell surface molecule was identified as the main receptor for HIV, reinforcing the rationale for maintaining CD4+ cell counts in hopes of finding a cure. The basic information discovered during the search for a treatment in HIV paved the way for growing knowledge. In 1985, molecular cloning and subsequent nucleotide sequencing of the virus took place. This allowed investigators to exact data of genomic information as well as provide evidence of other strains such as HIV-2.
For several years at a time, continued research and information continued to add onto the HIV research. This eventually led to the continued promotion of education in prevention and awareness of risk factors with HIV, emphasizing the importance of condom usage in target populations. This also accumulated into the first large milestone of HIV treatment, which provided evidence that antiretroviral therapy (ART) was effective in terms of managing symptoms and preventing mother-to-child transmission of HIV. Currently, the usage of ART has proved most effective in preventing HIV transmission with MSM as well, showing a 96% reduction in transmission rate. Therefore it was concluded that more combination strategies may provide the most progress in HIV reduction and maintenance.
In the insight for the future of HIV progress, research regarding elimination of latent viruses in HIV reservoirs or usage of stem cell transplantation as a treatment in HIV have improved as a whole. But despite the progress being made, it is important to take note that 34 million people still currently live with HIV worldwide. Therefore, biomedical science must continue to push towards a potential cure for HIV through identification of new biomarkers, discoveries of treatments as well as continuing the implementation of combination strategies.
Link to Source Paper: Barré-Sinoussi, Françoise et al. “Past, present and future: 30 years of HIV research.” Nature reviews. Microbiology vol. 11,12 (2013): 877-83. doi:10.1038/nrmicro3132, https://pubmed.ncbi.nlm.nih.gov/24162027/
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