Abstract
The current antiretroviral drugs have been efficient in the management of HIV by suppressing the virus's replication. It has, therefore, helped in changing this virus from a deathly disease to a chronic infection. The utilization of extremely active antiretroviral therapy (HAART) calls for a lifetime prescription to prevent viral rebound by reducing the viral load to undetectable low levels. This high maintenance of treatment and the various side effects of the drugs and non-HIV related morbidity have led to the need for a better form of therapy. There has been an extensive study on stem cell manipulation done to develop gene therapy for HIV treatment. Hematopoietic stem cell-based gene therapy has proven to be a promising approach in the treatment of this viral disease. This study looks at the potential to provide a life-long cure for HIV without the requirement for daily treatment. This therapy targets reconstruct the immune system of a patient by transplanting genetically modified hematopoietic stem cells with anti-HIV genes. This gives it great potential in providing a lifetime eradication of the virus by a single treatment. This paper covers the application of gene therapy technology, advantages as well as limitations, and the legal and ethical issues of the therapy.
Introduction
Human Immunodeficiency Virus infects the human CD4+ T cells. When not managed, the virus progresses, causing Acquired Immune Deficiency Syndrome (AIDS), which is the later phase of the disease. It was first discovered in 1981 when five men were treated for Pneumocystis jiroveci. The disease has since then evolved into a significant global health challenge. By the year 2012, the population of infected people was thirty-four million worldwide [1].
Depending on the stages of HIV, there are different signs and symptoms. In the first stages, the virus is most infectious, but most patients are not aware of their status at this stage. By the second week of infection, one may experience no symptoms or a flu-like kind of illness with fever, rash, headache, or sore throat. The disease progresses to weaken the immune system, and one can develop swelling of lymph nodes, fever, unexplained weight loss, cough, and diarrhea. Failure of treatment may lead to sicknesses such as tuberculosis (TB), cancers such as Kaposi's sarcoma, and cryptococcal meningitis. This disease is transmitted to a person mainly through the exchange of body fluids with an infected person or mother to child during delivery. It is, however, not transmitted through shaking hands, kissing, hugging, sharing food, and water, among others [2].
Sadly, the diversity of the virus hinders HIV vaccine development in HIV DNA. Also, the virus has got various mechanisms of evading the immune response. There are naturally occurring antibodies with a potency of neutralizing HIV activity. However, they are in very few people, and take a long time to develop. Besides, they have a high chance of somatic mutation. These factors are a hindrance to the development of a vaccine. It is, therefore, significant to study the need for a better and more efficient treatment for HIV. This is because the spread of this global pandemic is on the rise. Also, the use of HAART in the management of HIV has been useful so far but has not been effective in entirely eradicating the virus from the host. This form of control calls for a lifelong kind of treatment, which can be challenging to adhere to. Also, it does not eliminate the virus from the host but suppresses the viral load. A report from The Joint United Nations Programme on HIV/AIDS (UNAIDS) showed that by the year 2017, about 36.9 million people lived with HIV. It also showed an increase of almost 1.8 million new patients per year [3]. This calls for a more in-depth exploration of options available for the treatment
Gene therapy ensures that immune system is resistant to HIV to overturn viral replication. This happens without the involvement of HAART. This technology is appropriate for use in the treatment of HIV because, unlike HAART, it provides an option for the clearance of the virus. Its main goal is to provide a set of immune cells and reconstitute the system. This would help reduce disease infections and eliminate the virus from the reservoir. Also, these therapies, in contrast to HAARTs, do not require a lifelong kind of administration but allows for one-time treatment to cure the disease.
Biological Strategies of Stem Cell Gene Therapy in HIV Treatment
Mostly, biological approaches are preferred in treating many diseases including HIV. In treating HIV one can achieve better results through the replacement of the system of genetically modified immune cells. It may also involve the modification of antiviral proteins (AVPs), which hinder the entry of HIV and controls HIV replication. Also, there is the engineering of CD8+T cells. These cells are meant to identify and destroy the virus [4].
Immune cells are designed in a way to produce AVPs. Autologous CD8+ and CD4+ T cells or HSPCs may be engineered to secrete AVPs ex vivo. These modified genes are placed in viral replication sites. Here, they led to high concentrations of local secretion of AVPs. These modified gene cells are also referred to as producer cells. The secreted AVPs inhibit HIV by binding to HIV extracellular sites. For instance, HIV binding has been prevented by soluble CD4 (sCD4) and monoclonal antibodies (mAbs) that target CD4 binding sites.
Hematopoietic stem cells (HSC) can be modified through various approaches to make them resistant to HIV. This can be done via varying strategies. These include targeting the cellular genes involved in viral replication, HIV gene replication, or the utilization of genes that inhibit the replication process.
The co-receptor CCR5 is critical in the entry of HIV. Homozygous individuals for the deletion of thirty-two base pairs of this gene (CCR5, ∆32) are relatively resistant to HIV. Those with one copy of the same gene mutation do have slow progress of the disease. This has made them significant targets in antiviral therapy. Using CCR5 defective HSC treatment demonstrated a negative viral load. However, since these people are rare to get, gene therapies modification of HSC or autologous peripheral blood T cells to camouflage as CCR5, ∆32 phenotypes have been done. These modified HSC can be useful in engineering HIV-1 resistant immunity. Some of the ways to disrupt or reduce CCR5 expression includes the use of RNA interference (RNAi), the application of intrabodies, or the use of ribozymes to reduce CCR5 RNA.
HIV genes Tat and Rev are responsible for viral expression. These genes are made targets by gene therapy. They are targeted because of their early expression during replication and their essence in viral gene expression. Tat interacts with Transactivation response (TAR) at five’ while Rev binds Rev Response element (RRE), thus promoting HIV mRNAs export from the nucleus to the cytoplasm. Ribozymes, as well as shRNAs, are designed to target sites in the tat and rev RNA overlapping open frames. Hammerhead ribozymes target tat, catalytic RNA molecules modified to target some RNA species; this increases CD4+ count. These RNA copies inhibit Tat recognition of HIV TAR (Transacting response region), thus inhibits viral replication. HIV Rev, which is a viral regulatory protein, is also a target of gene therapy. Dominant forms of this gene inhibit replication [5]. TAR and RRE copies RNAs and mimics the natural ones and occupy the RNA-binding sites of tat and Rev.
HSC modification therapy also utilizes the utilization of genes that restrict the HIV replication. This is through the introduction of exogenous factors that inhibit the significant steps of HIV replication. A gp41-derived protein, C46, was created to inhibit the entry of HIV. These are proven to be tolerated well by the patients.
HIV is not immunogenic; therefore, it impairs critical parts of the immune system; as a result, patients will not create active immunity against it. Persistence of the viral load thus results in maintaining the chronic being of the disease. Therefore, another strategy is enhancing the host's antiviral immunity is by genetic modification of peripheral blood cells with cloned T cell receptors, TCR. Human immune system A TCR that is peptide-specific from an infected individual could be cloned and applied to modify the patient's peripheral cells. This recognizes HIV envelope glycoprotein and mediates the destruction of cytotoxic T lymphocytes (CTL) [6].
Another approach is the introduction of anti-HIV genes, intracellular immunization, it makes HIV target cells resistant to HIV. It requires the expression of antiviral cells in the proliferating cell [7]. These strategies, as explained, are useful in inhibiting virus replication and entry, among other vital steps in HIV infection. Therefore, they are proof that technology is effective against HIV.
Limitations Associated with Gene Therapy
HIV gene therapy has been promising in the cure of HIV. However, due to several challenges, this therapy has not been made the routine go for treatment. Some of these challenges are health-related, while others are not. Progression of the disease and escape mutants is one of the limitations. A single mutation in the target site or emergence of a new structure excluding the original site can result in the escape from siRNA therapy. This can be avoided by targeting conserved HIV sequences or use a combination of various siRNAs. There is a thin line in designing an RNA-based treatment. It could be either efficient or lead to toxicity alongside therapeutic effects. This calls for religious expression, for instance, in siRNA, whereby overexpression can lead to off-target results.
The use of a defective CCR5 gene for HIV treatment has proven to be challenging. Reason being that it is rare to get a CCR5, ∆32 homozygous donors. Besides, stem cell transplantation is accompanied by morbidities and mortality, reducing its application. The introduction of the exogenous factors that inhibit HIV replication into HSCs expresses an immunogenic protein. The immune system removes this protein due to its immunogenicity. Another issue is that nearby genes may be activated upon the insertion of genes alongside their promoters.
To maintain a long-lasting gene expression, random generic integration of vectors may occur, thus leading to tumorigenesis. Retroviral vectors coalesce into transcriptional start sites and gene regulatory regions of proliferating genes, causing tumorigenesis. Another challenge is that immune responses can annul any therapeutic effect. They produce immune responses against foreign particles expressed by the vector. The situation is aggravated, especially when the foreign peptide is from antigen-presenting cells (APC). The low ability of fixation of the modified gene of CD34+ cells there is low efficacy of therapy effects.
The application of a rare therapy in HIV treatment is faced by the obstacle of reaching out to the large population of infected persons. This therapy is not unique but also expensive, thus making it an issue to make it available to the people. The other challenge is seen in the clinical trial phase. Correct identification of an appropriate target population based on thorough risk-benefit analysis is a challenge too. There is a looming lack of valid cell-based endpoints that define efficacy. Also, there is a lack of safer methods of selecting gene-modified cells and the cost of manufacturing is very high.
HIV gene therapy requires HIV replication for a definite selection of modified genes. However, due to the cytopathic effect resulting from HIV replication, uninfected cells die too. In untreated patients, the immune system is hyperactive, thus causing systemic inflammation and chronic activation of the immune system, causing disruption of T cells. This creates an unfavorable environment for expansion and engraftment [4].
Feasibility of Gene Therapy
Gene therapy feasibility was proven in a patient name Timothy Brown, "Berlin Patient," who was the first documented person to be cured of HIV. He was under HAARTs for a while until he was found to have acute myeloid leukemia (AML). He underwent stem cell transplantation after chemotherapy proved fruitless. He received the bone marrow from a donor who had a homozygous CCR5, ∆32 mutations. After the transplant and recovery, this patient tested negative of both cancer and HIV [8]. This strategy has proven to, however, possible to practice commonly. This is because; it is rare to come across a person with defective CCR5. Despite having a small population of Caucasian origin naturally lacking it, it plays a significant role in other viral diseases. Also, there is a possibility that those without this gene are compensated by different genetic variations absent in other populations [4].
So far, the clinical trials have proven that long-term fixation of gene-modified cells is attainable. For instance, in patients receiving Tells infusions to express antisense RNA VRX496, there was a low viral load. Gene therapy does not apply to human pregnancy [3]. It could lead to mutations that are inheritable in the DNA. This makes this investigation limited for in vitro studies
Legal and Ethical Issues of Gene Therapy
Gene therapy has an effect on human DNA, which is the basis of life. This makes such a technology undergo much scrutiny on both legal and ethical issues. They come to play when considering the safety protocols necessary, clinical trials as well as the inclusion of the patients for experiments on the efficacy of the procedure. Several questions have been raised; one of them is whether it is necessary to try out a technology-filled with uncertainties on its side effects, yet there are other options for treatment. This technology is faced with the possibility of off-target effects, thus making the issue of safety a significant concern. This question can be argued that gene therapy provides hope for longer life with plans other than living a day to day kind of lifestyle depending on HAARTs.
It has raised concerns that participation in clinical trials brings about psychological uncertainties to the participants. These include the risk of possible transmission to their partners. After the trials, they come off with anxiety. People would not consider themselves entirely cured. This is because, in as much as the functional cure may bring about the omission from HIV treatment, they are likely to test positive.
Participants of the trials involving interruption of HAARTs are faced by potential risks associated with higher risks that are non- AIDS-defining, such as heart disease in persons with high viral loads. There are, therefore, chances of transmission in case viral load suddenly rebounds. This potential treatment to boost the immune system or clear the reservoirs off HIV may bring about severe or unpredictable side effects.
This technology is expensive, thus gives the stakeholders much profit. However, profit alone should not be guided in developing a life-changing project. It is a technology that benefits both the patient and the designers. This brings the question of whether it is an ethically right thing to do. It is questionable whether the patients are a means for research tool for gene therapy or a goal. The other question on gene therapy is when is this is when is the safest time to move to clinical trials from animals. The challenge is that an animal's physiology and anatomy do not entirely match that of humans. Therefore, this technology needs to be researched in humans to ensure their effectiveness. Human life and body are sacred; thus, choosing to try new research on them is not entirely ethical. Hence the question of whether it is ethical to test such on patients.
In pediatrics participating in clinical trials, a question on their safety is raised. It is necessary, therefore, that deeper considerations be made first before initiating trials. The collaboration of parents should be sort first to have their children participate in trials. Also, one should give informed consent to participate in such activities. A child cannot be asked to provide consent as they may not understand well the potential risks involved, among other factors. In such cases, the child's consent or dissent is what they ask of them.
For instance, in China, a scientist was arrested for creating the first gene-edited babies. The scientist claimed he was protecting the children from HI DrV. He faced worldwide criticism and a three-year jail term. The courts declared that he had crossed the bottom line of scientific research as well as ethics. Any genetic editing done is passed down through generations. This kind of change could present a lasting transformation in the human race. Besides, the safety of CRISPR technology is not established in human embryos. It was also not known whether before initiating this experiment, the parents were fully informed of the possible dangers it could come with [9].
Being an expensive technology, it is feared that gene therapy will be limited only to the rich. It is also concerned that this form of treatment will bring about disparities in the health care provision, among other interventions. Also, testing this form of technology may be done on third world countries, reducing them to lab rats yet, the success of this project may only be enjoyed by the rich who can afford it.
The law should come up with limits where the development of such technology should not go beyond. It should protect the individuals who participate in the clinical trials from avoidable harm. There should be a set of consequences for the biotechnologists too to avoid the misuse of the patient's body for other experimental during the research. It ought to put up a certain level of standards below which the involved technologists should not go. This is to maintain the safety of the persons.
The doctors have a legal obligation of communicating the test results to the patients. They should present the possible risks and benefits clearly to the patient in a language the patient understands. Also, while showing the results, the doctor should be careful to maintain the patient's privacy and only share the information with the individuals whom the recipient has given consent. The manufacturing companies should only provide gene therapy only on a doctor's involvement. The physician is necessary as they are needed to evaluate the patient's state of health and whether the use of such technology is advisable.
Conclusion
As research goes on, gene therapy safety has been seen to increase. This has made it an appealing strategy for the cure of HIV., Especially the HSC and anti-HIV approach are very promising. Modified HSC can generate long term renewable immune cells that are designed to be either having an ability to eliminate infected cells or resistant to HIV. With all the views put in place, this is an effective form of treatment that is preferable over HAART. Not only does it have minimal toxicities, but also it has proof of eliminating the virus from the body reservoirs. It is a promising therapy that could help in improving the life of a patient. This therapy gives hope to complete recovery. Besides, it is not a treatment form that requires one to take medications daily for the rest of their lives, which may discourage a person's compliance. In as much as it has got its challenges, it is an effective therapy. We are hopeful that with time, further research will eliminate the possible errors that it has as of now. Besides, everything with an advantage has a disadvantage. A review committing independent of both the government and pharmaceutical companies’ sponsors should be used to counter the ethical and legal concerns on this treatment method. This is to avoid any form of bias in the evaluation.
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References
- De Cock K, Jaffe H, Curran J. The evolving epidemiology of HIV/AIDS. AIDS. 2012;26(10):1205-1213. doi:10.1097/qad.0b013e328354622a
- World Health Organization. HIV/AIDS. World Health Organization; 2019. https://www.who.int/news-room/fact-sheets/detail/hiv-aids. Accessed May 5, 2020.
- Tsukamoto T. Gene Therapy Approaches to Functional Cure and Protection of Hematopoietic Potential in HIV Infection. Pharmaceutics. 2019;11(3):114. doi:10.3390/pharmaceutics11030114
- Falkenhagen A, Joshi S. Genetic Strategies for HIV Treatment and Prevention. Molecular Therapy - Nucleic Acids. 2018;13:514-533. doi:10.1016/j.omtn.2018.09.018
- Zhen A, Kitchen S. Stem-Cell-Based Gene Therapy for HIV Infection. Viruses. 2013;6(1):1-12. doi:10.3390/v6010001
- von Laer D, Hasselmann S, Hasselmann K. Gene therapy for HIV infection: what does it need to make it work?. J Gene Med. 2006;8(6):658-667. doi:10.1002/jgm.908
- Kitchen S, Shimizu S, An D. Stem cell-based anti-HIV gene therapy. Virology. 2011;411(2):260-272. doi:10.1016/j.virol.2010.12.039
- Hoxie J, June C. Novel Cell and Gene Therapies for HIV. Cold Spring Harb Perspect Med. 2012;2(10):a007179-a007179. doi:10.1101/cshperspect.a007179
- Dube K. HIV Cure Research Ethics Update Considerations for Cell and Gene Therapies. Presentation presented at the: 2019; UNC Gillings School of Global Public Health.
