CHAPTER 1 AIDS: Control and Possible Cure by Using Gene Therapy and Gene Editing Technology
MAHEK SHARAN,1 AJAY CHAUDHARY,1 and ABHIMANYU KUMAR JHA2*
1Department of Biotechnology, Faculty of Life Sciences, Institute of Applied Medicines and Research, Ghaziabad, Uttar Pradesh, India
2Professor and Head in Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India
ABSTRACT
Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS). This syndrome has raised global mortality rate from December 1999 to 2016. The number of patients suffering from AIDS increased to 36.7 million, resulting in 1 million deaths per year. HIV contains single-stranded RNA (ssRNA), integrase enzyme and reverse transcriptase that allows the conversion of its ssRNA into dsDNA, formation of long tandem repeats, integration of viral DNA into host DNA. Development of provirus and antibodies neutralization is by gp120 and gp41 utilization. This metabolism and protein expression by T-cell hijacking involves gag, tat, pol, env, and art genes, reducing the immunity. Depression is more prevalent among people living with HIV (PLWHIV) than that in general population at clinical stages II and III of HIV. The treatment of AIDS available, single receptor targeted/antiretroviral technology, viral eradication, and kick and kill strategy, only halt the disease or have major drawbacks but gene therapy and gene editing technology can possibly cure it. Protein VRCO7-αCD3 inhibits the activation and killing of latently infected T cell. CCR5 protein-encoding gene, devoid of virus adherence surface and stem cell transplantation, might cure AIDS completely by gene therapy. The alteration of CCR5 and direct cut of viral gene targeting provirus by gene editing technology may cure AIDS. Different approaches in this technology include blockage of pol and tat genes, blockage of long tandem repeats process with location and research on gene, and preparation of HIV vaccine.
1.1 INTRODUCTION
The disease which is often referred to as a slow poison for the body causing serious infections, tumors, and even certain cancer is acquired immunodeficiency syndrome (AIDS). The virus causing this deadly disease is human immunodeficiency virus (HIV), a type of a retrovirus enfold in a capsid, protein coat possessing two copies of ssRNA. It has enzymes, which help the virus to infect host cell and construct new viruses such as reverse transcriptase, the characteristic enzyme of retrovirus which converts its ssRNA to dsDNA and protease, an enzyme which cuts the host DNA and integrase (IN), which helps the virus dsDNA to bind to the host DNA.
The spread of this menacing disease started during the pre-1980s when HIV emerged in Kinshasa which is the largest city of Democratic Republic of the Congo in 1920 where HIV jumped from the chimpanzees to humans [2], marking the beginning of the epidemic of AIDS in 1980s. According to the UNAIDS global statistical data of 2017, around 36.9 million patients were infected and 940,000 patients were died, where there was occurrence of 1.8 million new infected cases. In the initial stage of AIDS, the patients experience a normal influenza-like symptoms such as body ache, fever, and many more followed by the final stage of infection where the immune system of the patient becomes completely nonfunctional along with unwanted weight loss, resulting in new infections and diseases such as tuberculosis that can lead to patient’s demise.
AIDS, which is commonly transmitted through the liquid exchange and from mother to newborn, requires a large investment in basic and clinical research with aim of developing safe, affordable, and ascendible cure for it. As no permanent cure, but only temporary treatment such as sustained viral remission and viral eradication such as antiretroviral treatment (ART) and kick and kill strategy to eradicate viral reservoir resulting in only cessation of disease. According to the UNAIDS global statistical data of 2017, ART for AIDS was received by 21.7 million.
The major drawbacks observed in the available current treatments for AIDS are the rebound of the disease once the treatment is stopped. Therefore, new techniques of biotechnology including gene therapy by mutation and stem cell transplantation [8] along with gene editing could serve as the permanent cure for this deadly disease and its epidemic by complete eradicating the virus, resulting in the rise of a healthy world.
1.2 EPIDEMIOLOGY
After the first case of AIDS was reported, millions of people have died because of it since then. AIDS was first reported in United States in 1981 and in 1983, in Central and East Africa, it was recognized among heterosexual men [2].
Approximately 3.7 million new infections were estimated from 1980 to 1987 and from 1984 to 1991, there was a decrease in new infections from 130,000 to 60,000 [3]. In year 2012, approximately 2.3 million new infections were reported which showed decline by 34% since 2000 [1]. Approximately 9.7 million of people had accessed antiretroviral drugs and the death rate of AIDS declined to 28% from 2006 to 2012 [1].
AIDS increased the mortality rate in some countries of sub-Saharan Africa with high prevalence of HIV with more than 10% of infected adults [3]. In the year 2012, there were 780,000 people living with HIV in China, out of which 46.5% were infected through heterosexual HIV transmission and 28.4% were the case of injection drug use (IDU) infection [1].
In 2012, India was reported to have largest number of people living with HIV among the countries of Asia which was 2.1 million people living with AIDS infection [1]. Since 2007, there was a decline in the number of people living with HIV from 2.23 million to 2.12 million in 2012 [4]. In India, the number of new infection was 300,000 in 1998, which decreased to 120,000 in 2012 [4].
1.2.1 Unaids Global Statistics On The Aids Epidemic [30]
Since the commencement of the epidemic of AIDS, 77.3 million people have become infected with HIV and killed around 35.4 million people from AIDS-related illnesses. In 2017, there were 36.9 million people living with HIV in which 1.8 million were children and 35.1 million were adults. Around 7,000 young women aged between 15 and 24 years become infected with HIV every week.
The regional statistics showed that in sub-Saharan Africa, three out of four new infections were reported, among adolescents girls aged 15–19 years. In 2016, around 10.4 million people developed tuberculosis and 1.2 million people were living with HIV. It was estimated that 49% of people living with HIV and tuberculosis are unaware of their coinfection. Only 47% of all people living with HIV are virally suppressed but not permanently cured.
1.3 CAUSE, SYMPTOMS, TRANSMITTANCE, AND PREVENTION OF AIDS
AIDS is still a major concern of all countries in the world. Even though there are treatments that control the disease but still are not able to cure it permanently, thus, raising the mortality rate.
1.3.1 CAUSE
HIV jumped from African chimpanzees having a similar strain like that of simian immunodeficiency virus. It is a virion that consists of enveloped particle of 100 nm diameter along with the nucleic matter that comprises of two ssRNA molecules of 7–10 kb in size. The virus structure has the envelope that enables it to infect the host and direct enters into its cell. 5′ end capping component, R gene which ensures correct end-to-end transfer and 3′ end component, PPT gene which is used as primer for DNA synthesis and U3 gene as signal in reverse transcriptase. The proteins such as protease and the genes such as pol which are responsible for proteolytic cleavage and integration of viral DNA into host and by the usage of all these components, the HIV is able to enter into host and converts its RNA to DNA by using the enzyme reverse transcriptase (RT) and integrates it in the host genome. The CD4+ T cells are the targets of HIV, which gradually destroys it as an indication. The research revealed that total lymphocyte count (TLC) can be considered as surrogate mar...