Human immunodeficiency virus causes a syndrome known as Acquired Immune Deficiency Syndrome. Human immunodeficiency virus consists of 3 structural gene, Gag, Pol, and Env, which are responsible for making structural protein for the replicating HIV. The other 6 gene products are regulatory element in its genome, which are tat, rev, nef, vif, vpr, and vpu, and are responsible for making the gene products that control the ability of HIV to infect or cause the disease. The pathogenesis of HIV could be explained as function of its life cycle, interaction with the host cell, and the number of HIV in an infected person. (1,4)
The entry of HIV into the host cell is facilitated by fusion of gp 120 with a co-receptor CD4+ human T- lymphocyte, which induces a conformation change in the structure of gp 120, exposing the gp 41. In addition to the CD4 receptor, a co-receptor, chemokine is required for HIV to infect the cells. Chemokines co-receptors include the families CXC and CC, which are found on the surface membrane helping in fusion of gp120 with CD4+ T-lymphocyte. The difference in chemokine co-receptors explains the selectivity of HIV strain in infecting the cells. Gp 41 contains two domains: HR1 and HR2. The hydrophobic part of gp 41 anchors into cell membrane and the loose HR2 domain folds into hairpin structure on HRI domain of gp 41. The process is called HR2 zipping, which allows interaction of virus with the cell membrane. This destabilizes the membrane and allows the HIV to enter the cytoplasm. The fusion of gp 120 with CD4 co-receptor on the surface membrane results in formation of syncytia, and thus, the cells die prematurely. (1,2)
HIV infection of CD4+ human T-lymphocytes begins during a latent phase when HIV reservoirs are formed. However, the lysis of human T-cells occurs during a productive phase when HIV 1 is reactivated. This results in weakening of human immune system. When T-cells are damaged, body can't fight against the pathogens. (1)
In addition, when HIV enters a host cell, it is recognized as antigen by CD4+ T-cells. Hence, infected cells release virions, which infect other CD4+ T-cells. Some HIV virions are carried to the lymph nodes and infect other cells of immune system. Thus, viruses become trapped in follicular dendritic cells (FDC), and HIV progression may reach in the germinal centers. Depending on amount of time from the start of infection to re-activation and viral expression, the disease can continue for years, and due to prolonged loss of CD4+ T-cells and its interaction with cells, the lymph nodes become disorganized. Thus, function of immune system decreases until the infection is overwhelmed, and we reach a stage known as AIDS.(1,4)
Although, the primary target for HIV is CD4+ T-cells, other cells with CD4+ receptors molecules are also infected. The CD4+ T-cells could be killed naturally when greater number of viruses buds off from the cell surface, damaging the cellular membrane or their interference with cellular machinery. The infected cell may fuse with the normal neighboring cells through CD4+ fusion, forming syncytia. This is called cell to cell spread of HIV, which leads the death of normal cell/uninfected cell. CD4+ T-cells may also undergo a programmed cell death known as apoptosis, in which the cellular regulation is destroyed by HIV proteins and CD4+ T-cells commit a suicide. In addition HIV particles bind to cell surface and mimic them the appearance of an infected cell, which could then be killed by T-cells. This is often called innocent bystanders.(1,4) Moreover, the long lived cells, monocytes and macrophages are among the reservoirs for HIV. A neurological abnormality known as AIDS dementia may results from HIV infection of macrophages and monocytes, which may travel to lungs and reach the brain, leading to the production of cytokines. This would result in inflammation of neuronal tissue, motor impairment, and may also affect cognitive reasoning. (1)
The clinical symptoms for HIV infection can be described in 3 phases: primary HIV infection, chronic asymptomatic phase, and lastly an AIDS. People with primary infection may experience flu like illness or mononucleosis, which are often known as acute retrovirus symptoms (ARS). Viruses are highly concentrated in blood, central nervous system, lymphatic system, and other places in the body. 50%of the people do not experience any symptoms. Primary infection occurs 2-6 weeks after infection and may last about 2-3 weeks. More than 50% of infected people may experience fever, fatigue, rash, muscle pain, sore throat, and swelling of lymph nodes. Between 5%-32% of the people may experience headache, diarrhea, nausea and vomiting, night and vomiting, weight loss, thrush, night sweats, cough, spleen enlargement and liver, neurological symptoms, and oral and genital ulcers. (1)
Moreover, in chronic asymptomatic phase, people usually do not show any signs or symptoms. As the viruses continue to replicate in an infected individual, the blood becomes highly concentrated with viruses, and AIDS is pronounced. Some infected individuals can develop AIDS within 5 years while others HIV infected individuals are AIDS free for over 15 years. The last stage is AIDS itself, and a person dies if not treated with antiretroviral therapy because body has lost/decrease CD4+ T-cells to fight against HIV.(1)
Nevertheless, the body has two types of natural defenses against viral infections. The non specific defenses are also known as an innate immunity, which protect the body immediately against any pathogen. These types of defenses do not retain any memory about previous infection. The second types of defenses are the specific or adapted immunity, which requires days to weeks for effective clearing of viruses, and they to retain memory about previous infection. It treats each pathogen and each species differently. (3)
The non specific defenses include interferon response, apoptosis, phagocytosis, dendritic cells natural killer cells, and a complement system. Interferon (IFN) is naturally occurring protein that cause death of both infected and uninfected cells so that viral infection can't be spread throughout the body. When a cell is infected with pathogen it secrets interferon. Interferon binds to receptors on neighboring cells, which causes the cell to express genes that are involved in antiviral activity. This leads to the destruction of both the viral and host mRNA and inhibition of protein synthesis. Thus, interferon is used in treating viral diseases, non malignant tumors, and immune disorder. (1,3)
Apoptosis or a programmed cell death programmed cell death (PCD) also used to remove unwanted or harmful cells in the body. The viral infected cells undergo apoptosis, which may also induce the neighboring uninfected cells to activate the PCD cascade by shutting down the production of growth factors. For cancer cell, cytotoxic T lymphocytes attach, and produce chemicals to kill the cancerous cells. T-lymphocytes recognize the surface markers on other cells in the body that label those cells for destruction. The observed CPE due to nuclease and protease activities would be the cell shrinkage from neighboring cells, condensation of chromatin, disintegration of nucleolus and nuclear membrane, and formation of apoptotic bodies, which are destroyed by macrophages.(1,3)
Phagocytosis is also a non specific defense but more direct in action in contrast to interferon and apoptosis in that they engulf and digest the foreign invaders. Examples of phagocytic cells are macrophages, blood monocytes, and neutrophils. Monocytes are white blood cells circulating in bloodstream for certain hours and become differentiated into macrophages. Macrophages engulf viruses and other foreign bodies in tissues. Neutophils are also white blood cells that contain enzymes, lysozyme, peroxidase and other substances that help in phagocytic activity. There are also dendritic cells that help the body to combat against pathogens. They stimulate T-cells and move to the site of infection where they internalize and digest the pathogens. (1)
Moreover, the natural killer cells (NK) also participate in early innate defenses against viral infection by destroying the tumor cells before they become cancerous. The natural killer cells are major histocompatibility molecules (MHC1), which are markers that mark all host cells as self and MHC 11 marks B-cells, macrophages and dendritic cells. This enables immune system to communicate with T-helper lymphocytes in order to remove the foreign bodies. Natural killer cells are stimulated by IFN α and β and other cytokines. Consequently, natural killer cells release perforins and other molecules. These molecules form pores in the membrane of the target cells and cause the cell to die. In addition to this, there is a complement system consisting of different serums and membrane glycoproteins that are activated in a cascade fashion. The proteins present in blood are activated by binding of complement proteins to viral antigen-antibody complex or via lectin pathway. Hence, Opsonization and neutralization lead to destruction of viruses and infected cells.(1,3)
In addition to above innate defenses, there are other innate immunities that protect the body physically against the viral infection. These are skin and mucous membrane. Skin is associated with langerhans cells that phagocytosize pathogens. Mucous membrane secrets mucous that traps the foreign invaders. The toll receptor (TL3), TL7 and TL8 recognizes dsRNA, ssRNA, and G-rich refion of viral RNA respectively. This signals the cell to turn on the genes that would destroy the foreign invaders. (3)
In addition to innate response, there are humoral responses (antibodies production) and cell mediated defenses (non antibody response). These are specific defenses provided by the body against viral infection. Antibody plays role in preventing viral infections where as cell mediated response eliminates infected cells from the body. B-cells and T-cells are two main types of lymphocytes that work together to protect body against foreign invaders. B-cells are born and mature in bone marrow where as T-cells are born in the bone marrow but move to the thymus gland. When B-cells engulf virus, the viral antigens are displayed on surface MHC 11 (roman 2) antigen presenting complex (APC) of the B-cell. Simultaneously, T-cells respond to APC that is displayed by macrophage. The clones T-cells bind to B-cells displaying viral antigen complex with its MHC11 (roman 2). Eventually, this stimulates B-cells to divide into plasma cells and memory cells. Plasma cells secrete specific antibodies that circulate within the body. Memory cells are long lived and retain the correct antibody on their surface. Thus, it will increase the amount of circulating antibody and produce a fast response when they encounter the same antigens again. (1,3)
Although T-cells and B-cells work together, antibody responds to immune system by neutralizing foreign invaders making them non infectious; opsonizing making it more recognizable by macrophage; forming immune complex by increasing phagocytosis; and complement activation increases immune response and leads to the destruction of infected cells. The cell mediated immunity activates T-cells that cause ingestion of foreign invaders by antigen presenting complex (APC). This enhances binding of Naïve T-cells. Thus, T-helper cells and B-cells are activated and lead to secretion of cytokines, interferon and cytotoxic, which would kill the infected cell. Whether, the immune system response to viral infection is innate or adaptive, the end result is the destruction or removal of infected cells. (1,3)
