.. hich are usually non-syncytium-inducing, require the CCR-5 receptor, which is found on both monocytes and T lymphocytes. This illustrates why these isolates can infect monocytes and primary lymphocytes, both of which express CCR-5, but not T-cell lines, which lack this co-receptor. By contrast, T-cell-tropic strains cannot infect monocytes because they lack the CXCR-4 co-receptor. CD8+ T cells are thought to also secrete other soluble factors-as yet unidentified-that suppress HIV replication.
The Loss of Cells of the Immune System Researchers around the world are studying how HIV destroys or disables CD4+ T cells, and it is thought that a number of mechanisms may occur simultaneously in an HIV-infected individual. Recent data suggest that billions of CD4+ T cells may be destroyed every day, eventually overwhelming the immune system’s regenerative capacity. Infected CD4+ T cells may be killed directly when large amounts of virus are produced and bud off from the cell surface, disrupting the cell membrane, or when viral proteins and nucleic acids collect inside the cell, interfering with cellular machinery. Infected CD4+ T cells may be killed when cellular regulation is distorted by HIV proteins, probably leading to their suicide by a process known as programmed cell death or apoptosis. Recent reports indicate that apoptosis occurs to a greater extent in HIV-infected individuals, both in the bloodstream and lymph nodes. Normally, when CD4+ T cells mature in the thymus gland, a small proportion of these cells is unable to distinguish self from non-self.
Because these cells would otherwise attack the body’s own tissues, they receive a biochemical signal from other cells that results in apoptosis. Investigators have shown in cell cultures that gp120 alone or bound to gp120 antibodies sends a similar but inappropriate signal to CD4+ T cells causing them to die even if not infected by HIV. Uninfected cells may die in an innocent bystander scenario: HIV particles may bind to the cell surface, giving them the appearance of an infected cell and marking them for destruction by killer T cells. Killer T cells also may mistakenly destroy uninfected CD4+ T cells that have consumed HIV particles and that display HIV fragments on their surfaces. Alternatively, because HIV envelope proteins bear some resemblance to certain molecules that may appear on CD4+ T cells, the body’s immune responses may mistakenly damage such cells as well. Studies suggest that HIV also destroys precursor cells that mature to have special immune functions, as well as the parts of the bone marrow and the thymus needed for the development of such cells.
These organs probably lose the ability to regenerate, further compounding the suppression of the immune system. HIV is Active in the Lymph Nodes Although HIV-infected individuals often exhibit an extended period of clinical latency with little evidence of disease, the virus is never truly latent. NIAID researchers have shown that even early in disease, HIV actively replicates within the lymph nodes and related organs, where large amounts of virus become trapped in networks of specialized cells with long, tentacle-like extensions. These cells are called follicular dendritic cells (FDCs). FDCs are located in hot spots of immune activity called germinal centers.
They act like flypaper, trapping invading pathogens (including HIV) and holding them until B cells come along to initiate an immune response. Close on the heels of B cells are CD4+ T cells, which rush into the germinal centers to help B cells fight the invaders. CD4+ T cells, the primary targets of HIV, probably become infected in large numbers as they encounter HIV trapped on FDCs. Research suggests that HIV trapped on FDCs remains infectious, even when coated with antibodies. Once infected, CD4+ T cells may leave the germinal center and infect other CD4+ cells that congregate in the region of the lymph node surrounding the germinal center. However, over a period of years, even when little virus is readily detectable in the blood, significant amounts of virus accumulate in the germinal centers, both within infected cells and bound to FDCs.
In and around the germinal centers, numerous CD4+ T cells are probably activated by the increased production of cytokines such as TNF-alpha and IL-6, possibly secreted by B cells. Activation allows uninfected cells to be more easily infected and increases replication of HIV in already infected cells. While greater quantities of certain cytokines such as TNF-alpha and IL-6 are secreted during HIV infection, others with key roles in the regulation of normal immune function may be secreted in decreased amounts. For example, CD4+ T cells may lose their capacity to produce interleukin 2 (IL-2), a cytokine that enhances the growth of other T cells and helps to stimulate other cells’ response to invaders. Infected cells also have low levels of receptors for IL-2, which may reduce their ability to respond to signals from other cells. Ultimately, accumulated HIV overwhelms the FDC networks. As these networks break down, their trapping capacity is impaired, and large quantities of virus enter the bloodstream.
The destruction of the lymph node structure seen late in HIV disease may prevent a successful immune response against not only HIV but other pathogens as well. This devastation heralds the onset of the opportunistic infections and cancers that characterize AIDS. HIV’s Strategy Researchers have discovered a devious strategy used by the human immuno-deficiency virus (HIV) to undermine the immune system. They found that even when HIV does not enter a cell, proteins in the outer envelope of the virus can bind to CCR5 receptor on the cell’s surface and initiate a biochemical cascade that sends a signal to the cell’s interior. This signaling process may activate the cell, making it more vulnerable to HIV infection.
It also may cause cells to migrate to sites of HIV replication, thereby increasing their vulnerability to infection. If the cell is already infected with HIV, activation may boost the production of the virus. HIV generally requires two receptors (as discussed in ‘The Role of CD8+ T Cells’) to enter a target cell: CD4, and either CCR5 or CXCR4, depending on the strain of virus. The strains of HIV most commonly seen early in HIV disease, known as macrophage-tropic (M-tropic) viruses, use CD4 and CCR5 for cell entry. Many strains of the simian immuno-deficiency virus (SIV), a cousin of HIV that infects non-human primates such as monkeys, also use these receptors for cellular entry. Researchers found that envelope proteins from four different M-tropic HIV strains and one M-tropic SIV strain induced a signal through CCR5 that caused cells to migrate in culture.
In contrast, envelope proteins from other strains of the viruses, known as T-cell tropic (T-tropic) strains, did not cause signaling. Chapter 3 Immunological Treatments for HIV/AIDS HRG 214: A joint effort between scientists and industry has resulted in the development of a new drug to treat patients in the advanced stages of AIDS. Dr. Frank Gelder, director of Immuno-diagnostic Testing Laboratories, Department of Surgery at Louisiana State University Medical Center in Shreveport, Louisiana, invented the drug, HRG214. HRG214 is formulated as an immuno-chemically-engineered group of antibodies that neutralize and inactivate essential steps in the life cycle of HIV.
HRG214 is the first immunology based pharmaceutical to show successful treatment of HIV infection. When HRG214 is used in conjunction with two additional drugs, one to initiate and one to control cytokine pathways, (the chemical signals by which cells communicate). CD8 lymphocytes and other cells, which fight infection, (present but not functioning normally in AIDS patients), are rapidly restored to normal function. This drug regime opens new therapeutic options for the care of HIV patients, including those in advanced stages of AIDS. In addition, CD4 and CD8 lymphocyte numbers have statistically increased, and marked clinical improvements have been observed in all patients receiving treatment with HRG214.
These improvements include increase in appetite and stamina, as well as marked improvements in AIDS-related conditions such as chronic fatigue syndrome, diarrhea, malabsorption, and other HIV-related diseases. Cytolin Unlike current AIDS drugs, which attack HIV directly, Cytolin would help the body’s immune system by correcting the immune system’s self-destruct mechanism that is triggered by an HIV infection. Cytolin is a monoclonal antibody designed to prevent one part of the immune system-a particular type of killer CD8 cells-from attacking another part-CD4 cells, the destruction of which results in AIDS. Cytolin is designed to protect the immune system’s natural defenses while antiviral drugs take the offensive against HIV. Cytolin is to be given in a doctor’s office, most often as an adjunct to a combination of antiviral drugs. Combinations, or cocktails, of antiviral drugs have helped some patients significantly reduce the level of their HIV infection, improving their health. However, the side effects of antiviral drugs can be so significant that at least 15 percent of patients cannot take them.
Even some patients who can tolerate antiviral therapy have continued to face declining health. Following injection with Cytolin, the patients demonstrated significantly reduced levels of HIV infection and clinical signs of immune system recovery, including increased levels of disease fighting CD4 cells. Conclusion First of all, HIV attacks the very cells that are responsible for the defense of the human body against invaders, the CD4+ T cells. However, HIV also targets other immune system cells with CD4 on their surface. Not only are HIV replication and the spread of the virus more efficient in activated cells, but chronic immune activation during HIV disease may result in a massive stimulation of a person’s B cells, impairing the ability of these cells to make antibodies against other pathogens. Chronic immune activation also can result in a form of cellular suicide known as apoptosis, and in the increased production of signaling molecules called cytokines that can themselves increase HIV replication.
This strategy shows that HIV does not to invade the CD4+ cells to inflict damage to the immune system. The chronic immune activation not only impairs the ability of B cells to make pathogens against other cells, but it also results in apoptosis, and an increased production of cytokines that may not only increase the HIV replication but also have other deleterious effects, such as the severe weight loss caused by increased levels of TNF-alpha. Now, finally researchers have found a two potentially successful immunological treatments, HRG 214 and Cytolin. HRG 214 neutralizes and inactivates essential steps in the replication cycle of HIV. Cytolin helps the immune system by correcting its self-destruct mechanism that is triggered by an HIV infection. Bibliography References: – Pantaleo G, , et al. The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia. Proc Natl Acad Sci USA 1997.
– http://camelot.emmes.com/avctn/index.htm – http://www.niaid.nih.gov/research/daids.htm – Kostirkis LG, Huang Y, Moore JP, et al. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nat Med 1998; 4:350-3. – Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells.
Science 1995; 270:1811-5. – Pantaleo G, Graziosi C, Demarest JF, et al. HIV infection is active and progressive in lymphoid issue during the clinically latent stage of disease. Nature 1993; 362:355-8. – Embretson J, Zupancic M, Ribas JL, et al.
Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 1993; 362:359-62. – HIV Pathogenesis and Viral Markers. HIV Clinical Management – Volume 2. 1999 Medscape, Inc. – Junqueira, Carneiro, and Kelly. Functionele histologie.
Utrecht 1996. – Meer, J van der, et al. Interne Geneeskunde. Bohn Stafleu Van Loghum.