The Immunology of Aids Introduction Although HIV was first identified in 1983, studies of previously stored blood samples indicate that the virus entered the U.S. population sometime in the late 1970s. Worldwide, an estimated 27.9 million people had become HIV-infected through mid-1996, and 7.7 million had developed AIDS, according to the World Health Organization (WHO). AIDS is a disease of the immune system, and is caused by Human Immuno deficiency Virus (HIV). HIV targets and infects T-helper cells and macrophages.
After infection, replication of the virus occurs within the T-helper cells. The cells are lysed and the new viruses are released to infect more T-helper cells. The course of the disease results in the production of massive numbers of virus (1 billion/day) over the full course of the disease. The T- helper cells are infected, and rapidly destroyed both by virus and by cytotoxic T cells. T-helper cells are replaced with nearly a billion produced per day. Over many years (average may be 10), the T-helper cell population is depleted and the body loses its ability to mount an immune response against infections. Thus, we mount a very strong immune response against the virus for a long time, but the virus is produced at a very high rate and ultimately overcomes the ability of the immune system to respond.
Since HIV belongs to a class of viruses called retroviruses, it has genes composed of ribonucleic acid (RNA) molecules. Like all viruses, HIV can replicate only inside host cells, commandeering the cell’s machinery to reproduce. However, only HIV and other retroviruses, once inside a cell, use an enzyme called reverse transcriptase to convert their RNA into DNA, which can be incorporated into the host cell’s genes. HIV belongs to a subgroup of retroviruses known as lenti-viruses, or slow viruses. The course of infection with these viruses is characterized by a long interval, up to 12 years or more, between initial infection and the onset of serious symptoms.
Like HIV in humans, there are animal viruses that primarily infect the immune system cells, often causing immuno-deficiency and AIDS-like symptoms. Scientists use these and other viruses and their animal hosts as models of HIV disease. The CDC currently defines AIDS when one of 25 conditions indicative of severe immuno-suppression associated with HIV infection, such as Pneumocystis carinii pneumonia (PCP) is present, or HIV infection in an individual with a CD4+ T cell count less than 200 cells per cubic millimeter (mm3) of blood. However, the question that now remains to be answered is ‘How does HIV effectively overcome the human immune system?’ In this paper I will try to answer this question. In the first chapter I will explain how HIV is transmitted and what its life cycle looks like. This in order to increase the understanding of how the virus operates. It can be seen as an introductory chapter to the main body of the paper, chapter 2.
In the second chapter the specific interactions between the virus and the human immune system will be discussed and shown why its is so threatening. In the last chapter I will deal with certain promising treatments against AIDS. Chapter 1 The Transmission of HIV Among adults, HIV is spread most commonly during sexual intercourse with an infected partner. During sex, the virus can enter the body through the mucosal linings of the vagina, vulva, penis, rectum or, very rarely, via the mouth. The likelihood of transmission is increased by factors that may damage these linings, especially other sexually transmitted diseases that cause ulcers or inflammation. Research suggests that immune system cells called dendritic cells, which reside in the mucosa, may begin the infection process after sexual exposure by binding to and carrying the virus from the site of infection to the lymph nodes where other cells of the immune system become infected.
HIV also can be transmitted by contact with infected blood, most often by the sharing of drug needles or syringes contaminated with minute quantities of blood containing the virus. The risk of acquiring HIV from blood transfusions is now extremely small in Western countries, as all blood products in these countries are screened routinely for evidence of the virus. Almost all HIV-infected children acquire the virus from their mothers before or during birth. The anatomy of HIV HIV has a diameter of 1/10,000 of a millimeter and is spherical in shape. The outer coat of the virus, known as the viral envelope, is composed of lipid bi-layer, taken from the membrane of a human cell when a newly formed virus particle buds from the cell.
Embedded in the viral envelope are proteins from the host cell, as well as 72 copies (on average) of a complex HIV protein that protrudes from the envelope surface. This protein, known as Env, consists of a cap made of three or four molecules called glycoprotein (gp) 120, and a stem consisting of three or four gp41 molecules that anchor the structure in the viral envelope. Within the envelope of a mature HIV particle is a bullet-shaped core or capsid, made of 2000 copies of another viral protein, p24. The capsid surrounds two single strands of HIV RNA, each of which has a copy of the virus’s nine genes. Three of these, gag, pol and env, contain information needed to make structural proteins for new virus particles.
The env gene, for example, codes for a protein called gp160 that is broken down by a viral enzyme to form gp120 and gp41, the components of Env. Three regulatory genes, tat, rev and nef, and three auxiliary genes, vif, vpr and vpu, that contain the information necessary for the production of proteins that control the ability of HIV to infect a cell, produce new copies of virus or cause disease. The protein encoded by nef, for instance, appears necessary for the virus to replicate efficiently, and the vpu-encoded protein influences the release of new virus particles from infected cells. The Life Cycle of HIV When HIV encounters its target cell, the external glycoprotein portion of the viral envelope (GP120) binds with high affinity to the extra cellular component of the receptor protein CD 4, present on helper lymphocytes(Helper T cells). The membrane portion of the viral envelope fuses to the lymphocyte membrane and the virus is expelled into the cell.
Then the reverse transcriptase of the virus copies the RNA into DNA. Once the DNA is integrated into the host cell genome, the presence of HIV has become a permanent part of the lymphocyte (Helper T). The viral production proceeds through a complex set of highly regulated steps. First, messenger RNA of the virus and viral proteins are produced. Proteins are then modified by a viral protease to become mature viral proteins. Current efforts at anti-viral therapy involve the use of reverse transcriptase inhibitors (notably AZT) and newly developed inhibitors of the viral protease.
AZT Chapter 2 The Immune System and HIV The body’s health is defended by the immune system. Lymphocytes (B cells and T cells) protect the body from germs such as viruses, bacteria, parasites, and fungi. When germs are detected, B cells and T cells are activated to defend the body. This process is hindered in the case of the acquired immuno-deficiency syndrome (AIDS). AIDS is a disease in which the body’s immune system breaks down. AIDS is caused by the human immuno-deficiency virus (HIV).
When HIV enters the body, it infects the CD4+ T cells, where the virus grows. The virus kills these cells slowly. As more and more of the T cells die, the body’s ability to fight infection weakens. A person with HIV infection may remain healthy for many years. People with HIV infection are said to have AIDS when they are sick with serious illnesses and infections that can occur with HIV. The illnesses tend to occur late in HIV infection, when only 200 T cells per cubic millimeter remain.
One reason HIV is unique is that despite the body’s aggressive immune responses, which are sufficient to clear most viral infections, some HIV invariably escapes. One explanation is that the immune system’s best soldiers in the fight against HIV-certain subsets of killer T cells- multiply rapidly following initial HIV infection and kill many HIV-infected cells, but then appear to exhaust themselves and disappear, allowing HIV to escape and continue replication. Additionally, in the few weeks that they are detectable, these specific cells appear to accumulate in the bloodstream rather than in the lymph nodes, where most HIV is sequestered. Viral Variation Another reason for the uniqueness of HIV are the dynamics of HIV replication. They also have profound implications for the generation of genetic diversity of HIV quasispecies in individual patients.
Virus isolates obtained from patients at the time of initial infection show little genetic heterogeneity. Over time, however, the population of viruses circulating in an individual patient becomes increasingly diverse. The rapid replication kinetics and high mutation rate of HIV reverse transcriptase drive the diversification of the HIV quasispecies in response to selective pressure from the host immune response. The rapid turnover of HIV also provides the ideal mechanism for producing variants with mutations that confer drug resistance, or permit escape from immunological control of HIV infection. When drugs that inhibit HIV-1 replication are partially or inappropriately administered, the resulting evolutionary pressure selects for the emergence of resistant strains.
In the case of lamivudine (3TC) or nevirapine, a single nucleotide change in the HIV-1 RT gene is sufficient to produce high-level resistance. The entire virus population evolves from wild-type to resistant in a matter of weeks when these drugs are given as single agents. Little or no viral variation emerges in patients with complete suppression of plasma HIV-1 RNA in response to potent combination therapy. The Role of Immune Activation in HIV Disease During HIV infection, however, the immune system may be chronically activated, with negative consequences. For HIV replication and spread are much more efficient in activated CD4+ cells. Chronic immune system activation during HIV disease may also 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 apoptosis, and an increased production of cytokines that may not only increase HIV replication but also have other deleterious effects.
Increased levels of TNF-alpha , for example, may be at least partly responsible for the severe weight loss or wasting syndrome seen in many HIV-infected individuals. The persistence of HIV and HIV replication probably plays an important role in the chronic state of immune activation seen in HIV-infected people. In addition, researchers have shown that infections with other organisms activate immune system cells and increase production of the virus in HIV-infected people. Chronic immune activation due to persistent infections, or the cumulative effects of multiple episodes of immune activation and bursts of virus production, likely contribute to the progression of HIV disease. The Role of CD8+ T Cells CD8+ T cells are important in the immune response to HIV during the acute infection and the clinically latent stage of disease. These cells attack and kill infected cells that are producing virus.
CD8+ T cells also appear to secrete soluble factors that suppress HIV replication. Three of these molecules-RANTES, MIP-1alpha and MIP-1beta-apparently block HIV replication by occupying receptors necessary for the entry of certain strains of HIV into their target cells. Researchers have hypothesized that an abundance of RANTES, MIP-1alpha or MIP-1beta, or a relative lack of receptors, notably CCR-5, for these molecules, block the entry of HIV. This may help explain why some individuals have not become infected with HIV, despite repeated exposure to the virus. A possible explanation for that is that some people have a mutation in the allele coding for that receptor.
Figure 2. New Co-receptors for HIV-1. T-cell-tropic strains of HIV-1, which are usually syncytium-inducing, require CXCR-4 as co-receptor. This receptor is found on T lymphocytes, but not monocytes. Mono-cytotropic strains, w …