HIV

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HIV

Introduction

The Human Immunodeficiency Virus (HIV) is the microorganism responsible for acquired immunodeficiency syndrome, or AIDS. HIV attacks the immune system, and eventually leaves the body vulnerable to potentially fatal opportunistic infections. An estimated 36 million people worldwide are infected with HIV.

History and Scientific Foundations

HIV is a type of “retrovirus” with a genetic code that is comprised of RNA rather than DNA. As it has no DNA, which is necessary to create RNA viral genome (genetic material) copies, it uses the DNA of infected host cells to create a new RNA genome for replicates (copies) of the virus. A retrovirus replicates by using a DNA intermediary, i.e., an infected cell's DNA. Retroviruses rely on the enzyme reverse transcriptase in order to perform the reverse transcription of its genetic code from its RNA into DNA, which can then be inserted into the host cell's genome using another enzyme. The virus then replicates as part of the cell's DNA. One of the major classes of HIV drugs targets reverse transcriptase, inhibiting the virus’ ability to create the DNA segment for insertion into the infected cell's DNA.

One of the most important features of HIV replication is its ability to generate large numbers of new genetic combinations through a process known as recombination. This, together with a high rate of genetic mutations of individual genes, enables HIV to rapidly create new drug-resistant strains. After HIV was identified as the cause of AIDS, researchers suspected that genetic recombination could also play a key role in the evolution of the virus. Very recently, studies of HIV infections worldwide have produced an estimate for the occurrence of HIV genetic recombination and have revealed that recombination frequencies appear to be much higher than expected. Recombination is currently regarded as a central aspect of the HIV infectious cycle.

HIV has a globular structure with a spiked envelope. The spikes on HIV virus carry the mystery of how the virus is attracted to CD4+ cells (a type of white blood cell) that play an important role in the immune system. The spikes on the HIV virus control the process by which the virus fuses with the targeted CD4+ cells. Despite intensive efforts by scientists, the spikes have been slow to reveal their structural and functional secrets. Recent advances are providing the first glimpses of the overall three-dimensional structure of the spiked envelope. Increasing knowledge of the viral envelope's component atomic structures offers new insights into the structural elements within the spike and could lead to entirely new avenues for the treatment of AIDS. The new treatments would target the ability of HIV to fuse with target cells, while current therapies interrupt viral replication.

The immune system has a so-called innate component (innate immunity) comprised of white blood cells called phagocytes, which migrate to affected areas and engulf disease-causing organisms (pathogens). Special cells of innate immunity called dendritic cells are particularly important for regulating immune response. When dendritic cells encounter foreign material, they have unique receptors that allow them to distinguish harmless and pathogenic (disease-causing) organisms. These cells carry fragments of pathogen to the lymph nodes, where they could stimulate a response by the adaptive immune system (called adaptive immunity), depending on the ability of the foreign material to cause disease.

If dendritic cells decide that the material is pathogenic (part of a virus or bacteria), they activate CD4+ helper T cells. (CD4+ refers to a surface protein on this type of T cell.) Helper T cells can then stimulate another group of white blood cells called B cells to produce antibodies that bind to the specific antigen and immobilize it, preventing it from causing infection. Antibodies are specific for only one antigen. Once activated, memory cells are produced that insure faster and stronger immune response when the body is re-exposed to the same pathogen.

Pathogens that escape antibody detection can enter and infect body tissue cells. The cell membrane of infected cells changes in a way that is recognized by T cells. Cytotoxic T cells kill infected cells, preventing them from producing more pathogen. Cytotoxic T cells must interact with Helper T cells to regulate the destruction of infected cells, in order to destroy cells that are infected by the specific microbe that has been presented to the helper cells by the dendritic cells.

HIV specifically attacks Helper T cells. Without an adequate number of Helper T cells, the immune system cannot signal B cells to produce antibodies to kill infected cells. When HIV has critically depleted the Helper T cell population, the body can no longer launch an adaptive immune response and becomes susceptible to many opportunistic infections, thus resulting in the immunodeficiency that characterizes AIDS. Research shows that the CD4+ membrane proteins are targets for HIV infection. Thus, memory helper T cells are quickly infected and destroyed in the mucus membranes of tissues. Only recently, researchers have recognized that the memory cell destruction occurs in the first several days after HIV infection, suggesting that therapies should begin as soon as the infection is detected.

Mysteries remain about how HIV causes disease, particularly the reason why there is uncontrolled viral replication in the majority of infected patients. In the past several years, investigation into HIV disease has focused on T regulatory (Treg) cells, a subset of CD4+ T-cells whose main function is to maintain a certain amount of tolerance in order to avoid autoimmunity (in which the immune system attacks the body's own tissues). Preliminary data point to two main roles for Treg cells in HIV: a detrimental effect in which HIV-specific immune responses are muted and a beneficial effect that limits immune activation (thus limiting the helper T-cell targets of HIV). There is currently a lack of standardized assays to measure levels and function of Treg cells, which continues to hamper research into this promising area. Thus, it is possible that HIV takes advantage of a feature of the immune system that naturally limits immune response.

WORDS TO KNOW

AUTOIMMUNITY: Autoimmune diseases are conditions in which the immune system attacks the body's own cells, causing tissue destruction. Autoimmune diseases are classified as either general, in which the autoimmune reaction takes place simultaneously in a number of tissues, or organ specific, in which the autoimmune reaction targets a single organ. Autoimmunity is accepted as the cause of a wide range of disorders, and is suspected to be responsible for many more. Among the most common diseases attributed to autoimmune disorders are rheumatoid arthritis, systemic lupus erythematosis (lupus), multiple sclerosis, myasthenia gravis, pernicious anemia, and scleroderma.

CD4+ T CELLS: CD4 cells are a type of T cell found in the immune system, which are characterized by the presence of a CD4 antigen protein on their surface. These are the cells most often destroyed as a result of HIV infection.

CYTOTOXIC: A cytotoxic agent is one that kills cells. Cytotoxic drugs kill cancer cells but may also have application in killing bacteria

OPPORTUNISTIC INFECTION: An opportunistic infection is so named because it occurs in people whose immune systems are diminished or are not functioning normally; such infections are opportunistic insofar as the infectious agents take advantage of their hosts’ compromised immune systems and invade to cause disease.

PATHOGEN: A disease causing agent, such as a bacteria, virus, fungus, etc.

RECOMBINATION: Recombination is a process during which genetic material is shuffled during reproduction to form new combinations. This mixing is important from an evolutionary standpoint because it allows the expression of different traits between generations. The process involves a physical exchange of nucleotides between duplicate strands of deoxyribonucleic acid (DNA).

Impact and Issues

The level of specificity of the science required to provide breakthroughs in the battle against HIV is unprecedented. Most disease cures and treatments that have been discovered during the past 100 years have been based on only limited knowledge of a microbe's ability to causes disease. As with the fight against cancer, the effort to find a cure for AIDS is leading scientists into ever more minute aspects of the pathogen, all the way down to the atomic structure of viral envelope spikes and the molecular mechanisms of genetic replication.

HIV is an amazingly versatile and adaptive enemy, probably owing to millennia of evolution in non-human primates and now being offered a new and relatively open ecological niche within humanity. While HIV transmission is preventable, a variety of social and behavioral factors have led to what will ultimately become the worst epidemic in terms of lives lost in the history of the human species. Also, as with the struggle against cancer, contending with the perplexing mysteries of HIV will leave a mark not only on the history and future development of medicine, but on human behavior and social evolution for the foreseeable future.

BIBLIOGRAPHY

Books

Palladino, Michael A., and David Wesner. HIV and AIDS (Special Topics in Biology Series). San Francisco: Benjamin Cummings, 2005.

Periodicals

Sempere J.M., V. Soriano, and J.M. Benito. “T Regulatory Cells and HIV Infection.” AIDS Rev. (January–March 2007): 9 (1): 54–60.

Web Sites

University of Arizona: The Biology Project. “Immunology and HIV. Immune System's Response to HIV.” <http://www.biology.arizona.edu/immunology/tutorials/AIDS> (accessed June 8, 2007).

Kenneth T. LaPensee

Infectious Diseases: In Context