Human immunodeficiency virus (HIV) is a lentivirus (slowly-replicating retrovirus) that causes acquired immunodeficiency syndrome (AIDS), a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive (1). A virus is a piece of genetic material, RNA or DNA, surrounded by a protein coat. To replicate, a virus must infect a cell and direct its cellular machinery to produce new viruses. A virus cannot reproduce without infecting a cell.
Viruses prey upon all living organisms, turning them into virus Xerox machines. Unlike a bacterium or a cell of an animal, a virus lacks the ability to replicate on its own. A virus does contain some genetic information critical for making copies of it-self, but it can’t get the job done without the help of a cell’s duplicating equipment, borrowing enzymes and other molecules to concoct more virus. HIV is a RNA virus, which means the virus instructions are stored in strands of RNA – not in strands of DNA.
A RNA virus is a Retrovirus. In order for the virus to take over the cell, it must copy the RNA instructions into DNA instructions (own words out of Microbiology book) Lentivirus (lente-, Latin for “slow”) is a genus of viruses of the Retroviridae family, characterized by a long incubation period. Lentiviruses can deliver a significant amount of viral RNA into the DNA of the host cell and have the unique ability among retroviruses of being able to infect non-dividing cells.
(2) AIDS (Acquired Immune Deficiency Syndrome) refers to any number of severe physical manifestations resulting from HIV infection. H – Human: because this virus can only infect human beings. I – Immune-deficiency: because the effect of the virus is to create a deficiency, a failure to work properly, within the body’s immune system. V – Virus: because this organism is a virus, which means one of its characteristics is that it is incapable of reproducing by itself. It reproduces by taking over the machinery of the human cell.
A – Acquired: because it’s a condition one must acquire or get infected with; not something transmitted through the genes I – Immune: because it affects the body’s immune system, the part of the body which usually works to fight off germs such as bacteria and viruses D – Deficiency: because it makes the immune system deficient (makes it not work properly) S – Syndrome: because someone with AIDS may experience a wide range of different diseases and opportunistic infections. In the early stages, an HIV positive person looks and feels perfectly healthy and is able to continue with all normal day to day functions.
Over a period of time (4-8 years on average) as the virus starts multiplying in the body, the immune system becomes weak and the body becomes susceptible to various diseases. That is the time when the person is said to have AIDS. Clinically, a person is said to have AIDS when they have HIV and another infection, called an “opportunistic infection” and/or their crucial immune cell (CD4+) count falls below 200cu/mm. As a result, AIDS is a condition caused by HIV. (Research Paper Florida Hospital of Altamonte Springs about AIDS). Symptoms of AIDS:
Primary HIV Infection A person may be infected with HIV but not know it, because many people who are infected do not have any symptoms for several years after getting infected. Primary HIV infection refers to the very early stages of HIV infection, or the interval from initial infection to the time that antibody to HIV is detectable. During this stage of HIV infection, patients typically have some symptoms of acute HIV seroconversion illness, very high HIV RNA levels of >100,000 copies/mL, and negative or indeterminate HIV antibody tests.
The diagnosis of patients with primary HIV infection is a clinical challenge because the symptoms of primary HIV are often absent, mild, or nonspecific. After infection with HIV, it takes a median of 25 days before the HIV antibody test becomes positive; in some individuals, it may be several months before seroconversion. About half of patients who become infected with HIV develop symptoms consistent with primary HIV infection. Symptoms typically appear a few days to a few weeks after exposure to HIV, and generally include several of the following: • Fever • Rash, often erythematous and maculopapular.
• Fatigue • Sore throat • Lymphadenopathy • Urticarial • Myalgia/arthralgia • Anorexia • Mucocutaneous ulceration • Headache, retro-orbital pain • Neurologic symptoms (e. g. , pain, numbness, loss of motor function) This symptomatic phase usually persists for 2-4 weeks or less, although lymphadenopathy may last longer. These symptoms and signs are similar to those of many other illnesses, including other viral syndromes, such as “flu” and “colds”. To diagnose early HIV infection, clinicians must consider HIV in the differential diagnosis for at-risk patients with symptoms resembling flu or mononucleosis.
A history of recent risk behaviors should be obtained from all patients who present with symptoms consistent with acute HIV infection. Advanced HIV Infection After the period of primary infection, an individual may live for several years to decades before experiencing new symptoms. During this period, the virus attacks the person’s immune system, and over time an individual may experience the following symptoms that may indicate advanced HIV infection: • Rapid weight loss and loss of appetite.
• Dry or productive cough • Recurring fever or profuse night sweats • Profound and unexplained fatigue • Swollen lymph glands in the armpits, groin, or neck • Diarrhea that lasts for more than a week • White spots or unusual blemishes on the tongue, in the mouth, or in the throat • Shortness of breath • Red, brown, pink, or purplish blotches on or under the skin or inside the mouth, nose, or eyelids • Memory loss, depression, and other neurological disorders.
After an individual’s immune system experiences significant damage from HIV infection, the person may progress to Acquire Immune Deficiency Syndrome (AIDS), a condition that is characterized by low CD4+ cells (below 200 cells/mL or below 14% of total lymphocytes) and/or one or more AIDS-defining clinical conditions, or Opportunistic Diseases (OD ). (3) The Biology of HIV [pic]www. google. com/Biology of HIV Basic HIV Biology: HIV, as with all viruses, cannot replicate on its own; it needs a host cell. The virus enters the cell and converts the machinery of the cell into a factory that reproduces the HIV.
HIV is a retro-virus which means that its genome is 2 RNA strands (not DNA like most other living organisms). An enzyme called reverse transcriptase turns the host cells DNA into RNA in order for the virus to fully infiltrate the host cell. Once this happens, the HIV DNA is integrated into the host cell DNA and the host cell starts producing HIV proteins. Thus allowing the HIV to take over, kill the cell, and further multiply. When HIV enters the body, it targets lymphocytes, a type of white blood cells which usually fight off infections.
On the surface of the lymphocytes (specifically the CD4+ lymphocytes) are different types of studded protein molecules such as CCR5. HIV acts like Velcro, binding itself to the studded protein molecules, using the protein’s surface as the corresponding side of the Velcro. On the spherical HIV, there are stalks and on the end of each stalk there are clumps of molecules called gp120. Essentially, the virus looks like a plastic ball covered with suction cups. Once inside, the HIV commandeers the cell’s DNA and begins to copy itself. The new copies burst out of the cell.
In the process, the cell is destroyed. The new copies are free in the body looking for new cells to invade. Billions of CD4+ cells are hijacked and destroyed each day, rapidly multiplying into billions of new HIV viruses. Within days of infection, millions of copies of the HIV have made its way into the lymph nodes and can hide there for many years before reappearing. A person infected with HIV rarely shows symptoms initially. It is—at this point—before the start of an immune response, that the person is probably most infectious.
A few weeks after infection, the body produces killer T cells in response. This stage is called the “seroconversion” stage. The killer T Cells drive the virus back, but cannot eliminate it. Rapid mutations of the virus hinders the killer T’s ability to recognize the virus. The production of killer T cells can cause a person to feel flu-like symptoms. Antibodies (Y-shaped molecules with mitten-like protrusions) latch onto and kill infected cells and microbes. Lymphocytes and antibodies clear most of the virus particles, but some viruses escape by mutating.
The body must constantly adapt a new immune system response to tackle the constant mutations. HIV is a highly variable virus that mutates very easily in the human body to outsmart the immune system. This means there are many different strains of HIV, even within the body of a single HIV positive person. Based on genetic similarities, the numerous virus strains may be classified into types, groups and subtypes. HIV-1 and HIV-2 are the most common types of HIV. The HIV virus begins a slow war on the immune system. As CD4+ cells die, the immune system becomes increasingly impaired.
A person is said to be diagnosed with AIDS when they have a positive HIV test and their CD4+ cell count is less than 200/cubic millimeters (cu. mm); AND/OR they have a positive HIV test and an opportunistic infection. A healthy, uninfected person usually has 800 to 1,200 CD4+ cells per cu. mm of blood. (4) The progression of HIV to AIDS may range anywhere from 1 to 10 years, or longer. (5) Advanced HIV Biology: On the Cellular Level: STEP ONE: Entry of HIV into cells Infection typically begins when an HIV particle, which contains two copies of the HIV RNA, encounters CD4+ cell.
One or more of the virus’s gp120 molecules binds tightly to CD4 molecules on the cell’s surface. The binding of gp120 to CD4+ results in a conformational change in the gp120 molecule allowing it to bind to a second molecule on the cell surface known as a co-receptor. The envelope of the virus and the cell membrane then fuse, leading to entry of the virus into the cell. The gp41 of the envelope is critical to the fusion process. In the early stage of HIV disease, most people harbor viruses that use, in addition to CD4, a receptor called CCR5 to enter their target cells.
With disease progression, the spectrum of co-receptor usage expands in approximately 50 percent of patients to include other receptors, notably a molecule called CXCR4. Virus that uses CCR5 is called R5 HIV and virus that uses CXCR4 is called X4 HIV. Although CD4+ T cells appear to be the main targets of HIV, other immune system cells with and without CD4 molecules on their surfaces are infected as well. Among these are long-lived cells called monocytes and macrophages, which apparently can harbor large quantities of the virus without being killed, thus acting as reservoirs of HIV.
CD4+ T cells also serve as important reservoirs of HIV; a small proportion of these cells harbor HIV in a stable, inactive form. Normal immune processes may activate these cells, resulting in the production of new HIV virions. Cell-to-cell spread of HIV also can occur through the CD4-mediated fusion of an infected cell with an uninfected cell. [pic] STEP TWO: Reverse transcription In the cytoplasm of the cell, HIV reverse transcriptase converts viral RNA into DNA, the nucleic acid form in which the cell carries its genes.
STEP THREE: Integration The newly made HIV DNA moves to the cell’s nucleus, where it is spliced into the host’s DNA with the help of HIV integrase. HIV DNA that enters the DNA of the cell is called a provirus. STEP FOUR: Transcription For a provirus to produce new viruses, RNA copies must be made that can be read by the host cell’s protein-making machinery. These copies are called messenger RNA (mRNA), and production of mRNA is called transcription, a process that involves the host cell’s own enzymes.
Viral genes in concert with the cellular machinery control this process; the tat gene, for example, encodes a protein that accelerates transcription. Genomic RNA is also transcribed for later incorporation in the budding virion. STEP FIVE: Translation After HIV mRNA is processed in the cell’s nucleus, it is transported to the cytoplasm. HIV proteins are critical to this process; for example, a protein encoded by the rev gene allows mRNA encoding HIV structural proteins to be transferred from the nucleus to the cytoplasm. Without the rev protein, structural proteins are not made.
In the cytoplasm, the virus co-opts the cell’s protein-making machinery—including structures called ribosomes—to make long chains of viral proteins and enzymes, using HIV mRNA as a template. This process is called translation. STEP SIX: Assembly and budding Newly made HIV core proteins, enzymes, and genomic RNA gather inside the cell and an immature viral particle forms and buds off from the cell, acquiring an envelope that includes both cellular and HIV proteins from the cell membrane. During this part of the viral life cycle, the core of the virus is immature and the virus is not yet infectious.
The long chains of proteins and enzymes that make up the immature viral core are now cut into smaller pieces by a viral enzyme called protease. This step results in infectious viral particles. (6) Transmission of HIV For HIV transmission to happen, the following TWO conditions MUST be met: 1. The virus must be present in sufficient quantities for transmission. 2. The virus must have a way to enter into the bloodstream. There are only FOUR fluids in the body that can effectively transmit HIV: blood (and its products), semen (“cum”, including pre-seminal fluid, “pre-cum”), vaginal fluids, and breast milk.
HIV is spread in FOUR major ways: • Unprotected sexual contact with an infected person. • Using HIV-contaminated needles and/or syringes (for example, sharing needles for recreational drug injection with someone who is HIV+ but also from reusing needles/syringes in unhygienic medical settings). • Through transfusions of UNTESTED infected blood or blood clotting factors. • Babies born to HIV-infected women may become infected before or during birth or through breast-feeding after birth. HIV cannot pass through unbroken skin—the skin is the largest of the organs that make up the immune system.
HIV can get into the blood stream from: direct blood-to-blood contact, open cuts, sores, lesions, and mucosal membranes (vaginal and anal walls, tonsils, inner cheek walls). HIV is unable to reproduce outside its living host (unlike many bacteria or fungi, which may do so under suitable conditions), except under laboratory conditions, therefore, it does not spread or maintain infectiousness outside its host. HIV is NOT spread through casual contact. Sexual Transmission: The most common route (over 70%) for HIV transmission is through the exchange of sexual fluids (semen, vaginal fluids) and blood during heterosexual intercourse.
Among adults, HIV is spread most commonly during sexual intercourse with an infected partner. During intercourse, the virus can enter the body through the mucosal linings of the vagina, vulva, penis, or rectum or, rarely, via the mouth and possibly the upper gastrointestinal tract after oral sex. The likelihood of transmission is increased by factors that may damage these linings, especially other sexually transmitted infections that cause ulcers or inflammation. (7) HIV Testing There are several different types of screening tests for HIV.
HIV can be detected with a blood test, a test of the oral mucosal transudate (taken from the inner cheeks or gums), RNA, and for particles of the virus. The serologic test for HIV, the ELISA test, was developed and approved of in 1985. A person infected with HIV does not show any external signs of infection until progression to AIDS, which can take from six months to ten years. • When a person is infected with HIV, it generally takes three to six months for the body to produce antibodies to HIV. This is called the ‘window period’. • During the ‘window period’, a person will not test positive for HIV even if infected.
• The HIV test is available at most government hospitals and Voluntary Counseling and Testing Centers at a minimal charge for most people and free for those in target groups. • The test is confidential and the results are not revealed to anyone but the person taking the test. To help maintain confidentiality testing centers are sometimes housed in the same facilities as other medical offices. Unfortunately medical confidentially is not as strictly enforced as it is in developed nations. • The pre-and post-test counseling by counselors helps HIV positive people to clarify all their doubts and cope with the infection emotionally and physically.
More about the ‘window period’ and why it is important: The test for HIV looks for the antibodies against the virus, rather than the virus itself. Upon infection, it can take the body several months to make antibodies against the virus, so that if a person is tested soon after infection they will receive a false negative. However, they will still be able to infect others. That period of time is known as the ‘window period. ’ That’s why it’s important to be tested after six months and abstain from sex in the interim.
Most people will develop detectable antibodies within 2 to 8 weeks (the average is 25 days). Even so, there is a chance that some individuals will take longer to develop detectable antibodies. Therefore, if the initial negative HIV test was conducted within the first 3 months after possible exposure, repeated testing should be considered 3 months after the exposure occurred to account for the possibility of a false-negative result. Ninety seven percent will develop antibodies in the first 3 months following the time of their infection. In very rare cases, it can take up to 6 months to develop antibodies to HIV.
Negative (Non-reactive) Test Results: A negative or non-reactive test could mean that the person is not infected with HIV. Or the person is, in fact, positive but has not begun producing antibodies. In this case, re-testing once the person is out of the “window period” is highly recommended. (8) Antiretroviral Treatment for HIV Treatment for HIV has improved significantly. And although there is still no cure for AIDS, current therapies are able to inhibit the virus from replicating to reduce morbidity and death, giving patients longer and healthier lives. Currently available drugs do not cure HIV infection or AIDS.
They can suppress the virus, even to undetectable levels, but are unable to completely eliminate HIV from the body. Antiretroviral drugs, also called antiviral drugs, for HIV are medication that interferes with the replication of retroviruses. Types of Antiretroviral treatment for HIV Antiviral drugs can be categorized into 3 main classes: 1) Reverse transcriptase (RT) inhibitors These RT inhibitors interfere in a very important step in the HIV life cycle called reverse transcription. This step is where the viral RNA is converted to DNA which is crucial for replication of the virus.
An enzyme known as reverse transcriptase is required for this step. There are two main types of RT inhibitors: • Nucleoside/nucleotide RT inhibitors (NRTI) – These are similar to the building blocks used to make DNA, except they are faulty. In the process of converting RNA to DNA, the virus uses the faulty building blocks resulting in a halt the process and complete HIV DNA is not produced and the virus can’t replicate. In 1987, Retrovir®, or AZT became the first antiretroviral to be approved. Interestingly, AZT was originally used for cancer treatment, although it failed efficacy tests and was associated with high side effects.
Today, there are currently 13 FDA-approved NRTI drugs. Current FDA-approved Nucleoside/nucleotide RT inhibitors (NRTI) drugs are RetrovirCombivir VidexTrizivir HividEpzicom EpivirTruvada Videx EC Ziagen Zerit Emtriva Viread Source: http://www. fda. gov/oashi/aids/virals. html • Non-nucleoside RT inhibitors (NNRTI) – These bind to the enzyme reverse transcriptase and stop the virus from converting RNA to DNA. Viramune®, approved in 1996, was the first NNRTI. There are currently 3 FDA-approved NNRTI drugs. Current FDA-approved Non-nucleoside RT inhibitors (NNRTI) drugs Rescriptor Viramune Sustiva.
Source: http://www. fda. gov/oashi/aids/virals. html (2) Protease inhibitors (PI) Aside from the reverse transcriptase, HIV also uses protease, another enzyme, to assemble new viral particles. Protein inhibitors therefore interfere with the activity of protease. The first protease inhibitor, Invirase, was approved in 1995.
There are currently 11 FDA-approved protease inhibitors for HIV treatment. Agenerase Aptivus Crixivan Fortovase Invirase Kaletra Norvir Prezista Reyataz Viracept Source: http://en. wikipedia. org/wiki/Protease_inhibitor_%28pharmacology%29 http://www. fda. gov/oashi/aids/virals.html (3) Fusion Inhibitors HIV infects human cells by being able to invade and enter human cells.
The viral protein, GP41, is important for entry of virus into the cell. Fusion inhibitors works by binding the GP41 and prevents the virus from fusing with a cell’s membrane and entry into the cells. Fuzeon®, FDA-approved in 2003, is currently the only fusion inhibitor. Fuzeon Source: http://www. hivandhepatitis. com/hiv_and_aids/hiv_treat. html http://www. fda. gov/oashi/aids/virals. html Highly Active Antiretroviral Therapy (HAART) Unfortunately, antiretrovirals are limited in their activity.
When HIV replicates, it often makes mistakes, thus creating different versions or strains HIV that may become resistant to antiretroviral drugs. For antiretroviral treatment to be effective for a long time, it has been found that taking a combination of antiretroviral drugs is better. In combination, the rate at which resistance develops is also greatly reduced. The term Highly Active Antiretroviral Therapy refers to a strategy where a combination of three or more antiretroviral drugs is used for treatment. The combination includes at least drugs from two classes of antiretroviral drugs.
When used properly, the combination of drugs has been successful in HIV treatment by suppressing the virus and reducing the rate of opportunistic infections. It should be noted that although HAART has greatly reduced the number of deaths due to HIV/AIDS, it has been thought to increase survival time by between 4 to 12 years. However this strategy cannot suppress the virus completely and transmission of HIV can still occur. Adherence and commitment to a certain ARV or HAART regime is the best way to controlling HIV levels.
Source: http://www. niaid. nih. gov/factsheets/treat-hiv. htm http://en.wikipedia. org/wiki/HIV#Treatment Glossary Antibodies – Infection-fighting protein molecules in blood or secretory fluids that tag, neutralize, and help destroy pathogenic microorganisms such as viruses. apoptosis – Cellular suicide, also known as programmed cell death.
HIV may induce apoptosis in both infected and uninfected immune system cells. B cells – White blood cells of the immune system that produce infection-fighting proteins called antibodies. CD4+ T cells – White blood cells that orchestrate the immune response, signaling other cells in the immune system to perform their special functions.
Also known as T helper cells, these cells are killed or disabled during HIV infection. CD8+ T cells – White blood cells that kill cells infected with HIV or other viruses, or transformed by cancer. These cells also secrete soluble molecules that may suppress HIV without killing infected cells directly. cytokines – Proteins used for communication by cells of the immune system. Central to the normal regulation of the immune response. cytoplasm – The living matter within a cell. dendritic cells – Immune system cells with long, tentacle-like branches.
Some of these are specialized cells at the mucosa that may bind to HIV following sexual exposure and carry the virus from the site of infection to the lymph nodes. See also follicular dendritic cells. enzyme – A protein that accelerates a specific chemical reaction without altering itself. follicular dendritic cells (FDCs) – Cells found in the germinal centers (B cell areas) of lymphoid organs.
FDCs have thread-like tentacles that form a web-like network to trap invaders and present them to B cells, which then make antibodies to attack the invaders.germinal centers – Structures within lymphoid tissues that contain FDCs and B cells, and in which immune responses are initiated. gp41 – Glycoprotein 41, a protein embedded in the outer envelope of HIV.
It plays a key role in HIV’s infection of CD4+ T cells by facilitating the fusion of the viral and cell membranes. gp120 – Glycoprotein 120, a protein that protrudes from the surface of HIV and binds to CD4+ T cells. gp160 – Glycoprotein 160, an HIV precursor protein that is cleaved by the HIV protease enzyme into gp41 and gp120.immune deficiency – The inability of the immune system to work properly, resulting in susceptibility to disease.
Immunosuppression – Immune system response to foreign invaders such as HIV is reduced. integrase – An HIV enzyme used by the virus to integrate its genetic material into the host cell’s DNA. Kaposi’s sarcoma – A type of cancer characterized by abnormal growths of blood vessels that develop into purplish or brown lesions. killer T cells – See CD8+ T cells. lentivirus – “Slow” virus characterized by a long interval between infection and the onset of symptoms.
HIV is a lentivirus as is the simian immunodeficiency virus (SIV), which infects nonhuman primates. LTR – Long terminal repeat, the RNA sequences repeated at both ends of HIV’s genetic material. These regulatory switches may help control viral transcription. lymphoid organs – Include tonsils, adenoids, lymph nodes, spleen, and other tissues. Act as the body’s filtering system, trapping invaders and presenting them to squadrons of immune cells that congregate there. macrophage – A large immune system cell that devours invading pathogens and other intruders.
Stimulates other immune system cells by presenting them with small pieces of the invaders. microbes – Microscopic living organisms, including viruses, bacteria, fungi, and protozoa. monocyte – A circulating white blood cell that develops into a macrophage when it enters tissues. opportunistic infection – An illness caused by an organism that usually does not cause disease in a person with a normal immune system.
People with advanced HIV infection suffer opportunistic infections of the lungs, brain, eyes, and other organs. organelles – Small structures inside a cell, generally bounded by membranes.pathogenesis – The production or development of a disease.
May be influenced by many factors, including the infecting microbe and the host’s immune response. pathogens – Disease-causing organisms. protease – An HIV enzyme used to cut large HIV proteins into smaller ones needed for the assembly of an infectious virus particle. provirus – DNA of a virus, such as HIV, that has been integrated into the genes of a host cell. replicate – Process by which a virus makes copies of itself. retrovirus – HIV and other viruses that carry their genetic material in the form of RNA and that have the enzyme reverse transcriptase.reverse transcriptase – The enzyme produced by HIV and other retroviruses that allows them to synthesize DNA from their RNA.
References 1) http://en. wikipedia. org/wiki/HIV 2) http://en. wikipedia. org/wiki/Lentivirus 3) www. niaid. nih. gov, www. Aids. gov/Basics, www. emedicinehealth. com 4) , AIDS the Biological Basis put in own words by Jones & Bartlett 5) www. aidsinfonet. org 6) AIDS, the Biological Basis put in own words by Jones & Bartlett 7) www. aids. org/topics/aids-faqs/how-is-hiv-transmitted 8) hivtest. cdc. gov [pic].