Immunology and HIV Basics

Immunology and HIV Basics Vlastimil Mayer Treatment Update Seminar – Prague, 24-26 November, 2006 Immunology Basics       The most basic data about the human IMMUNE SYSTEM the human body IMMUNE DEFENSES against infection the important role of LYMPHOCYTES (white blood cells) - CD4 T – LYMPHOCYTES (and HIV infection) - the number of CD4 T – lymphocytes in blood (CD4 CELL COUNT). Data are used for:  a) monitoring of the HIV - infection development  b) the estimation of risk for HIV infection related illnesses  c) recommendations about anti-HIV treatment  d) monitoring of the treatment effectivity Treatment Update Seminar – Prague, 24-26 November, 2006 HIV and AIDS          HIV - infection HIV – disease – AIDS: the late phase of the HIV disease AIDS: Acquired Immune Deficiency Syndrome (SIDA, SPID) A – because it is largely an infection catching the people I – because it relates to the immune system D – because it damages functions of the immune system S – because it describes a collection of different infections and various illnesses ocurring in the organism with severely damaged functions of the immune system Treatment Update Seminar – Prague, 24-26 November, 2006 The Immune System      IMMUNE SYSTEM (simplified scheme): Protects the body against infections Unlike other body systems (e.g. circulatory or respiratory systems) the immune system has not a strict and definite anatomical structure, but is rather a "diffuse„ organ, composed mainly from specific cells (typical are cells called LYMPHOCYTES) circulating in blood and lymph or present in the body in various lymphatic organs (e.g. lymph nodes, spleen). Development of the cells of the immune system STEM CELLS IN THE BONE MARROW:  line of stem cells from which originate red blood cells and many different kinds of other blood cells  line from which originate white blood cells (mainly lymphocytes): Treatment Update Seminar – Prague, 24-26 November, 2006 Immune Sytem cont’d       For our purpose are important lymphocyte subpopulations: 1) B-lymphocytes T- lymphocytes various “killer„ lymphocytes After recognition in the body of “foreign„ substances (ANTIGENS, e.g. viruses, bacteria), the immune system becomes activated, triggering its reactions to the presence of the antigen (IMMUNE RESPONSE). (Antigen: is a word for small parts of e.g. infectious agents – i.e. “foreign substances"– recognised by the immune system) Treatment Update Seminar – Prague, 24-26 November, 2006 Immune System cont’d        Important part of the defence reaction , the IMMUNE RESPONSE, is the production of ANTIBODIES by B – lymphocytes Antibody is a type of protein, made in response to a "foreign"substance (antigen), is present in the blood. Antibody binds to only a specific antigen, in order to destroy it or making easier for white blood cells to destroy the antigen. This part of immune response based on antibody is called humoral immune response. In HIV infection the majority of produced antibodies is unfortunately not protective. They are used for diagnostic purposes – i.e. laboratory test looks for antibodies specific to the HIV , detecting specific response of the body to this virus. Production of detectable amount of antibody takes 3 – 4 weeks, but also several months or longer. Treatment Update Seminar – Prague, 24-26 November, 2006 Immune System cont’d        The second main way that body deals with different infections is: CELL-MEDIATED IMMUNE RESPONSE (cellular immunity, based on response of two main types of Tlymphocytes to the antigen , i.e. of CD4 and of CD8 cells. CELLULAR IMMUNE RESPONSE IS UTMOST IMPORTANT FOR TO FIGHT VIRUSES, including HIV CD4 T- lymphocytes (CD4 CELLS) , called also helper cells, are INDISPENSABLE and central for effective orchestration of the large number of cell-mediated immune defence mechanisms, icluding those killing the infected cells. CD8 T- lymphocytes (CD8 CELLS) kill the HIV-infected cells (helped by CD4 cells) Treatment Update Seminar – Prague, 24-26 November, 2006 Immune System cont’d  CD4 cells (CD4 lymphocytes) are very susceptible to the HIV VIRUS, being the most important target cells for this infection Treatment Update Seminar – Prague, 24-26 November, 2006 Immune System and HIV            Virus, after infecting susceptible cells, reproduces inside them. The infected cells die more quickly The cells, susceptible to HIV infection are the cells that body uses to fight infection (mainly CD4 cells) Consequences: HIV infection makes the body to produce more CD4 cells to fight the newly reproduced virus The new cells provide more targets for HIV to infect them and reproduce in them. Amount of the virus increases. Due to signals from infected CD4 cells the non-infected CD4 cells also die more quickly These processes over time decrease continually the number of CD4 cells HIV is slowly winning the race This is why the CD4 cells number of an infected individual, as measured by CD4 count, drops After many years the body gets very tired and the rest of the immune system is worn out Drugs against the HIV blocks its reproduction as quickly and allow to the immune system to improve its functions Treatment Update Seminar – Prague, 24-26 November, 2006 HIV Infection      The CD4 count (full name: CD4 T-lymphocyte count) is the result of a blood test, telling how many of CD4 cells are in a cubic millimetre of blood. I.e. - how much HIV has damaged the immune system – data important for to estimate the risk of HIV – related illnesses , when is needed to start treatment, but also how treatment works The average CD4 count for a HIV-negative person is between 600 1600, but a few people have naturally lower or higher counts than this. A few weeks after infection CD4 count drops a bit .Then as the immune defenses begin to fight back, the CD4 count recovers and stabilise (3-6 months or longer), but not to the levels as before infection . Then the trend for the CD4 count is to gradually go down over several years (the fall about 50 cells/ cubic millimetre per year, in non-treated persons). Treatment Update Seminar – Prague, 24-26 November, 2006 Disease Progression          Most people´s immune system controls HIV very succesfully without drugs for many years. After treatment the CD4 count should rise again to higher values. The time it takes for someone´s CD4 count to drop (for example to 200 cells / cubic millimetre) varies a lot between different people (non-treated average progressors, – about 70% - attain this level after 5 –9 years) There is no way of telling, how quickly will someone with HIV progress, other than monitoring its CD4 counts over time. A single CD4 count doesn´t mean very much. Several results obtained over time will show what the TREND is. The CD4 percentage (CD4 %) is sometimes also a good indicator about immune system changes. It is the percentage of total lymphocytes that are CD4 cells. An HIV-negative person has a percentage od about 40%. Example: a CD4% of 12-15% is about the same as a count of under 200 cells / cubic millimetre. Treatment Update Seminar – Prague, 24-26 November, 2006 HIV and OI’s         The lower a person´s CD4 count, the higher the risk that they will develop HIV-related illnesses (e.g. opportunistic infections appearing if the immune system is damaged). This is why monitoring of CD4 levels is important, especially when the infected individual is not on treatment. Different illnesses become more likely at different CD4 counts. Many serious and life threatening illnesses become a risk when the CD4 count drops under 200 cells / cubic millimetre. ––––––––––––––––––––––––––––––––––––––––––––––––––––The use of CD4 count is important for decisions about starting treatment. (In details discussed in other lessons). –––––––––––––––––––––––––––––––––––––––––––––––––––––- Treatment Update Seminar – Prague, 24-26 November, 2006 HIV Basics - Virology       The most basic data about: the HIV virus and infection monitoring of the infection (viral load test) the natural history of the HIV-disease basics of the HIV drug resistance CD4 and viral load test – their relations Treatment Update Seminar – Prague, 24-26 November, 2006 HIV Basics       H I V stands for "Human Immunodeficiency Virus“ Immunodeficiency means "reduced immunity“ Viruses are the smallest from microbes, HIV: an organisms with spheric shape, cca 1/10 000 millimeter. Its genetic material is inside a protein envelope, on the surface of which are virus antigens, diagnostically important Any virus can reproduce only inside cells of another living organism. Some viruses are harmless, other can cause disease. Only humans can be infected by HIV. Therefore virus spreads from person to person. Examples of viruses causing a disease, also in HIV-infected people: hepatitis A,B,C viruses, cytomegalovirus, herpes virus Treatment Update Seminar – Prague, 24-26 November, 2006 HIV Basics Treatment Update Seminar – Prague, 24-26 November, 2006 HIV Basics cont’d       HIV is a difficult virus to catch, but at the same time people can become HIV-positive only after one exposure to the virus. The risk of catching HIV is closely related to the risk of the virus (or of HIV -infected lymphocytes e.g. from blood) coming into contact with broken skin, facilitating its penetration into the body of another person. Infection is effectively transmitted also by injection of fluids containing HIV. The risk of HIV transmission is highest when virus levels in the body are high. Only about 2% of the HIV (called free virus) in the body of a HIV – positive person are in the blood. Most HIV is in the cells of lymphatic system (lymphocytes, lymph nodes etc.) where it reproduces. HIV levels in the blood are measured using VIRAL LOAD TEST. HIV dies very quickly in blood or other bodily fluids once they are outside of the body Treatment Update Seminar – Prague, 24-26 November, 2006 HIV Infection and Progression       The "natural history” of any illness is the term used to describe how that illness normally progress, if left untreated. It is important to understand the development of the HIV infection . The development of the HIV infection is very individual. Some people (less than 5%) will become ill within a few years and some people (also less than 5%) can go for 8-12 years or even more before they need treatment. The majority of people with HIV stay well for many years after infection. Viral load testing showed that HIV is not a dormant infection. It is gradually progressive viral infection, that is always active. This means also that HIV-positive people can transmit the HIV during the whole time of their infection. With HIV infection they are recognized several different phases during its development. Treatment Update Seminar – Prague, 24-26 November, 2006 Acute Infection      Infection: this is the moment when virus, after penetrating into the body, infect the first hosts cells.Shortly thereafter they are carried to the lymph nodes , where the virus starts to reproduce (to multiply). PRIMARY HIV INFECTION:  acute primary HIV infection    During the first days / weeks HIV reproduces intensively. Viral load shoots very high – the individual is very infectious High level of viral activity produces in about or more than 50 % people influenza-like disease with temperature The body reacts with a specific immune response (humoral as well as cell-mediated) against this new infection. First are produced antibodies to fight the virus. During 1 – 3 months the immune response is strong enough to be detected by HIV-antigen blood tests (seroconversion from negativity to positivity)  early HIV infection Viral load drops in most people due to the immune response , then a certain balance between HIV reproduction and immune response usually establishes (set point). Not signs of disease, but in some individuals are observed enlarged lymph nodes (lymphadenopathy). As early phase are considered first 6 months after infection. Treatment Update Seminar – Prague, 24-26 November, 2006 Chronic HIV Infection CD4 / mm3  stage without signs of illnesses (6–10 or more years) 750-500 (200)  stage when various illnesses may appear (1 – 5 years) 500-100  c) Late stage infection – AIDS below 50  During the chronic phase viral load increases slowly, CD4 count decreases  Chronic infection can take 2 - 10 years until the majority of people need treatment. With treatment, chronic infection can be lifelong (20, 30 or 40 or more years). Re-infection with another, e.g. drug resistant HIV can complicate the situation.  Late stage infection is the most serious stage. Usually in people with no access to treatment, who are only diagnosed very late or whose treatment has stopped working Treatment Update Seminar – Prague, 24-26 November, 2006 Viral Load Test     VIRAL LOAD TEST measures how much HIV is in a sample of blood . Without this test, developed around the year 1990, it is most probably that combination therapy would never have been developed and later continuously perfected. There are several types of viral load tests. The viral levels (amounts of the virus) in the blood sample are measured according the number of the HIV genetic material (RNA) copies produced during the virus reproduction. For this purpose is used the polymerase chain reaction (PCR). For to make the cont more easy, the small amounts of the virus are multiplied by PCR many times. For this reason the individual result from one testing is not very accurate and can have a 3-fold margin of error. Important is to look on the trend of results over several test. Results of the viral load test are expressed as the number of HIV RNA copies in one milliliter of plasma.   Treatment Update Seminar – Prague, 24-26 November, 2006 Viral Load Test cont’d       At present are used tests able to measure down to 50 copies / mL. The viral load levels may be in various phases of the HIV-disease as low as 50 or less copies / mL or as high as several hudreds thousand or more copies / mL. After infection, the viral load levels are very high, but due to immune response the values drop to much lower levels. In the chronic phase of HIV infection, the levels of virus increase, over several years, again . E.g. if CD4 count drops to around 200 cells / mm3, viral load levels are around 50.000 – 200.000 copies / mL. If anti-HIV treatment brings viral load level to less than 50 copies / mL, then treatment is working and can last for many years. In practice, it is usual to test the viral load every 3-6 month when not on treatment, and every 3 months when on treatment. One month after starting treatment or after making treatment change, it is recommended to test the viral load again. Treatment Update Seminar – Prague, 24-26 November, 2006 HIV in Compartments        We measure viral load in blood, which is one compartment, several other important places in the body have barriers , limiting both HIV and HIV drugs from moving freely. These places are referred as compartments or sanctuary sites. They include the genital tract and the central nervous system (brain and spinal column). HIV can develop differently in each compartment, viral load levels can be different as well as HIV drug resistance. Viral load values measured in blood does not inform completely what is going on in individual other compartments. This makes HIV-disease a very complicated illness, sometimes difficult to treat. Treatment Update Seminar – Prague, 24-26 November, 2006 HIV and Treatment Issues     Everyone who is HIV-positive and not on-treatment, produces every day several billion new susceptible cell , in which – after infection – the virus reproduction takes place. In making very large number copies of itself, the virus also makes lots of small mistake in his genetic material. They are called mutations. Mutations change various properties of the virus. Also confer the resistance to drugs, used for the treatment of the given individual. Virus with the resistant mutations will continue to reproduce and eventually become major type of patient´s HIV. In the patient with a drug resistant virus the future treatment may be complicated. The higher the viral load in a patient on-treatment, the more likely that it will develop a drug resistant HIV. This why it is so important to get the viral load in him as low as possible, as quickly as possible and ideally below 50 HIV RNA copies / mL. The cooperation of patient is very needed (adherence etc.) Treatment Update Seminar – Prague, 24-26 November, 2006   Generally, when viral load is low, CD4 counts will be high In a similar way, when CD4 counts are low, viral load will be high. Treatment Update Seminar – Prague, 24-26 November, 2006