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AIDS • Acquired immune deficiency syndrome • A group of illnesses resulting from immune system damage caused by infection with HIV. 1 Human Immunodeficiency Virus (HIV) structure. • The outer shell of the virus is known as the viral envelope. • Embedded in the viral envelope is a complex protein known as env, which consists of an outer protruding cap glycoprotein (gp) 120, and a stem gp41. • Within the viral envelope is an HIV protein called p17 (matrix), and within this is the viral core or capsid, which is made of another viral protein p24 (core antigen). 2 • The major elements contained within the viral core are: - two single strands of HIV RNA - a protein p7 (nucleocapsid) - three enzyme proteins p51 (reverse transcriptase) p11 (protease) p32 (integrase) 3 HIV Replication • HIV has a diameter of 1/10,000 of a millimetre. • HIV belongs to class of viruses called retroviruses • These have genes composed of ribonucleic acid (RNA) molecules. • Retroviruses, like all viruses, can only replicate within a living host cell because they contain only RNA and they do not contain DNA. • Retroviruses use RNA as a template to make DNA. 4 • Infection begins when HIV particle encounters a T-Helper cell with a surface molecule called CD4. • Virus particle uses gp120 to attach itself to the cell membrane • Then enters the cell. • Within cell, virus particle releases its RNA • The enzyme reverse transcriptase then converts the viral RNA into DNA. 5 • New HIV DNA moves into the cell's nucleus • With the help of the enzyme integrase its then inserted into the host cells DNA. • Once in the cell's genes HIV DNA is called a provirus. • The HIV provirus is then replicated by the host cell, which can then release new infectious virus particles. 6 Origins of HIV 1). Simian Virus • HIV part of family of viruses – Lentivirusus • Lentiviruses found mainly in non human primates • Primate Lentiviruses collectively known as Simian (monkey) viruses (SIV) • Simian immunodeficiency virus (SIV) • HIV accepted as a descendant of SIV HIV – 1 corresponds to SIV in green monkey HIV – 2 corresponds to SIV in chimpanzee 7 2). Crossed species? • Virus crossed from chimps to humans • Zoonosis – transfer of virus from animals to humans e.g. • Eating chimp for food • Iatrogenic transfer (via medical experiments) - Oral polio vaccine Chat. Grown in chimp kidney cells in Congo. Contamination of vaccine with chimp SIV - Vaccine given to 1x106 people in Belgium Congo, Ruanda and Urundi 8 Transmission of HIV • Cannot survive dry conditions. • No air transmission, body fluids only • Blood Products • Drug Misuse • Sexual Transmission • Mother to child transmision - pregnancy - labour and delivery - breastfeeding 9 HIV Subtypes • 2 types of HIV: - HIV-I, predominant type - HIV-2, less easily transmitted • Both HIV-I and HIV-2 transmitted by: - sexual contact, through blood, and from mother to child • They appear to cause clinically indistinguishable AIDS. • However, HIV-2 is less easily transmitted • Period between initial infection and illness is longer in the case of HIV-2. 10 • HIV-I mutates readily • HIV-I has many different strains • Strains classified into 2 groups: - Group M - 10 distinct subtypes (A-J) - Group O - other subtypes • Subtypes differ in: 1. Mode of transmission subtype B – homosexual contact / intravenous drug use subtype E / C – heterosexual transmission 11 2. Genetic composition 3. Subtype distribution B; Americas, Japan, Australia, Europe A,D; Africa C; South Africa, India E; Central Africa, Thailand, Asia F; Brazil, Romania G,H; Russia, Central Africa I; Cyprus O; Cameroon 12 The Groups of Antiretroviral Drugs • There are three main groups of anti-HIV drugs. • Each of these groups attacks HIV in a different way. - Reverse Transcriptase Inhibitors - Protease Inhibitors - Fusion or Entry Inhibitors 13 Reverse Transcriptase Inhibitors • 2 Types: (a) Nucleoside Reverse Transcriptase Inhibitors (b) Non-Nucleoside Reverse Transcriptase Inhibitors 14 Nucleoside Reverse Transcriptase Inhibitors • First type of drug available to treat HIV infection (1987) • HIV needs enzyme reverse transcriptase to be able to infect healthy cells and reproduce itself in a person's body. NRTIs: - inhibit reverse transcriptase. - drugs slow down the production of the reverse transcriptase enzyme - make HIV unable to infect cells and duplicate itself. 15 Non Nucleoside Reverse Transcriptase Inhibitors • Drugs started to be approved in 1997 • These drugs also stops HIV from infecting cells by intervening with the trancriptase of the virus. • The non-nucleoside drugs work slightly differently from the nucleoside analogues • They bind in a different way to the cell's reverse transcriptase. • The non-nucleoside drugs block the duplication and the spread of the HIV. 16 Protease Inhibitors • The third type of antiretrovirals. • Inhibit protease. • Almost every living cell contains protease. • Protease is a digestive enzyme that breaks down protein and is one of the many enzymes that HIV uses to reproduce itself. • The protease in HIV attacks the long healthy chains of enzymes and proteins in the cells and cuts them into smaller pieces. 17 • The infected smaller pieces of proteins and enzymes continue to infect new cells. • Protease inhibitors (PI) take effect before the protease in HIV has the chance to break down the protein and enzymes. • The PI slow down the duplication of the virus and so prevent infection of new cells. • The NRTIs and NNRTIs only have an effect on newly infected cells. • PI are able to slow the process of immature noninfectious virus becoming mature and infectious. • PI also work in cells that have been infected for a long time, by slowing down the reproduction of the virus. 18 Fusion or Entry Inhibitors • Fourth group of antiretrovirals called Fusion or Entry Inhibitors. • These drugs have yet to be approved and are currently going through clinical trials in the UK and the USA. • The surface of HIV carries proteins called gp41 and gp120. • These are the proteins, which allow HIV to attach itself to, and enter into cells. • By blocking one of these proteins, fusion inhibitors slow down the reproduction of the virus. 19 • For example, T-20, the fusion inhibitor that is closest to approval, sticks to the protein gp41. • The T-20 fusion inhibitor differs from the other antiretrovirals in that it needs to be injected. • T-20 is a protein and cannot be taken orally, since it would be digested in the stomach. • It is hoped that the results from the T-20 trials across the USA and Europe will completed and returned to the Federal Drug Agency (FDA) by autumn 2002. 20 Progression of HIV • Acute retroviral syndrome – flu, cough, rash • Asymptomatic phase – 5-6 years • Symptomatic phase – AIDS • Opportunistic infection – Pneumonia, cancers 21