Acquired Immunodeficiency Syndrome AIDS

1. Acquired Immunodeficiency SyndromeAIDS

2. Epidemiology • HIV is a blood-borne pathogen • Routes of transmission: blood or blood products IV drug abuse Heterosexual & Homosexual activity Maternal-child transmission before or during childbirth • Predominant means of transmission is heterosexual contact

3. Meet the wily HIV virus Viruses are simple microorganisms consisting of nucleic acid protected from the environment by a layer of proteins. Viruses have surface molecules that act as receptors for molecules found on the surface of target cells. The specificity of the receptors helps viruses infect selected target cells which determines the symptoms of that particular infection. A virus will attach to the target cell, insert its genome into the cell, utilize the cell’s protein synthesizing capacity to translate viral proteins, replicate these proteins, and release them from the cell to infect other cells. McCance & Huether (2006) page 280

4. Pathogenesis HIV is a type of virus called retrovirus, which carries genetic information in the form of RNA rather than DNA. Retroviruses use a viral enzyme, reverse transcriptase, to convert RNA into double-stranded DNA. Using a second viral enzyme, an integrase, the new DNA is inserted into the infected cell’s genetic material where it may remain dormant, where it can remain latent for years. However, if the cell is activated, translation of the viral information may be initiated, resulting in the formation of new virions, lysis and death of the infected cell, and shedding of infectious HIV particles. McCance & Huether (2006). Pages 280-1. Picture: The Body (2009). The Complete HIV?AIDS Resourse

5. HIV Infection • HIV infects cells in the immune system and the central nervous system. The main type of cell that HIV infects is the T helper lymphocyte. These cells play a crucial role in the immune system, by coordinating the actions of other immune system cells. A large reduction in the number of T helper cells seriously weakens the immune system. • HIV infects the T helper cell because it has the protein CD4 on its surface, which HIV uses to attach itself to the cell before gaining entry. This is why the T helper cell is sometimes referred to as a CD4+ lymphocyte. Once it has found its way into a cell, HIV produces new copies of itself, which can then go on to infect other cells. • Over time, HIV infection leads to a severe reduction in the number of T helper cells available to help fight disease. The process usually takes several years. • HIV infection can generally be broken down into four distinct stages: primary infection, clinically asymptomatic stage, symptomatic HIV infection, and progression from HIV to AIDS. Avert (2009) The Different Stages of HIV Infection.

6. HIV to AIDS The primary surface receptor on HIC is the envelope protein gp120, which binds to the molecule CD4, found primarily on the surface of helper T cells. Other co-receptors on the target cells are the chemokinereceptors CXCR4 and CCR5. Different strains of HIV1 are selective for the CXCR4 or CXCR5 co-receptors. McCance & Huether (2006). Page 282 Image : Kortright, (2008)

7. HIV to AIDS Strains that prefer the CXCR4 co-receptor tend to be T-Cell tropic, and cause infected cells to fuse and form a multinucleate syncytium. Strains that react better with the co-receptor CCR5 are macrophage-tropic, usually cause the primary HIV infection Primary cellular targets for HIV • CD4-positive Th cells • Dendritic cells • Macrophages • CD8-positive Tcells • Double-positive thymic cells • NK cells • Neural cells • McCance & Huether (2006). Page 282

8. Primary sites of infection are usually the lymphoid areas of the mucosal surfaces. Dendritic cells and mucosal T cells spread the infection to other lymphoid organs in the lymph nodes. • McCance & Huether (2006). Page 284 • CD4+Th cells decrease by lysis or apoptosis, thymic production of new T cells is decreasesd and lymph nodes are damaged. • Circulating antibody against HIV appears rapidly after infection.

9. Binding and Fusion: HIV begins its life cycle when it binds to a CD4 receptor and one of two co-receptors on the surface of a CD4+ T- lymphocyte. The virus then fuses with the host cell. After fusion, the virus releases RNA, its genetic material, into the host cell. Reverse Transcription: An HIV enzyme called reverse transcriptase converts the single- stranded HIV RNA to double-stranded HIV DNA. Aidsinfo(2009)U.S. Department of Health and Human Services.

10. The HIV Life Cycle Integration: The newly formed HIV DNA enters the host cell's nucleus, where an HIV enzyme called integrase "hides" the HIV DNA within the host cell's own DNA. The integrated HIV DNA is called provirus. The provirus may remain inactive for several years, producing few or no new copies of HIV. Transcription: When the host cell receives a signal to become active, the provirus uses a host enzyme called RNA polymerase to create copies of the HIV genomic material, as well as shorter strands of RNA called messenger RNA (mRNA). The mRNA is used as a blueprint to make long chains of HIV proteins.

11. The HIV Life Cycle Assembly: An HIV enzyme called protease cuts the long chains of HIV proteins into smaller individual proteins. As the smaller HIV proteins come together with copies of HIV's RNA genetic material, a new virus particle is assembled. Budding: The newly assembled virus pushes out ("buds") from the host cell. During budding, the new virus steals part of the cell's outer envelope. This envelope, which acts as a covering, is studded with protein/sugar combinations called HIV glycoproteins. These HIV glycoproteins are necessary for the virus to bind CD4 and co- receptors. The new copies of HIV can now move on to infect other cells.

12. Terms CD4 receptor: A protein present on the outside of infection- fighting white blood cells. CD4 receptors allow HIV to bind to and enter cells. Co-receptor: In addition to binding a CD4 receptor, HIV must also bind either a CCR5 or CXCR4 co-receptor protein to get into a cell. T-lymphocyte: A type of white blood cell that detects and fights foreign invaders of the body.