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Chapter 1

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STAT 2230
Dan Meegan

Chapter 1- Understanding HIV • Why study evolution? o The tools and techniques of evolutionary biology offer crucial insights into matters of life and death • Human Immunodeficiency Virus (HIV) causes Acquired Immune Deficiency Syndrome (AIDS) o HIV is an emerging virus, it rapidly evolves drug resistance and it is deadly • Evolutionary biology is the science devoted to understanding two things: o How populations change through time following modifications in their environment o How new species come into being 1.1- The Natural History of the HIV/AIDS Epidemic • List of worst epidemic in human history according to the number of deaths: o Influenza-50 to 100 million deaths-across the globe o Black Death (1347-1352)-took 30%-50% of the European population-about25 million lives o New World small pox-released in 1520 by European conquistadores-decimated Native American populations across two continents • AIDS is among the worst epidemics in human history o Was first recognized in 1981 o So far infected more than 65 million people o 25 million have already died o By year 2020, a total of 90 million lives would have been claimed by AIDS o According to World Health Organization, AIDS is responsible for about 4.9% of all deaths worldwide o Sub-Saharan Africa is mostly affected by this epidemic • HIV establishes a new infection when a bodily fluid holding the virus, usually a blood or semen, carries it from an infected person directly onto a mucous membrane or into the bloodstream of an uninfected person o Can be passed during heterosexual sex, homosexual sex, oral sex, needle sharing, transfusion with contaminated blood products, childbirth, and breastfeeding • An HIV infection can be acquired only from someone else who already has it! What is HIV? • Like all viruses, HIV is an intracellular parasite that cannot reproduce on its own o It invades specific types of cells in the human immune system o It uses enzymatic machinery and energy of these cells to make copies of itself, killing the host cells in the process • Figure 1.5 (Pg. 7) contains the life cycle of HIV in detail. o The life cycle includes an extracellular phase and an intracellular phase o During the extracellular phase, the virus moves from one host cell to another, and can be transmitted from host to host o Extracellular form of a virus is called a virion, or virus particle o During intracellular or parasitic phase, the virus replicates  HIV initiates its replication phase by latching onto two proteins on the surface of a host cell • HIV binds to two surface proteins on the target cell called CD4 and coreceptor  This binding fuses the virion’s envelope with the host’s cell membrane and spills the contents of the virion into the cell • These contents include the virus’s diploid genome (two copies of a single-stranded RNA molecule) and 3 proteins: o Reverse transcriptase- transcribes the virus’s RNA genome into DNA o Integrase- splices the DNA genome into the host cell’s genome o Protease- which plays a role in the preparation of new viral proteins • In HIV and other retroviruses, flow of genetic information is different than in cells and in viruses with DNA genomes • In retroviruses, genetic information does not follow the familiar route from DNA to mRNA to proteins o Instead it flows from RNA to DNA, then to mRNA to proteins  Once HIV’s genome is inserted into the host cell’s chromosomes, the host cell’s RNA polymerase transcribes the viral genome into mRNA, and the host cell’s ribosomes synthesize viral proteins • New virions assemble in the host cell cytoplasm, then bud off the cell membrane and enter the bloodstream • There, the new virions may find another cell to infect in the same host, or be transported to a new host o Significant feature of HIV’s life cycle is that the virus uses the host cell’s own enzymatic machinery, its polymerases, ribosomes, and tRNAs – in almost every step How Does HIV Cause AIDS? • HIV parasitizes immune system cells, particularly helper T cells. After a long battle against the virus, the immune system’s supply of helper T cells is badly depleted. Because helper T cells play a crucial role in the response to invading pathogens, this leaves the host vulnerable to a variety of secondary infections. • Through research on how SIVsm (simian immunodeficiency virus) in monkeys, it was concluded that the host’s own immune response contributes to the development of immunodeficiency o Human HIV patients treated with antiretroviral drugs plus the immunosuppressant cyclosporine maintained higher helper T cell counts than control patients treated with antiretrovirals alone • T cells derive from stem cells in the bone marrow • These stem cells generate precursors that mature into naive T cells in the thymus • Naive T cells are activated in lymph nodes • An activated T cell undergoes a burst of proliferation, yielding effector and memory cells o These circulate in the blood and move through tissues • A large fraction of the body’s memory cells reside in lymphoid tissue associated with mucus membranes lining the nose, mouth, lungs, and especially the gut • Naive T cells and memory T cells are long lived o But effector cells, which actively engage in the fight against invaders, are short lived • Any given T cell lineage has a finite capacity for replication-a capacity that is reduced with each cell division o So with each burst of replication within a T cell lineage brings that lineage closer to exhaustion • Sustained immune activation during HIV infection can ultimately deplete the body’s supply of helper T cells and lead to the collapse of the host’s defences • An untreated HIV infection exhibits distinct phases, in which the loss of helper T cells happens at different rates and appears to be driven by different mechanisms • In the acute or initial, phase, HIV virions enter the host’s body and begin to replicate • HIV gains entry into a host cell by first latching onto the cell-surface protein CD4, then binding to a coreceptor • The coreceptor used by most of the HIV strains responsible for new infections is CCR5 o These viral strains can thus infect dendritic cells, macrophages, regulatory T cells, and especially memory and effector helper T cells • HIV replicates explosively, and the concentration of virions in the blood climbs steeply o At the same time, the concentrations of CD4 T cells plummet, largely because HIV kills them while replicating o Hardest hit are the memory helper T cells in the lymphoid tissues of the gut o Since the gut is both large and vulnerable to penetrations by pathogens, the loss of these T cells is a severe blow to the body’s defenses • The acute phase ends when viral replication slows and the concentration of virions in the blood drops o This slow down may be because that the virus simply runs short of host cells it can easily invade • In addition, the immune system mobilizes against the infection and killer T cells begin to target host cells infected with HIV o The host’s CD4 T cell counts recover somewhat  This slows HIV, but it has not been stopped • As the chronic phase begins,
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