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Chapter 1

Chapter 1

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McMaster University

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 then 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, the immune system struggles to recover form its initial losses while continuing to fight the virus o Throughout the chronic phase, the immune system remains highly activated • Chronically activated state of the immune system may enhance some aspects of the host’s response to HIV • It also generates a steady supply of activated CD4 T cells in which HIV can replicate o And it burns through the host’s supply of naive and memory helper T cells by stimulating them to divide and differentiate into short-lived effector cells o Replacement of lost helper T cells ultimately depends on the production of new naive T cells by the thymus o Thymic output declines with age, however and is also impaired by HIV infection o HIV infection also damages the bone marrow and lymph nodes • as the battle goes on, immune system’s capacity to regenerate steadily erodes • viral load climbs again and the CD4 T cell counts fall • Chronic phase ends when the concentration of helper T cells in the blood drops below about 200 cells per cubic millimetre • With few helper T cells left, the immune system can no longer function o The patient develops AIDS o Syndrome is characterized by opportunistic infections with bacterial and fungal pathogens that rarely cause problems for people with robust immune systems • An HIV-infected individual that does not have the effect of anti-HIV drug therapy, if the individual has begun showing symptoms of AIDS, then the individual typically can expect to live two or three more years • AIDS begins when HIV infection has progressed to a point where the immune system does not function properly. • AZT, one of the first anti-AIDS drugs, turned out to be typical 1.2- Why does AZT Work in the Short Run, But Fail in the Long Run? • To combat viral infections, must look for drugs that are capable of inhibiting enzymes special to the virus o a drug that blocks reverse transcription should kill retroviruses with minimal side effects  rationale behind azidothymidine (AZT) • HIV’s reverse transcriptase uses the viral RNA as a template to construct a complementary strand of DNA o Reverse transcriptase makes the DNA using building blocks-nucleotides-stolen from the host cell o AZT is similar in its chemical structure to the normal nucleotide thymidine-so similar that AZT fools reverse transcriptase into picking it up and incorporating it into the growing DNA strand  There is a crucial difference between the normal thymidine and AZT • Thymidine has a hydroxyl group (-OH) • AZT has an azide group (-N )3  The hydroxyl group that AZT lacks is precisely where reverse transcriptase would attach the next nucleotide to the growing DNA molecule  Thus reverse transcriptase is now stuck, unable to add more nucleotides and therefore it cannot finish its job  AZT thus interrupts the pathway to a new viral proteins and new virions • AZT could lose its effectiveness in either or both of two ways: o One way is that the patient’s own cellular physiology could change  After it enters a cell, AZT has to be phosphorylated by the cell’s own thymidine kinase enzyme to become biologically active • Perhaps long-term exposure to AZT causes a cell to make less thymidine kinase o Thus causing it to become less effective over time  When this hypothesis was tested, it was proven to be incorrect • Concentrations of phosphorylated AZT did not change over time o Other way AZT could lose its effectiveness is that the population of virions living inside the patient could change so that the virions themselves would be resistant to disruption by AZT  When this was tested, it was concluded that in most patients, evolution of AZT- resistant HIV takes just 6 months • How do you distinguish between a resistant virion versus a susceptible one? o To answer this, we must figure out how an HIV virion can be capable of replicating in the presence of AZT?  Simplest answer might be to change the active site in the reverse transcriptase enzyme, making it less likely to mistake AZT for the normal nucleotide
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