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Biology 1001A Lecture 2.pdf

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Western University
Biology 1001A
Beth Mac Dougall- Shackleton

Biology 1001A | 2012 LECTURE NOTES Lecture 2 Evolution in Action: HIV –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– The HIV Pandemic - outbreaks of infectious disease are called epidemics - when they are not confined to one place in the world, they are called pandemics - identified 30 years ago in 1981 - AIDS (Acquired Immunodeficiency Syndrome) is caused by the HIV virus - it has spread worldwide, so there is a world wide outbreak of this disease - affects all inhabited continents - many areas are far more affected than others - Sub-Saharan Africa has been very heavily affected by the HIV pandemic - about 60% of the affected people live in Sub-Saharan Africa - radical life expectancy decrease in these countries - despite the efforts, the number of people with HIV continues to rise - total of 33 million people infected with HIV - total children with HIV 370,000, concentrated in Sub-Saharan Africa - the number of people living with HIV has increased over the last 20 years GroupON - Still no cure for HIV/AIDS. Why not? - fast mutation rate that makes it unresponsive to vaccines - hides and disguises itself to avoid the body’s immune system - maybe body has no natural immunity against the virus - maybe the problem is that there is too many different strains of the virus Tree of Life: where do viruses fit in? - viruses do not fit on the tree of life because they are not living - viruses are not living because they require a host to replicate and perform functions - viruses cannot perform metabolic processes because they are not cells - viruses are obligate cellular parasites, they cannot reproduce without entering a host cell - they use materials in the host cell to replicate themselves - anti-viral therapy often has serious side effects because anti-virals have to target the mechanisms being used by the virus to reproduce, which is the cell’s mechanisms of reproduction - for this reason, stopping the virus would likely result in the death of the cell - the viruses use the infrastructure of the host to do their work The Central Dogma of Molecular Genetics - information flows in one direction in cell based life - DNA can either replicate itself to make more DNA or DNA can be transcribed to RNA, but not the other way around, i.e. DNA can not be made from RNA Biology 1001A | 2012 - but in retroviruses like HIV do not store their genetic information in the form of DNA, but instead store it as RNA - retroviruses have to use reverse transcription to create DNA that can be integrated into the host cell - reverse transcription has no proofreading enzymes and is therefore error prone - this is part of the high mutation of retroviruses and HIV in particular - the mutation rate in HIV is 1 million times higher than in human cells HIV Lifecycle: Hijack Immune Cells - designing a drug to kill the virus is difficult to do without destroying too many of the host cells - how retroviruses work - retroviruses work around the typical manner of protein synthesis - retroviruses start with RNA and use reverse transcription to make DNA - reverse transcription is carried out by reverse transcriptase - DNA must be made from RNA so that the viral genetic sequence can be incorporated into the host DNA - there are no proofreading enzymes, therefore reverse transcription is highly error prone, this causes the frequent mutations of the virus - enzyme intergrase splices the viral DNA into the host genome - host cell mechanism of replication is hijacked by virus and begins to transcribe and translate new viruses - new viral particles then either bud off from the cell or lyse out - either method of exiting results in new viral particles entering the host system to infect more cells and begin the process of taking over the cell once again - since HIV targets immune cells specifically, the lysis of cells when the viral particles exit is the reason that HIV is able to take out the host immune cells - the host would typically succumb to a secondary infection which would be at an advantage due the host’s compromised immune system Anti-Retroviral therapies (ARTs) inhibit virus specific enzymes - to create an effective antiretroviral, finding an enzyme to target and disable would be ideal - inhibiting reverse transcription is ideal because it is not something that the cell has to do in order to function and survive, therefore stopping reverse- transcription would be unlikely to kill the host cell - Azetothymine (AZT) was one of the first antiretroviral therapies - AZT mimics thymidine and inhibits reverse transcriptase - AZT is similar in structure to thymine - when reverse transcriptase places an available AZT molecule in the nucleotide chain, the entire process is stalled because the next nucleotide cannot be attached to AZT, thus AZT inhibits reverse-transcription - AZT was able to slow the progression of HIV to full blown AIDS, but it eventually it stopped working - soon AZT resistance developed in patients - the amount needed increases until it stops working altogether Biology 1001A | 2012 - within six months, the virus becomes completely resistant and the drug has zero impact - so why did AZT stop working? - mutations
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