HIV Lecture Notes 2024 - Dr. Beth MacDougall-Shackleton - PDF
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University of Western Ontario
2024
Dr Beth MacDougall-Shackleton
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Summary
This document is a set of lecture notes from a university class, likely a biology or immunology class. Dr MacDougall-Shackleton's lecture notes summarize the evolution of HIV, the challenges in developing effective treatments, and discusses HIV resistance to AZT. Topics include the lifecycle of HIV, treatments, and associated resistance mechanisms and examples.
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Dr Beth MacDougall-Shackleton [email protected] Office hours Friday 10-12, BGS 2084 (the weeks that I teach) And/or ask questions on the Brightspace forums! https://join.iclicker.com/DIHH & sign into your iclicker account...
Dr Beth MacDougall-Shackleton [email protected] Office hours Friday 10-12, BGS 2084 (the weeks that I teach) And/or ask questions on the Brightspace forums! https://join.iclicker.com/DIHH & sign into your iclicker account 2024- Lecture 2- Evolution in action: Human immunodeficiency virus Context: ~430 000 deaths/year from malaria; 400 000 from influenza; 11 000 from 2014-2016 Ebola outbreak; 3 million in 2020 from Covid-19 HIV prevalence worldwide < 0.5 0.5–1 1–2 2–3 3–5 5–10 10–20 >20 Source: UNAIDS special analysis, 2021. Note: Data includes 244 countries and territories. Zoonotic diseases spread (spill over) to humans from nonhuman animals 75% of new infectious diseases more likely between closely related species often not very harmful in the original host (reservoir) but much SIV (simian immunodeficiency virus) has a long history of infecting nonhuman primates. Multiple spillovers to humans ( HIV) Where do viruses fit in the tree of life? Viruses protein shell with nucleic acid genome inside (DNA or RNA, single or double stranded) obligate parasites (need to infect cells to make proteins and replicate) Herpesvirus Coronavirus HIV (dsDNA) (ssRNA, +strand) (ssRNA, retrovirus) Relative to antibiotics (drugs used to treat bacterial infections) or antifungals (drugs used to treat fungal infections), antiviral drugs are harder to design and usually have more serious side effects. Retroviruses, including HIV, have an RNA genome replication DNA reverse transcription (RT) transcription 1. High mutation rate RNA 2. Specific to retroviruses translation protein HIV lifecycle: targets immune cells Virion fuses with host immune cell Viral reverse transcriptase reverse- transcribes viral RNA to ds DNA Viral integrase splices viral DNA into host DNA Viral DNA gets transcribed, translated, and forms new virions DNA RNA protein reverse transcriptase (RT) The drug AZT is a nucleoside analog – shaped almost like thymidine (T) What happens when RT adds AZT to the chain? What happens after a few months of AZT treatment? nucleotide sequence of reverse transcriptase gene position of genes: susceptible to AZT CCCATTAGCCCTATTGAGACTGTACCAGTAAAATTAAAGCCAGGAATGGATGGCCCAAAAGTTAAACAAT GGCCATTGACAGAAGAAAAAATAAAAGCATTAGTAGAAATTTGTACAGAGATGGAAAAGGAAGGGAAAA TTTCAAAAATTGGGCCTGAAAATCCATACAATACTCCAGTATTTGCCATAAAGAAAAAAGACAGTACTAAA TGGAGAAAATTAGTAGATTTCAGAGAACTTAATAAGAGAACTCAAGACTTCTGGGAAGTTCAATTAGGAA TACCACATCCCGCAGGGTTAAAAAAGAAAAAATCAGTAACAGTACTGGATGTGGGTGATGCATATTTTTC AGTTCCCTTAGATGAAGACTTCAGGAAGTATACTGCATTTACCATACCTAGTATAAACAATGAGACACCAG GGATTAGATATCAGTACAATGTGCTTCCACAGGGATGGAAAGGATCACCAGCAATATTCCAAAGTAGCAT GACAAAAATCTTAGAGCCTTTTAGAAAACAAAATCCAGACATAGTTATCTATCAATACATGGATGATTTGTA TGTAGGATCTGACTTAGAAATAGGGCAGCATAGAACAAAAATAGAGGAGCTGAGACAACATCTGTTGAG GTGGGGACTTACCACACCAGACAAAAAACATCAGAAAGAACCTCCATTCCTTTGGATGGGTTATGAACT CCATCCTGATAAATGGACAGTACAGCCTATAGTGCTGCCAGAAAAAGACAGCTGGACTGTCAATGACATA CAGAAGTTAGTGGGGAAATTGAATTGGGCAAGTCAGATTTACCCAGGGATTAAAGTAAGGCAATTATGTA AACTCCTTAGAGGAACCAAAGCACTAACAGAAGTAATACCACTAACAGAAGAAGCAGAGCTAGAACTGG CAGAAAACAGAGAGATTCTAAAAGAACCAGTACATGGAGTGTATTATGACCCATCAAAAGACTTAATAGCA GAAATACAGAAGCAGGGGCAAGGCCAATGGACATATCAAATTTATCAAGAGCCATTTAAAAATCTGAAAA CAGGAAAATATGCAAGAATGAGGGGTGCCCACACTAATGATGTAAAACAATTAACAGAGGCAGTGCAAA AAATAACCACAGAAAGCATAGTAATATGGGGAAAGACTCCTAAATTTAAACTGCCCATACAAAAGGAAAC ATGGGAAACATGGTGGACAGAGTATTGGCAAGCCACCTGGATTCCTGAGTGGGAGTTTGTTAATACCCC TCCCTTAGTGAAATTATGGTACCAGTTAGAGAAAGAACCCATAGTAGGAGCAGAAACCTTC change to two nucleotides confers AZT resistance position of genes: resistant to AZT CCCATTAGCCCTATTGAGACTGTACCAGTAAAATTAAAGCCAGGAATGGATGGCCCAAAAGTTAAACAAT GGCCATTGACAGAAGAAAAAATAAAAGCATTAGTAGAAATTTGTACAGAGATGGAAAAGGAAGGGAAAA TTTCAAAAATTGGGCCTGAAAATCCATACAATACTCCAGTATTTGCCATAAAGAAAAAAGACAGTA CTAAATGGAGAAAATTAGTAGATTTCAGAGAACTTAATAAGAGAACTCAAGACTTCTGGGAAGTTCAATTA GGAATACCACATCCCGCAGGGTTAAAAAAGAAAAAATCAGTAACAGTACTGGATGTGGGTGATGCATATT TTTCAGTTCCCTTAGATGAAGACTTCAGGAAGTATACTGCATTTACCATACCTAGTATAAACAATG AGACACCAGGGATTAGATATCAGTACAATGTGCTTCCACAGGGATGGAAAGGATCACCAGCAATATTCCA AAGTAGCATGACAAAAATCTTAGAGCCTTTTAGAAAACAAAATCCAGACATAGTTATCTATCAATACATGGA TGATTTGTATGTAGGATCTGACTTAGAAATAGGGCAGCATAGAACAAAAATAGAGGAGCTGAGACAACAT CTGTTGAGGTGGGGACTTTACACACCAGACAAAAAACATCAGAAAGAACCTCCATTCCTTT GGATGGGTTATGAACTCCATCCTGATAAATGGACAGTACAGCCTATAGTGCTGCCAGAAAAAGACAGCTG GACTGTCAATGACATACAGAAGTTAGTGGGGAAATTGAATTGGGCAAGTCAGATTTACCCAGGGATTAAA GTAAGGCAATTATGTAAACTCCTTAGAGGAACCAAAGCACTAACAGAAGTAATACCACTAACAGAAGAAG CAGAGCTAGAACTGGCAGAAAACAGAGAGATTCTAAAAGAACCAGTACATGGAGTGTATTATGACCCATC AAAAGACTTAATAGCAGAAATACAGAAGCAGGGGCAAGGCCAATGGACATATCAAATTTAT CAAGAGCCATTTAAAAATCTGAAAACAGGAAAATATGCAAGAATGAGGGGTGCCCACACTAATGATGTAA AACAATTAACAGAGGCAGTGCAAAAAATAACCACAGAAAGCATAGTAATATGGGGAAAGACTCCTAAATT TAAACTGCCCATACAAAAGGAAACATGGGAAACATGGTGGACAGAGTATTGGCAAGCCACCTGGATTCC TGAGTGGGAGTTTGTTAATACCCCTCCCTTAGTGAAATTATGGTACCAGTTAGAGAAAGAAC CCATAGTAGGAGCAGAAACCTTC * * How does HIV become resistant to AZT? Evolution of AZT resistance mutations variation in AZT-resistance AZT resistance passed from ‘parents’ to ‘offspring’ not all virions reproduce when AZT is present, some forms (AZT- resistant) are more likely to reproduce than others (AZT-susceptible) viral population changes over time VARIATION + NONRANDOM SURVIVAL _______________ ??? “Mutation proposes, selection disposes” New genetic variants (mutations) are constantly occurring, regardless of the environment The environment (in this case, presence vs absence of AZT) affects which variants become more common, not which variants occur HIV rapidly evolved resistance to our first drug, AZT How have we been able to treat HIV/AIDS? Resistance to one drug is easy: resistance to many drugs is less likely Fusion inhibitors, CCR5 inhibitors work here RNA Non-nucleoside RT inhibitors DNA work here genome Nucleoside/nucleotide analogs integration work here (e.g. AZT) Integrase inhibitors work here genome replicated viral proteins synthesized Protease inhibitors work here HIV’s high mutation rate also makes vaccine development challenging mutations in other viral genes change the outer structure of the virus enables HIV to evade our immune system difficult to generate vaccine to account for all potential variants there is still no universal HIV vaccine, and perhaps may never be 2024- Summary: Evolution in action evolution can be very fast even non-living things can evolve viral evolution involves themes such as – evolutionary history – mutation and variation – natural selection – humans as an evolutionary force
