Plagues and Pandemics Part 3 PDF
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This document provides an overview of poxviruses, including smallpox and variolation. It details the characteristics, transmission, and history of these viruses. The text mentions their impact on human populations and the development of vaccines.
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Lecture 27: Poxviruses Virus have different types of genomes ○ +sense: the genome can be translated into proteins ○ - sense other strands must be transcribed to make viral proteins ○ Th type of genome can give you some clue...
Lecture 27: Poxviruses Virus have different types of genomes ○ +sense: the genome can be translated into proteins ○ - sense other strands must be transcribed to make viral proteins ○ Th type of genome can give you some clues as to how th virus replicates and how the virus evolves Pox viruses ○ Family: poxviridae ○ Double stranded DNA genome ○ Of note: the first vaccine and the only human virus to be completely eradicated Some characteristics of pox viruses ○ Poxviruses are big ○ Linear dsRNA genome of 170-250 kb ○ Replicated in the cytoplamsm of the cells ○ Virions can be seen with just light microscopy Pox viruses have large genomes and many genes ○ Tightly packed genome ○ Genes are not overlapping and do not have intorns ○ Replicate in the cell cytoplasm Poxviruses are experts in immunomodulation ○ Infected cells that sense viral infection release a aset of molecules that are called interferons (IFNs) ○ Nearby uninfected cells that have the IFN receptor will make many proteins inside the cell whose function is to combat viral infection ○ Poxviruses make a decoy receptor for interferons ○ Blocks signaling that turns on antiviral gene program Smallpox is an ancient disease if humans ○ Transmission: respiratory droplets (prolonged contact) ○ Fomites or close contact ○ Lethality: 30% ○ Earliest evidence of smallpox form more than 3000 years ago in India China and Africa ○ Endemic in Asia by 1000 CE and Endemic in every Europena country at the end of the 19th century Ancient remains can be used to sequence and dateSmallpox using phylogenetics ○ 2020: Viking age variola Virus discovered ○ Phylogenetics tells us this virus is at least a couple thousand years old. ○ I will schedule some time for us to connect. Variolation was an ealy form of vaccination forSnallpox ○ It was observed that survivors of smallpox were subsequently protected from the disease ○ 16th century: first reference to inoculation/variolation with dried pox in china ○ Variolation Drie material form infected persons ground up and placed under skin or h=inhaled, thus protecting the newly infected individual Risk of death went down The first vaccines: Cowpox protected against smallpox ○ 1790s Edward Jenner noted that milkmaids exposed to cowpox did not develop smallpox ○ He inoculated neighbour’s kid with smallpox scabs and the boy di dnot become sick ○ He calle dthe process vaccination after the word vacca (latin for cow) Current smallpox vaccine ○ Poxvirus infect a wide range of mammalian species ○ They can infect a wide range of species. ○ Smallpox vaccines Live attenuated Unknown origin and attenuation history Orthopoxus diversity: dimportance of genetic relatedness ○ Cross-species transmission of poxviruses can occur Cowpox form cows to humans Monkeypox from small mammals to humans Spread within humans limited after such transmission Eradication of smallpox globally by 1980 ○ Current immune protectio in human population ○ 70% if globa population not immune to smallpox A new poxvirus epidemic - MPOX ○ MPOX endemic in parts of Africa likely a rodent reservoirs spillover ○ 2022: spread predominantly in the gay community (this was new) MPOX is not new ○ Made first important observation of sexual transmission of monkeypox ○ Different versions of MPXV are infecting people across epidemics Lecture 28: Plagues and Pandemics Plagues and Pandemics ○ Lowest case fatality rate ever seen for Marburg infections ○ Rwanda has built up a robust health care systems ○ Contact tracing: monitoring health and testing ○ Experimental vaccines and treatment were delivered at the center of the outbreak. Poliovirus ○ Family: picornaviridae ○ Genus: enterovirus Transmitted through fecal-oral route Characteristics of Picornaviruses ○ Single stranded RNA genome of 8 kb (positive sense) ○ Viral genome is “infectious” ○ RNA is both message(mRNA) and genome of the virus ○ No envelope (membrane) ○ They have protein shells ○ Host species: humans and other mammals ○ transmission : fecal oral or respiratory ○ 3 poliovirus ‘serotypes’ all are variants that infect people ○ Diseases: paralysis, “summer cold” meningitis, polio Replication of Picornoviruses ○ Picornoviruses make lost of individual proteins by cleaving a large ‘poly protein’ with a virally encoded protease. Picornoviruses rearrange host cell membrane structures dramatically ○ Picoraviruses replicate in close association with lipid membranes ○ Viral RNA replication machinery associated with these membranes Poliovirus ○ Poliovirus is an enterovirus: transmits through the intestine vira the fecal oral route and infect motor neruons. ○ Most infections are mild or asymptomatic ○ US 0.5 to 1% result in parlysis ○ 30% are permanent ○ 40% of those who recover suffer a pos polio syndorm 30-40 years later ○ 5-10% of those paralyzed die when breathing muscles become immobile Poliovirus in the 1950s ○ Patients in iron lungs helping the to breathe Stages of poliovirus replication in a host ○ Ingested polio replicates in oropharyngeal and intestinal mucosa ○ Excreted in feces over a period of several weeks after infection ○ Reaches the blood thorugh the lymph nodes ○ In some cases enters the central nervous system through retrograde axonal transport. Why is poliovirus so successful as a pathogen ○ Only found in humans but able to infect virtually all humans ○ No treatment once infected ○ HIGHLY contagious: very stable in the environment and secreted for weeks Proteing shell with no lipid membrane ○ High number of asymptomatic infections Vaccine Development: the solution to Polio ○ Two polio vaccines were developed Inactivated poliovirus (IPV) By Jonas Salk Attenuated Oral Poliovirus 1960s By Albert SAbin and team ○ The development of HeLa cell line models allowed poliovirus to be grown in a lab and led to a vaccine HeLa cells: taken without consent ○ Henretta Lacks died in 1951 from an aggressive cervical cance ○ Doctors took cells and grew them in the lab (incredibly immoral) ○ Played a key role in development of polio vaccines and many other major biomedical studies ○ There was no consent given at the time - now what do we do Poliovirus vaccine development ○ Salk vaccine Available 1955 Inactivated virus Killed virus = no replication Made by formalin inactivation of wild-type virus ○ Sabin Vaccine 1959 Attenuated virus Live virus = can replicate Created through attenuation Attenuation ○ Attenuation seeks to isolate virus that induces immunity but not disease Reversion of virulence and vaccine-associated paralytic poliomyelitis (VAPP) ○ Poliovirus acquire 2% nucleotide divergence in the 5 days that it take sthe virus to go from the mouth to the gut in one another ○ OPV can mutate when it replicates and revert to a virulent form known as vaccine-derived poliovirus which can transmit to unvaccinated contracts ○ Because of this, OPV is no longer used in countries that have eradicated polio “Salk” inactivated vaccine ○ Advantages Nor virus spread form vaccine’no risk of vaccine related poliomyelitis Induces serum antibodies that protect against infection of the CNS ○ Disadvantages Does nto protect against infection of the intestine Does not stop spread Needs to be injected Not as cheap. “Sabin” Ora Polio virus (OPV) ○ Advantages Easy to administer without training Cheap: sabin assigned the rights of the vaccine to the WHO Replication in intestine induces mucosal immunity and prevents new infection ○ Disadvantages V irus is shread:infection of immunocompromised hosts or native population OPV can replicate in vaccines which which means it can mutate Reversion to wild typ non attenuated strain can infect other people. ○ Poliovirrus for Polio eradication: can we get there Resossn fro Poliovirus vaccine success No animal reservoir Two affective vaccines Not a lot of antigenic variation Cheap and ebay to deliver OPV Poliovirus eradication ○ Polio remains endemic in two countries: Pakistan and afghanistan Lecture 29: Measles Virus Meales ○ Family: Paramyxoviridae ○ ‘Myxa’ - Greek for mucus ○ Sungel stranded, negative sense ○ RNA genome ○ Genus Morbilivirus Example species: measles, rinderpest, cetacean morbilivirus ○ Morbili = latin for the “little disease” ○ Measles = diminutive of Latin “misella” or misery History of Measles: another ancient infection ○ Described in the 10th century by Persian Physician Rhazes ○ 3000ya: human population density became sufficient to support measles ○ Population centers in the Fertile Crescent ○ Domestication of cattle? Closest to the morbillivirus in cows Some characteristics of Morbilliviruses ○ Single-stranded RNA genome of 15-16kb ○ Host species: humans, dogs, cattle cetaceans ○ Transmission: respiratory ○ Diseases: Measles, SSPE, immunosuppression Bits and pieces of Measles Virus ○ Measles virus genome encodes only 6 proteins ○ The hemagglutinin protein is on the surface of measles virions and binds the host cell receptor ○ The Nucleoprotein is important in protecting the RNA genome Measles virus spread into and out of the body ○ MV enters the airway and infects macrophages and dendritic cells ○ These cells move the virus to the local lymph nodes V ○ irus then spreads to the additional lymph tissues and organs ○ Infection spreads to the epithelium in the airway ○ Progeny viral particles are released in the trachea and expelled by coughing and sneezing. Measles infects and kills memory lymphocytes ○ Immune responses mediated by B and T cells to other pathogens will be erased Measles pathogenesis ○ Infection adn severe depletion of activated and memory T and B cells ○ Immunosuppression thought to be a direct result of this lymphoid cell killing by the virus Immune amnesia ○ Complications or death by opportunisitic infections ○ Severe immunosuppresion can last several years Measles and “immune amnesia” ○ Memory B and T cells respond to infection to make antibodies ○ Immunological memory: the second exposure to an antigen results in a more potent immune response ○ Measles virus infection causes elimination of the antibody repertoire globally ○ This massivley wipes out preexisting immunity against other pathogens ○ Would this wipe out immune memory generated by immunization Yes it would Measles can cause disease in a chronic infection: SSPE ○ Raer chronic infection in brain can happen (fatal) ○ SSPE (subacute sclerosing panencephalitis) ○ Cognitive decline, impaired motor functions, seizures R0: Basic Reproduction Number ○ A figure expressing the average number of cases of an infectious disease arising by transmission from a single infected individualm in a population that has not previously encountered the disease R0 1: each infection causes more than one new infection (disease will spread Measles is one of the most contagious viruses around today ○ Rnot for measles virus is 15! ○ Transmission by airborne droplets ○ One of the most contagious viruses that we know of. The measeles vaccine: incredibly effective ○ The measles Vaccine is a live, attenuated vaccine (chicken cells) ○ Protective for life Measles immune memory is strong and long lasting ○ Measles epidemic in Faroe islands in 1781 ○ No measles for the next 65 years ○ 1846: measles infected >75% of the population ○ M ajority of the elderly residents did not get newly infected = 60+ years of immunity ○ This is immune memory Herd immunity can protect a population ○ In a non-immune population a pathogen with a high r0 will spreadquickly through a population ○ Population level immunity builds over a time as a pathogen infects more individuals and vaccines increase ○ Herd immunity can be achieved through infection or vaccination Mesles infection controlled infection in the 1970s ○ Measles has a very high “Herd immunity Threshold” Measles vaccination rates aren’t high enough to eliminated Measles. ○ Dramatic drops in Measles cases, but tough to get to >90% Disneyland: Not always teh most magical place ○ Dec 28th 2014 unvaccinated child hospitalized with Measles infection ○ Many more infection all from Disneyland Disneyland outbreak: large impact on vaccintation rates ○ State of California did a few things in response to Disneyland Meales outbreak ○ Educational materials to school staff on the proper application of conditional admission for kindergartners who were not up to date on required vaccinations Measles immunization campaigns in trouble due to SARS CoV 2 pandemic ○ 41 countries cut off measles immunization campaigns in 2020-2021 ○ Pandemics can impact other pandemics Help in the fight against measles a new vaccine delivery modality ○ Plastic disc with microneedles vaccination in a few minutes ○ Advantage: Easy to deliver and administer ○ Initial clinical trials in The Gambia show this si highly effective Lecture 30: Zika and Dengue Virus Zika and Dengue ○ Family Faviviridae ○ Single stranded, positive sense ○ RNA genome ○ Flavi = yellow ○ Genus Flavivirus Example species: zika, Dengue, Yellow Fever West nile. Dengue Virus is spreading locally in the US (usually travel associated) Some characteristics of Flaviviruses ○ Host species: humans, mammals, insects ○ Transmission: vector-born (mosquitoes ○ Diseases: hemorrhagic fever, encephalitis ○ Eprotein: target of antibody recognition Flaviviruses: long polyprotein is cleaved by a viral protease. ○ Genomic RNA looks like host mRNA ○ A viral protease and host proteases cleave the long genomic polyprotein Dengue virus infects multiple hosts: humans and mosquitoes ○ DENV replicates in people and infects mosquitoes ○ DENV replicates in the mosquito vector ○ Mosquitoes transmit DENV to people Dengue viruses circulate in both human and primate cycles with different mosquito vectors. ○ DENV replicates in both human (urban) and primate (sylvatic) cycles Dengue is a zoonotic spillover form infected primates ○ Dengue is viruses ciculating in human population now are cross species transmission from infected primates ○ Molecular clock analysis can date transmission of viruses that have entered the human population Flaviviruses: emerging and established human pathogens Half of world’s population currently at risk for dengue infection ○ Annually: ~390 million total dengue infections Increased global connectivity and climate change have expanded the geographic range of mosquito vectors Dengue virus infections range form asymptomatic to severe ○ 96 million get DHF and/or DSS + Dengue Fever ○ 294 million are asymptomatic or unreported ○ ¾ of Dengue infections are asymptomatic Dengue Diesease: pathogenesis ○ Dengue Disease High fever Nausea Vomiting Rash Aches and pains to the eyes, joints or bones ○ Severe Dengue 1:20 people shock internal bleeding and death ○ Dengue virus: 4 serotypes Serotype: a group of organisms distinguished by their shared specific antigens as determined by serologic testing Antibody responses to one serotype of DENV cross-react with the other serotypes Antibodies can protect from infection with the same DENV Antibodies can (in some cases) enhance dengue virus infection ○ Antibody dependent enhancement Occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they are unable to prevent infection adn instead enhance infection Secondary DENV infection has increased severe disease risk due to ADE ○ Fc GAmma receptors on many immune cells bind to antibodies ○ ADE = antibody-dependent enhancement ○ DENV can enter cells using antibodies = mor virus ○ DENVE infection vira this route may also result in aberrant cytokine secretion form these cells ○ Together this leads to increased severe disease risk A vaccine for DENV: ADE presents serious challenges ○ There is a live attenuated DENV vaccine that includes all 4 DENV serotypes ○ Major limitation: in those that have not been infected with DENV the vaccine acts as a primary infection and predisposes vaccinees to more severe risk in a subsequent DENV infection ○ Vaccines does not induce cytolytic T cell responses A bacterium is being deployed to fight DENVE infections ○ Wolbachia naturally infects many mosquito species ○ DENV transmission decreases in mosquitoes with Wolbachia Zika Virus: a DENV like flaviviurs that infects humans ○ Typically no or mild symptoms: fever, rash, headaches, joint pain etc ○ However sever infections can occur in pregnant women Zika virus: additional modes of transmission ○ Zika outcomes ○ Zika transmission DENVE and ZIKVL cross-reactive antibodies ○ Zika virus antibodies cross react with DENV viruses ○ REisk of severe DENVE disease increases after a Zika infection DENV and Zika can co-circulate in many places aroudn the globe Very littel Zika virus currently circulating globally Lecture 31: RSV Family: Pneumoviridae ○ Pneumon in Greek: lung ○ Single stranded, negative sense RNA genome ○ Genus: orthopneumovirus Characteristics of orthopnerumoviruses ○ Negative sense RNA genome ○ Hosts: humans, cattle, rodents RSV in only humans and chimps ○ Transmission: respiratory ○ Virus isolated in the lav in 1956 but we only now have a vaccine Some Charcterisitics of orthopneumoviruses ○ Glycoproteins (F and G) are targets of host antibody responses RSV pathogenesis and transmission Primarily an upper Respiratory Tract infection ○ ○ Young children: lower respiratory Tract infection (pneumonia, respiratory failure) ○ Re-infection common Where did RSV come from? ○ First siolated form chimpanzees in 1956 ○ Upper respiratory tract infection only in adults ○ Closely related viruses in cows and more distantly related viruses in bats RSV infection show strong seasonality RSV infections are most severe in babies less than one years old ○ Young babies are most susceptible to sever RSV illness ○ Immunopathogenesis Major challenges for RSV vaccine development ○ Early age of infection ○ Evasion of innate immunity ○ Natural immunity does not prevent reinfection ○ Vaccine enhanced illness occurred with original RSV vaccine An RSV vaccine cadiddate in trials: enhanced disease ○ Nonneutralizing antibodies resulted in immunocomplexes forming inflammatory deposits in lung tissue ○ Falin inactivated vaccine enhanced disease with subsequent infetion in clinical trials Respiratory Syncytial Virus replication cycle ○ The viral glycoprotein envelop changes shape quite dramatically during fusion with the cell membrane Good anti-RSV antibodies bind to specific places on the RSV F glycoprotein ○ The F protein exists in multiple shapes ○ Key antibody binding sites are not found in the postfusiuon F protein ○ Making antibodies to the postfusion is not helpful and can be harmful RSV vaccine: rational design ○ We want to only immunize people with perfusion F protein ○ Mutations introduced into RSV F protein Highly effective RSV vaccine approved in 2023 ○ Moderna RSV vaccine 83.7% effecting at preventing lower respiratory disease ○ Vaccinationg preganant women protects babies A monoclonal antibody therapy for RSV ○ Antibody similar to antibodies elicited by the vaccine ○ Given to very high-risk infants Lecture 32: Influenza Family: Orthomyxoviridae ○ Ortho = “true” ○ Myxo = “mucus” S ○ ingle Stranded, negative sense RNA genome ○ Genus Alphainfluenzavirus Betainlfuenzavirus Influenze viruses have various shapes ○ Can be enveloped, spherical, or filamentous Influenza: life cycle ○ Genome segments are packaged and virus buds from the cell ○ mRNA is exported from the nucleus and is translated ○ mRNA are made and new copies of the genome Some characteristics of Orthomyxoviruses ○ Negative sense RNA genome ○ Segmented genome ○ Hosts: aquatic birds, human, pig, horse, seals, cows and more ○ Transmission: Respiratory, Fecal-oral (bird) Orthomyxoviruses: a closer look ○ NP = nucleoprotein, coats/protects genome inside cells ○ HA - surface glycoproteing, binds receptor, fusion protein. ○ NA = surface glycoprotein Fish may have been ancient hosts of influenza ○ Fish influenza-like viruses are closely related to all the influenzas that infect mammals Influenza viruses: more than just one virus ○ There are 4 general types of influenza viruses C viruses: cause mild illness and are not thought to cause human flu epidemics D viruses: primarly affect cattle and are not known to infect or cause illness in people A and B viruses: cause th flue season almost every winter in the US A viruses: the only inflluenza viruses known to cuase flu pandemics Influenza A is the most important inflenza virus for human health ○ Cause local epidemics or pandemics with significant infection rates ○ Influenza A has wide host range and epidemiology involves close contact of humans, farm animals and birds ○ Zoonotic spillover plays an important role in influenza biology Orthomyxoviruses: a closer look ○ Serotype: determined by NA subunits Neuraminidase is needed for release of virions form the infected cells ○ Virions have NA on their surface which allows for cleavage of sialic acid on the cell surface to be released form the cell ○ NA is the target for the major antiviral agents for influenza Sialic Acid (sugars) attached to proteins are the receptor for influenza viruses ○ Sugars attached to proteins and lipids ○ Glycocalyx: dense, gel like meshwork surrounding the cell ○ S ialic acid - suagar component of the glycocalyx that influenza uses to bind to and enter cells. Influenza infects the respiratory epithelium in the lungs ○ Respiratory transmission Upper respiratory tract infection: less severe Lower respiratory tract infection: more severe ○ Virus replication peaks ~48 hours after infection and declines slowly thereafter wiht little shedding of virus after days 6 to 8 Severe influenza: infection with influenza can cause a “cytokine storm” ○ Order Influenza infects lung epithelial cells and macrophages Cytokines released More immune cells are recruited More cytokines released ○ Influenza virus Infection cytokines /chemokines More immune activation Cytokine storm ○ Immunopathology can be a major contributor to severe influenza infections Influenza is one of the Big Ones ○ >one billion cases of seasonal flu annually ○ Half a million deaths globally ○ 3-5 million severe cases ○ In the US: 10s of 1000 die each year from influenza People born more recently have a lower risk of dying from influenza ○ Drop in influenza morality in US may be due to behaviroral / hygeine effects Vaccination “Flu season” is ramping up in the US ○ More Flu A than Flu B ○ Lowest rates of infection in summer, ruses through fall into winter (like RSV) Influenza is seasonal (peaks in late Fall//winter in both hemispheres) Influenza is less seasonal near the equator ○ Viruses at the Equator seed seasonal epidemics in N and S hemisphere ○ Data that leads to this interpretation: molecular epidemiology. Orthomyxoviruses: the genome is broken up into segments ○ Influenza genes are on each of the 8 segments Influenza can “Reassort its genome ○ The separation of genes on different segments has a major impact on influenza evolution ○ 2 different influenza viruses can infect the same cell ○ When new viruses are made they can be made up of gene segments from both viruses Reassortment viruses can cause major pandemics ○ The 1918 flue: looked different than Influenza A viruses that were circulatin in the population before ○ Uniquley severe among influenza infection in healthy adults ○ Should we expect a 1918-like pandemic to happen again? History of influenza pandemics in humans ○ 1918 - H1N1 “spanish Influenza ○ 1957 - H2N2 “asian flu” ○ 1968 - H3N2 “ Hong Kong Flu” ○ 1977 H1N1 “Russian flu” ○ In the initial years of teh pandemics up to 50% of the human population becomes infected Lecture 34: Influenza II Reassorted viruses can cause MAJOR pandemics. ○ The 1918 Flu: looked different than Influenza A circuses that were circulating in the population before ○ Uniquely severe among influenza infection in healthy adults Viruses can emerge from animal reservoirs Crosse species viral transmission evets zoonoses ○ Ebola, influenza, and HIV A new influenza in Spring of 1918 ○ “Spanish Flu” ○ Name Spanish flu but this is a misnomer ○ First case was in Kansas spread in US troops Where did the 1918 influenza strain come from? ○ Influenza infected tissues were collected and stored in ‘fixative’ ○ Permafrost: can recover viral sequences. 1918 segments are closely related to virus sequences found in birds ○ Influenza A ○ 1918 gene segments are closely related to avian sequences ○ 1918influenza: avian virus new to infecting humans 1918 influenza infections were deadly ○ October1918: 195,000 deaths in the US during one month The scale of the1918 influenza pandemic was massive ○ 20-40 million influenza deaths world wide during the 1918/19 pandemic ○ Indegenous peoples (alaska) hit particularly hard: Villages wiped ou, some lost most of their adult population ○ Large decreas in life expectancy The 1918 influenza was unusual in its high death rate among adults Cross reactive immune responses to influenza ○ There is evidence that an H1 virus circulated in 1851 There is evidence that an H3 virus circulated in late 1800s ○ Unusual severity in adults may be explained by cross reactive immune responses ○ Infividuals born in early to mid 800s had seen H1 flu before = cross reactive immunity ○ Individuals born in late 1900s had not seen H1 flu before and instead had seen a different HA = cross reactive (but not protective) immunity Influenza HA is important in virus evolution including shifts, drift and for vaccination ○ HA mediates receptor binding ○ HA is the majore target for antibody recognition ○ Virsu mutation leads to antibody/immune escape Surface protein of viruses that excape immune responses contain many adaptive mutation ○ Mutations in viral sequences can lead to loss of antibody = “ immune escape” ○ Antibodies recognize influenza HA. ○ Orthomyxoviruses (including influenza) have a high rate of ‘antigenic’ evolution (escape from immune responses) Surface proteins contain many adaptive mutations ○ Influenza Ha is rapidly evolving Variation in viral sequences arises in several way ○ Small scale change:: antigenic drift Antigenic drift ○ Point mutations in HA and NA in existing human variants ○ Annual epidemics ○ Some cross protection ○ Antigenic drift is selection for escape from neutralizing antibodies Antigenic Shift ○ Reassortment of new HA and/or NA RNA segments from other strains into humans ○ Global pandemic ○ Little cross protection ○ Up to 30% of the human population becomes infected Influenza viruses: mutation in sequnce accumulate over time ○ Seasonal evolution (drift) is why we need a new influenza vaccine each year Antigenic drift: selection on amino acid mutatiuons over time changes immune recognition in population Seasonal influenza vaccines ○ Influenza vaccines: both inactivated and live attenuated ○ Given in Oct/Nov each year (before seasonal influenza peak) ○ In a good sease, flue vaccines ~60% effectiveness but can be lower ○ Flu vaccines provide additional protection even if you do get sick Influenza vaccines: historically made in eggs ○ Egg based flu vaccines ○ DisadvantagesL need lots of eggs not all flue strains grow in eggs Influenza vaccines: making the right vaccines at the right tie isnt easy Predicting circulating strains across seasons is challenging ○ High does vaccine are more effective in older people ○ Influenza mortality usually highest iun the very young and very old ○ A high dose vaccine is recommended for older adults. Lecture 34 cont.: Influenza III Zoonoses A reservoir of influenza A diversity resides in aquatic birds ○ Transmission differences: Influenza grows in the intestinal tract of aquatic birds and causes little or no disease Influenza typically grows in respiratory tract of mammals Avian HA uses a slightly different Sialic Acid compared to human-infecting influenza HAs ○ Higher virulence and lack of efficient person to person transmission likely due to this difference in sialic acid expression in human respiratory tract Avian influenza infections can often be more severe in outcome ○ Many human “Avian Flu” infections: higher virla loads and increased levels of chemokines/cytokines produced by bronchial epithelial cells and alveolar macrophages. Influenza can “ Reassortment” its genome ○ The separation of genes on different segments has a major impact on influenza evolution 2 different influenza viruses can infect the same cell When new viruses are made they can be made up of gene segments from both viruses Transfer of segments from avian influenza strains leads to new pandemic human strains ○ H1N1 ○ 1918 H1N1 birds -> people ( no reassortment) but big change in immunogenecity ○ Immunogenicity: the ability of a foreign substance, such as an antigen to provoke an immune response ○ Reassortmennt can lead to large changes in immunogenicity History of Influenza pandemics in humans ○ In the initial years of the pandemics up to 50% of the human population becomes infected 2009: H1N1 “Swine Flu” pandemic ○ Unusual cluster of respiratory illness in la gloria Mexico (very late in season for flus cases to spike) ○ Samples sent to American Canadian CDCs and types as “swine flu” ○ The vaccine came late but the severity was not super high Unusual for the lack of morbidity in persons >65 yrs old ○ Only 5% of people infected with 2009 H1N1 wer e over 53 years old ○ Higher levels of infection and severe illness in younhger age groups ○ C ross reactive immunity: there is antigenic similarity between the 2009 H1N1 and much older strains ○ ~⅓ of people > 50 yrs tested has antibodies that neutralized 2009 H1N1 ○ Still circulates today New influenza serotype infected people (2013-2017) ○ High morbidity and mortality ○ Mostly direct contact with poultrybut at least 4 confirmed clusters ○ A complex reassorted virus ○ Controlled by culling of birds and more intense surveillance of people H5N1 Avian influenza ○ H5N1 - avian segments only no reassortment ○ VERY Virulent in domestic poultry = Highly pathogenic avian influenza (HPAI) ○ Dramatic and unpredictable spread among wild and domestic birds ○ Can have exceptionally high mortality rate in humans but not always 2019 - nowL increases in the number of infections of poutlry and wild birds with H5 subtype H5N1 HPAI found thoughout the US in Birds Not just for the birds: HPAI has become widespread in many wild birds but also in mammals recently ○ Most recently dairy cows So far: relatively mild symptoms but what are we worried about? ○ Reassortment and or mutations ○ H5N1 vaccines under development: estimated 10 million doses by early 2025 ○ Seasonal flu vaccines being given to workers in close contact with dairy cows Many potential pathways to pandemic influenza We need to keep an eye on avian influenza ○ Vigilance about non-seasonal influenza virus infections ○ Specific vaccine for H5N1 should be produced, stockpiled and tested with new variants ○ Changes in farming/ranching/public health practices? ○ Will immunity to some HAs and NAs protect us There are significant barriers to Zoonosis ○ Most animal viruses are unable to replicate in the human body ○ Bottle neck in viral emergence Lecture 35: Ancient Viruses Retroviruses ○ Retroviruses are “retro” because they convert their RNA genomes into DNA (goes against the Central dogma of Biology) ○ Retroviruses insert their genome into the genome of the host cell Permanent Human Endogenours Retroviruses ○ HERVs Similar genomic organization to exogenous retroviruses Possess a reverse transcriptase gene similar ot all retro viruses HERVs are “ virus fossils” footprints of prior infection with retroviruses HERVs are transmitted vertically in the germline through successive generations Endogenization of a virus: Germ line invasion ○ Viruses typically infect “somatic” cells in the boyd Somatic cells: cells other than reproductive cells in the body ○ Infection of germ line cells leads to transmission to offspring ○ Vertical transmission leads to transmission of an endogenized virus ○ Requires the virus to become a part of the host genome Endogenous Retroviruses are derived from different types of exogenous retroviruses The evidence of “paleoviruses”: ancient extinct viruses ○ How do we know about ancient viral infections? Historical records Molecular clocks Endogenized copies Koala Retrovirus: endogenization in process ○ KoRV (Koala Retrovirus) is a retrovirus currently infecting Koala populations ○ Deadly: immunodeficiency and cancer ○ KoRV can infect germline cells and become vertically transmitted KoRV transmitted horizontally and vertically in Koalas ○ KoRV is transmitted horizontally in blood, feces etc ○ Endogenized KoRV can reinfect and replication in the genome and infect new Koalas KoRV related retroviruses found in other mammals ○ Bat KoRV Galv Endogenous Prosimian Immunodeficiency Viruses: relatively recent genome invasion ○ Lentiviruses similar to HIV are many million of years old EVEs ( endogenour Virla Elements ○ Many tupes of ruses have invaded genomes across the tree of life Co-option of viral sequences by the host ○ A viral gene sequence integrated into the germlinbe of our ancestors ○ Vertical transmission: transfer of a virus from the parent directlyto the offspring Co-option of a retroviral envelope for host biology: the story of syncytin ○ A special layer of cells form at maternal fetal interface in the placenta ○ Kay to nutrient and waste exchange ○ A retrovvirla envelope was co optedto form this specialized layer of cells Syncytin fuses cells in a way that is similar to how virla envelop fuse viral and vell membranes Syncytin as an example of co options: putin it all together Lecture 36: HIV H uman Immunodeficiency Virus Family:retroViridae ○ Retro = “backward” ○ Lenti = “slow” Describes the slow disease preogression of the founding member of the Genus ○ Single-stranded, positive sense RNA genome (reverse transcribing ○ Genus: Lentivirus Example Species: Human Immunodeficiency Virus (HIV) HIV - the virus that cause AIDS ○ HIV: Human Immunodeficiency Virus ○ AIDS: Acquired ImmunoDeficiency Syndrome ○ AIDS results from CD4+T cell depletion causing severe immunosuppression and an increase in opportunistic infections The gravity and scale of the ongoing HIV 1 pandemic ○ 86 million people have been infected with HIV ○ 40 million people have died from HIV/AIDS ○ 39 million people currenlty living with HIV ○ 0.7 audlts ages 15-49 worldwide have HIV ○ WHO African region: 1 in 25 with HIV Estimated number of people living with HIV ○ New HIV infections are still occuring ○ Siem global regions have a much higher burden ○ In Africa: more new HIV infections in women than in men Some Characteristics of Retroviruses ○ Host species: humans and other primates ○ Transmission:secual contac, blood, breastfeeding ○ Diseases: HIV, AIDS Structure of the mature HIV 1 virus particle ○ HIV virions in their mature form have a characteristic conical core structure ○ Shape of this ‘core’ may help in entering the nucleus through the nuclear pore. HIV is a retrovirus ○ Retroviruses have small RNA genomes ○ All retroviruses use an enzyme called reverse TRanscriptase to make a DNA copy of their RNA genome ○ The DNA copy of the viral genome inserts itself into the host DNA genome (through a process called integration) ○ Retroviruses become a permanent part of the cells they infect Retroviruses: In conflict with the central dogma History of Retroviruses ○ 1 970: Howard Temin and David Baltimore independently discovered reverse transcriptase ○ 1975: Awarded Nobel Prize for this work which challenged the central dogma HIV-1 Viral Genome ○ The HIV genome: two copies carried in the viral particle, each a single strand of RNa of ~10,000 nucleotides and a few core genes + accessory genes ○ LTR = Long Terminal Repeat ; does not code for a protein, instead encodes instruction for the expression, reverse transcribing and packaging of the genome Multiple viral proteins are made form the three key precursor proteins ○ Gag processed to form Matrix protein Capsid protein Others ○ Pol processed to form Reverse trancriptase Protease Integrase ○ Env processed to form: ○ Gp120 ○ Gp41 HIV Accessory Genes ○ All retroviruses have GAG, Pol, and Env ○ Lentiviruses have additional accessory genes HIV viral Lifecycle Part I: Entry ○ Hiv infects: CD4+ T cells Macrophages, and Dendritic Cells ○ First gp120 on the virus attaches to the CD4 receptor on T cells ○ Then gp41 mediates membrane fusion and viral capsid and RNA genome are delivered into the cell ○ HIV entry: the role of the co receptor CCR5 an CXCR4 are called chemokine receptors; their normal function on cells is to detect the chemical signals that tell immune cells where to travel in the body CD4 on a host cell is necessary byt not sufficient to mediate coral entry A second receptor called the co receptor is required to permit viral entry HIV can use on eo two different co receptor CCR5 or CSCR4 ○ Structures of HIV 1 Env during viral entry ○ HIV envelope undegoes complicated changes in shape to mediate fusion of virla and cell membranes HIV preferentially infects immune cells duet to CD4 and CCR5/CDCR receptor usage Where did HIV come from ○ HIV is a zoonosis ○ HIV-1 Clade M spread worldwide = pandemic HUmans have two distinct lentiviruses unique cross species transmissions ○ Simian Immunodeficiency Viruses (SIVs) are closely related to HIV Over 40 species of African monkeys have an endemic lentiviruses ○ ○ Two of these have transmitted to hominids. HIV infection in humans resulting form unique cross species transmission events HIV 1 ○ Group M “major” > 50,000,000 cases 12 subtypes ○ Group N “ Non O/P” ○ Group O “outlier” ○ Group P “Pending” HIV 2 ○ 2,000,000 cases total ○ Group A Most pandemic ○ Group B How did SIV jump into humans? ○ HIV chimp to human transition was a zoonosis ○ HIV causing the global pandemic is not repeatedly spread form an animal reservoir ○ Likely explanation for transfer of chimp virus to humans is blood-blood transfer during the butchering of bushmeat Lecture 37: HIV #2 Timeline of HIV in the US ○ March in 1983:CDC addresses transmission risks ○ AIDS may be caused by an infectious agent that is transmitted secually or through exposure to blood products. ○ Jan 1983: “Ward 86” opens at UCSF as teh first outpatient AIDS clinic in the country May 1983: HIV is discovered as the virus that causes AIDS Barre-Sinoussi and Mantagnier Jan 1985: AIDS caused by HIV ○ 1985: first public mention of AIDS by Ronal Reagan ○ March 1987: ACT UP forms as a grassroots political group to end the pandemic ○ March 1987: First antiretroviral drug was invented ○ 1992: AIDS become #1 cause of death for US men aged 25-44 HIV Virla LIfecycle part II ○ Reverse Trasncription and Integration First gp120 on the virus attaches to the CD4 receptor on T cells T hen gp41 mediates membrane fusion and viral capsid and RNA genome are delivered Then RNA genome is reverse transcribed into DNA and the DNA copy is then integrated into the T cell genome by integrase Mutation rate of replicating HIC is phenomenally high ○ Our DNA polymerases that replicate our DNA ○ 1 in 1,000,000,000 base pairs mutate per cell division. ○ HIV reveres transcriptase 1 in 10,000 base pairs mutate per round HIV replication Approx one mutation every time HIV replicates Reverse Transcription andIntegration Retroviruses stably integrate their DNA into host cell chromosomes ○ Once integrated teh virus remains for the life of the cell Persistence: infection is not easily cleared becasue there is a long lived reservoir of infected cells Latency: integrated, but silence proviruses are not seen by the immune system ○ HIV infection is chronic ○ Cells that are infected pass these genomes onto daughter cells during cell division Assembly and Release ○ The integrated provirus directs the creation of new RNA vrla genomes and new viral proteins ○ HIV Protease: Cuts up a precursor protein inot its smaller functional proteins ○ New viral particles are then assembles and then are released from teh cell to infect new cells Protease in the HIV Life Cycle ○ Protease cleaves itself from Gag and cleaves apar other Gag and Pol proteins Protease cleavage: Mature and Infectios virus HIV has 2 stages: acute and chronic ○ Acute HIV infection Fli like sumptoms 50-90% of people ahve symptoms 2 to 4 weeks after infection Lasts for a free days or a few weeks ○ Chronic Infections Severe immunodeficiency -> AIDS CD4 T cells are lost during HIV infection in 2 ways ○ Fidirect killing by virus ○ Immune mechanisms HIV pathogenesis ○ AIDS is a disease of helper CD4 T cells ○ The immune system is damaged during acute infection and chronic infection ○ In untreated people, the virus is chronic and the disease is progressive D ○ estruction of the immune system leads to opportunistic infections ○ Latency is the key reason why virus is not cleared even when antiretroviral therapy is administered CD4 T cells are the “ master conductors” of the immune system ○ Without them the immune response falls apart ○ Help B cells make antibodies ○ Help CD8 T cells ○ Allow the recruitment and activation of innate immune cells HIV Pathogenesis: acute phase ○ Initial peak of viremia (presence of virus in the blood ○ Flu like symptoms (immune response) HIV pathogenesis: Chronic phase ○ Viremia is controlled and reaches a low level ○ Number of CD4+ T cells slowly declines as virus immune responses kill them ○ CD4 T cells reach low enough level that th immune system begins to fail ○ Virus replicates out of control -> further loss of immune system function -> opportunistic infections Why are teh number or CD4 T cells declining ○ CD4 T cell decline is gradual and involves a cycle of CD4 T cell infection CD4 T cell death CD4 T cell replacement ○ Eventually immune exhaustion and immune system ‘collapse’ = sever immunodeficiency Lecture 38: HIV and AIDS III A IDS is the result of depleted CD$+ T cell sand a severely compreomised adaptive immune system. Opportunistic infections are common when chronic HIV infection progresses to AIDS TB is the leading casue of death globally among people living with HIV ○ Lethal synergy between HIV and TB ○ Coinfection is a HUGE problem ○ Many TB deaths are occuring in people with HIV TB is an example of an opportunistic infection in PWH HIV and Measles Pathogenesis comparison ○ HIV Persistent (chri=onic infection Severe, long-term immunosuppression (no recovery) Infection and devere depletion of T cells Deadly opportunistic infections ○ Measles Measles is usually only acute. Almost always no viral persistence Immunosuppression improves eventually Depletion of B cell memory Deadly opportunistic infections HIV can be treated: antiretroviral drugs ○ 1987: AZT first drug to treat HIV infection (RT inhibitor) Side effects and the development of resistance can be major issues for Anti retroviral Therapy Antiretroviral Therapy (ART) targets multiple steps of the HIV lifecycle ○ Binding and fusion ○ Uncoating ○ Reverse transcriptase ○ Integrase ○ Protease ○ Using drugs together means virus catn easily evolve to escape When used in combination this is know as: ○ Highly-active antretrovirla Therapy (HAART) Reasons to be hopeful ○ Treatment as prevention is >96% effective ○ ART Healthy immune system No transmission with viral suppression Current state of things ○ Antiretroviral therapy blocks viral replication at multiple steps, but is not a cure ○ ART can prolong the life expectancy of People with HIV to close to normal lifespan and can prevent transmission ○ HIV + ART + individual still: Have a higher risk for certain cancers Have higher risk of developing neurocognitive disorders ○ WE still need and HIV vaccine and we need and HIV cure Reasons to be hopeful ○ Big steps in status treatment and viral load suppression ○ Among people living with HIV the percetn who: Know their HIV positive Are receiving treatment An are virally suppressed ○ 2040 Goal of “ending AIDS” as a public health threat: “95-95-95” PrEP: Pre-Exposure Propheylaxis ○ PrEP can reduce your chances of getting HIV from sex (99%) or infection drug use (>74%) ○ PrEP requires high levels of adherence ○ PrEP only protects against HIV not against other HIVs ○ PrEP can be pills or shots Global access to most effective PrEP: Making progress but still a long way to go… ○ Access to this therapy globally is and will octinue to be a major challenge More reasons to be hopeful ○ Prevention works: Treatment as prevention U=U (undetectable = untransmissible) The more widespread use of PrEP UNAIDS Goals ○ Better antiretrovirla therapies: longer acting drugs, lower toxicity, better resisitance profiles, mroe convenient combinations, broadly neutralizing antibodies under development There is no HiV VAccine ○ HIV may be particularly hard to generate ummunity to ○ We dont know what kind of immunity should be elicited to provide protection Very fer cases of transient or sustained remission off ART suggest that a cure may be possible ○ Major challenge: latent virus can reactivate as drugs dont cure infection ○ Some people dont reboudn after removing ART Immune systems are controllign infection? Cells from some people are (mostly) resistant to HIV: CCR5 ○ A mutation in the CCR5 gene encodes a version of the HIV co receptor that is not expressed on the surface of cells Gene editing for HIV cure: coming soon? ○
