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HIV genomic structure and function
this presentation we're going to cover,the structure of the HIV genome and the,function of the individual genes here's,a map of the genome uploaded to,Wikipedia or Wikimedia Commons by Thomas,splode Stowe sir sorry if I just,slaughtered your name deed but out of,all of the images of the gene map of the,HIV genome that I have seen I like this,one the best because it shows a couple,of really important things the first,thing that it shows is that we have,three different reading frames now if,you've had a genetics class and I hope,you have then you understand that,whenever you have your nucleotide so,you'll have three nucleotides let's say,an a/c and a tea right like that and,each one of these will be grouped,together and that will tell the the,ribosome to to make one specific peptide,or one specific amino acid and so well,if you had a C T G a for example your,ribosome depending on where the start,codon is could have made this as a,reading frame starting with a CT and,then moving on to the next three we'll,put another T there or it could have,started right here and made this the,reading frame and then moved on to the,next one and so you can see that there,are three possible reading frames and,HIV cleverly has included genes into all,three reading frames the most texts,about HIV are going to get at least to,the surface level and they're going to,tell you that there are some structural,proteins those structural proteins being,gagged paul and in the ghek I really,don't know what gags aims for but Paul,was named because it contains the,polymerase the reverse transcriptase,which is a polymerase the end because it,encodes the two major envelope proteins,the gp120 and gp41 we'll talk about what,those are but the envelope protein and,gag it just contains a whole bunch of,very on structural proteins,all three of these are grouped together,and called structural proteins the thing,this shows is that some genes are,separated so you can see that the TAT,gene transcriptional activator is,actually separated and it's in two,different reading frames is important,and the Rev gene I've kind of marked,through the word Rev the Rev gene is,also similar tat and Rev are known as,regulatory proteins so we have our,structural proteins we have our,regulatory proteins and the rest of them,are classified as as accessory proteins,now a few things that the image I just,showed you didn't demonstrate is that,there are several splice donor sites,they're usually labeled with a D and,there are splice acceptor sites labeled,as an A so if you're looking at a,picture of the HIV genome and it has DS,and A's marked oh those are just splice,donor sites and splice acceptor sites,the mRNA can be spliced into 30,different mRNA pieces or species and so,that one HIV mRNA can become greater,than 30 other mRNAs and I already,pointed out that it can read in all,three reading frames this is called,being polycistronic well which reading,frame you get the most of or the least,of is dictated by two things the first,thing is how close is it to the 5 prime,end of the mRNA and the second thing is,what is the efficiency of of the,initiation codon so in different places,different initiation codons are going to,have different efficiencies there's one,other thing here that can affect what,the reading frame is and that is whether,or not we have a frameshift induced into,the the peptide chain as it's growing,and that I'll explain in a little bit,but that's how we get all of the the,pull the pol pol proteins and another,thing just to keep you cognizant of all,of the RNA is classified as whether,it is unwise partially spliced or fully,spliced and that I'll explain in more,detail later as well and the major,groups I didn't point out in that image,that one of the major groups is called,the LCR they long terminal repeats so,the LCR segment is at the end of the,genome so you've got the three the five,and three prime ends and except this,segment there that's called an LTR that,segment is actually what dictates,whether or not the gene is whether or,not the virus is active or inactive then,you have your structural proteins which,are the gag pol and M you have your,regulatory proteins cat and Rev and the,accessory proteins vp r vp u v and net,now even though it's a rate and,accessory protein i you like to classify,an F in with cat and Rev for two reasons,first of all it breaks all these down,into three groups of three and the,second reason is because cat Rev and,Ness are all considered early proteins,they are transcribed and processed into,proteins early in the life cycle early,after the HIV has infected the cell and,then all of the rest of the proteins are,created late in the life cycle late,after the virus has infected the cell,and so you can think of it like this you,have LTR then you have these structural,proteins and then you have the others of,the others some are late proteins and,some are early proteins and so here,again is a map of the genome and I want,to point out again th
The above is a brief introduction to this enzyme functions to generate functional viral protein products encoded by the hiv genome.
Let's move on to the first section of this enzyme functions to generate functional viral protein products encoded by the hiv genome.
The HIV Viral Replication Cycle
The HIV Viral Replication Cycle
okay this is the second of a series of,videos that I'm doing on the HIV virus,so the human immunodeficiency virus in,this video I'm largely just going to,focus on the viral replication cycle,really explaining what it is and how it,works this is when I actually suggest,students know there are a whole bunch of,antiretroviral therapy drugs that our,patients go on antiretroviral therapies,sometimes referred to as cart which is,combined antiretroviral therapy or art,for antiretroviral therapy or anti,retrovirals there's all sorts of,different acronyms but really what it,means is that you've got a cocktail of,drugs that are working together at,different stages in the virus's life,cycle to inhibit its effectivity okay,when I think of the viral life cycle I,like to break it up into stages like any,other viral life cycle and then break,down where I think it could be stopped,okay,the virus genome itself consists of two,identical copies of the RNA genome okay,and the RNA genome is found within a,nucleo capsid in the core of the,enveloped virus okay so you have a,couple of different steps right there to,kind of think of as to how we could,potentially inhibit this structure of,virus the RNA is protected by a capsid,structure this nucleo capsid and that's,where you're gonna find the HIV p24,which is a protein you may hear me talk,about that other points in these videos,specifically when we get to diagnostic,testing okay all right I grabbed this,picture I think from the CDC I'm gonna,slightly renumber things so the first,number I'm actually gonna have is,attachment so remember initially the,virus is going to attach to two,receptors the first one is cd4 and,that's gonna be done it's gonna be bound,by gp120 and then there's going to be a,co-receptor that all,- binds to gp120 early an infection it's,emmetropic and it'll be ccr5 later it's,T tropic and will be cxcr4 this is,actually the stage where the attachment,inhibitor antiretroviral drug Marah,Barak works this one has not actually,been used a ton recently it really only,works to block the gp120 ccr5 binding so,if you have any rx for virus at all this,will not be an effective antiretroviral,so it really only works in emmetropic,virus okay so we have one attachment and,that uses Rev that can be inhibited by,maroc so then our second step is,actually fusion over here so fusion and,penetration so binding of both,co-receptors actually triggers kind of a,conformational change which is shown,here in gp120 and GP 40 and that,actually allows fusion of the viral and,cellular membranes which is kind of,what's being shown here okay,following fusion the capsid is going to,enter the cytoplasm and that's when,actually the whole thing really kicks,off alright so at this point we're going,to move into reverse transcriptase okay,or reverse transcription reverse,transcription is largely going to occur,in the cell's cytoplasm in during,reverse transcription the RT which is,the reverse transcriptase which is,encoded by the pol gene in the HIV,genome basically it uses tRNA in the,virion in the virion as a primer and it,synthesizes a complementary negative,stranded DNA which is basically just,cDNA it also degrades the positive sense,RNA strand and synthesizes the,corresponding DNA positive sense strand,so basically we're going from our viral,RNA we've made our we've got a reverse,transcriptase it's going to synthesize a,complementary viral DNA,it's gonna get rid of the RNA and then,make another DNA so now we have a nice,double-stranded viral DNA component as I,mentioned before the RT is the major,target for antiretroviral therapy so the,RT is actually inhibited by two,different classes of drugs the NRT is,and the N n RT is the NRT is inhibit,reverse transcriptase using analogs of,the natural ATGC nucleotides that are,normally used by the reverse,transcriptase to build the DNA strands,they are competitive inhibitors they,competitively inhibit the reverse,transcriptase so examples of the N RTI's,would be things like a back of year and,treesa to be an Antonov aveer to Nava,beer being a very commonly used,antiretroviral currently the N NRT is,our the non-nucleoside reverse,transcriptase inhibitors they inhibit,reverse transcriptase by binding,directly to the reverse transcriptase,enzyme itself they're not integrated,into the DNA strand so examples of this,one actually include things like a,sovereign's nevirapine and della Verity,okay so the other thing I'll mention,about the RT at this point is that the,RT makes a lot of mistakes it's a very,very very error-prone and this is,actually a really big problem there is,approximately one error per every 200,bases or approximately five errors per,genome made by the RT this would be the,equivalent of me basically making an,error on every single slide in every,single youtube video I ever make or at,least one typo on every page of every,node I've ever written but here's the,kicker it's not just me making a mistake,on you know one video right it's I make,a mis
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Day 5 DNA viruses gene expression strategies
Day 5 DNA viruses gene expression strategies
so what I want to do with this little,mini lecture is talk to you about some,of the strategies DNA viruses use for,gene expression there's just too much to,cover in class so I thought I would do,half online and half in class so the,first thing I want you to remember is,how we express genes the goal is to make,protein so you've got DNA to RNA,remember we're gonna make mRNA and then,translation to protein a couple other,things to remember that in order to,express a gene the promoter has to be,recognized by RNA polymerase and,transcription factors,once that gene is transcribed to RNA,you'll need a five prime cap and a three,prime,poly a tail these are essential,components for translation which I'll,show you in a second and the other,concept I want to remind you of is this,idea of alternative splicing where you,can have one RNA with multiple exons and,different exons can be joined and you're,going to produce different proteins so,alternative splicing is a way to go from,one RNA to multiple proteins and the,reason I bring this all up are that some,viruses use similar strategies so what,we're really talking about today is,getting to mRNA and then getting it,translated,and we've talked a little bit about how,to get to a positive sense RNA molecule,when we talked about some of the genome,replication strategies so your,double-stranded viruses you have four,classes class one two six and seven okay,and these are going to look a lot like,normal transcription because they're,starting out with double-stranded DNA so,class one already double-stranded DNA,you just need to get RNA polymerase on,there to make mRNA class two if you,remember that goes from single-stranded,DNA to double-stranded DNA and class,seven goes from double-stranded DNA that,is partially double-stranded actually,goes to RNA which goes back to,double-stranded DNA but as far as gene,expression is concerned you're all of,these are starting with double-stranded,DNA so it's pretty straightforward like,eukaryotic cells do the asterisks here,is for something that I had forgotten to,mention when genome replication is that,to make double-stranded DNA the cell has,to be in S phase so it has to be going,through cell cycle because that is when,DNA polymerase and the other DNA,replication genes or proteins I should,say are being expressed so unless the,DNA virus encodes its own replication,genes such as DNA polymerase and,anything else it needs a lot of DNA,viruses will actually induce s-phase in,the cell so that the host cell is,producing those essential proteins,needed,again that goes back more with genome,replication but I wanted to mention it,alright so for gene expression we're,going to assume the double-stranded DNA,is made and that the gene expression is,happening in the nucleus and this is,true for all of these different viruses,except for poxviruses which is like,smallpox vaccine E virus cow pox monkey,pox these are these large DNA virus yeah,DNA viruses that replicate and express,their genes in the cytoplasm so I'll,show you a little information about that,since this is all happening in the,nucleus these viruses can use the host,RNA polymerase and the host splicing,machinery so it's really straightforward,the final step in gene expression which,is translation,for all viruses DNA RNA viruses all,viruses use the hosts ribosomes so all,translation happens in the cytoplasm the,thing I want you to remember about,translation and the reason I emphasize,five-prime crap 3-prime poly a tail is,because this is how translation happens,so these are eukaryotic initiation,factors they make a cap binding complex,that will then recruit the ribosome so,this is how you carry otic translation,happens you can see that the poly a tail,is important the five prime cap is,important this is all for recruiting the,ribosome so for DNA viruses we don't,have an issue here because the mRNAs are,being made from double-stranded DNA and,using the host RNA polymerase a cap and,tail will be put on so what we're going,to talk about for DNA viruses is kind of,how they control their gene expression,so this is hepatitis A hepatitis sorry,human papilloma virus HPV it's a double,stranded DNA virus and some of the,interesting things I want to point out,is that it encodes some of its own,transcription factors so,one of the things you have to remember,is even though transcription translation,is straightforward because it's using,the eukaryotic cell information or I'm,sorry eukaryotic cell proteins you still,have to be able to recruit RNA,polymerase to the promoters of the virus,so a lot of viruses have very few,promoters so E and Al stand for early,and late gene expression so there are,early promoters and there are late,promoters so these transcription factors,encoded by the virus can start promoting,early transcription and then as other,proteins are made they can promote,transcription of delayed genes so the,late genes you can see are the capsid,which makes sense you want to express,all your genes f
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Virology Lectures 2020 #6: RNA directed RNA synthesis
Virology Lectures 2020 #6: RNA directed RNA synthesis
all right good afternoon welcome back as,you can see our latest case count is,over 40,000 that is far above the SARS,outbreak the debts or 910 which is also,more than SARS again mostly in China,very little overseas although there's a,little bit of transmission but if you,look transmission overseas if you look,at the epidemic curve the oranger cases,in china mainland china in the bottom is,the rest of the world so again I don't,know if that's an actual plateauing or,not we'll see next time I wanted to,point out something that came out on,Friday that some people have found this,virus in pangolins that's a Pangolin,which are apparently protected in China,but people still hunt and use them for,various purposes they isolated nucleic,acid from these animals,99% genome identity with the corona,virus that's now circulating in people,so this may have been an intermediate,between bats and people somehow however,I understand that these were in the,south of China so I don't know how that,plays into the situation this hasn't,been published yet it's in review maybe,it'll be out this week so we'll see what,happens but this is a remarkably rapidly,moving situation and I would not be,surprised if it continues to rapidly,move however today we are rapidly moving,on to RNA directed RNA synthesis so,we're going to talk about RNA synthesis,for the next two lectures today it is,going to be,RNA synthesis made from RNA templates,and just to put this in a historical,perspective it's not something you need,to know for an exam or anything back in,1935 Stan Lee crystallized tobacco,mosaic virus made crystals which you,know in theory can be used for,determining the x-ray structure but we,didn't have the power to do it back then,but he thought this was cool because he,said oh it's an infectious protein but,he ignored the 5% of his crystals that,were RNA and that of course turned out,to be not very important,in 1944 in experiments I alluded to,earlier DNA of bacteria was shown to be,the genetic material Avery MacLeod,McCarty took DNA from one bacterium and,put it in another and showed that you,could transfer properties that way,thank you 52 the hershey-chase,experiment shows DNA is the genetic,material of phages 1953 the structure of,DNA is soft so now we have established,that GNA can be genetic material 1956,the Franco Conrad experiment I told you,about with tobacco mosaic are showing,that RNA is the genetic material as well,so now we are on our way to studying,both of these nucleic acids by 1959 they,had found RNA and many different animal,viruses and in the 1960s people began to,get interested in how this these RNA,viruses how their genomes were copied,you know the initial idea was that it,was copied by a host cell enzyme but as,people did experiments that turned out,to be not the case and the viruses we're,going to talk about today in terms of,the baltimore scheme are ones that,encode an RNA dependent RNA polymerase,and that will be our double-stranded RNA,viruses group 3 our negative strand RNA,virus is group 5 and our group for the,plus stranded RNA virus is three,different groups all of which encode RNA,dependent RNA polymerase is the,retroviruses groups,we keep separately because they company,code a different enzyme reverse,transcriptase that copies RNA into DNA,and that's so cool that it gets a,lecture by itself so here's the first,experiment done to show that in cells,infected with an RNA virus a new,activity is made that can synthesize RNA,was actually done by David Baltimore so,this was the guy who made that Baltimore,scheme right so as a graduate student,here in New York City at Rockefeller he,did these experiments and this got him,on the road to thinking about making a,scheme for all these viruses so what he,did is he took cells infected with,poliovirus he added he made an extract,of these cells at different times after,infection and then he added to the,extract for the four precursors of RNA,one of which had a radioactive label on,it probably that you and then he,incubated it and measured RNA synthesis,he looked for label radioactive label,being incorporated into RNA and what he,found which is shown on this graph so,we're looking at on the bottom the X's,hours post infection and on the left why,this is polymerase activity so the open,circles are he's measuring synthesis of,RNA and then in red on the right these,this is synthesis of virus pfu per mil,so he also did a plaque assay at every,time point and you can see that at,around two hours post infection remember,this is done,the RNA synthesis is done in an extract,at about two hours post infection,between two and three hours you see the,the onset of RNA synthesis in these,cells and this was good evidence that,this was some kind of RNA polymerase,activity now he did another experiment,which is not shown here he threw a drug,into this experiment separately called,actin and myosin D actinomycin D is,known to block RNA polymerase of host,cells it blocks the copying of RNA from,
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Targeting Viral DNA for the Cure of HIV and other Chronic Infections
Targeting Viral DNA for the Cure of HIV and other Chronic Infections
and i want to talk to you about the,problem of of chronic and latent viral,infections and this is something that,sort of john alluded to i've been,interested in really since i came on and,came into laboratory medicine,both from a diagnostic point of view and,then also really understanding the virus,and more recently now,starting to think about what we can do,about the virus so,to get us started,on this topic i i want to give us an,example sort of the the money one to,think about which is hiv,and sort of the unique challenge that,hiv presents to us as we think about,treatments and especially as we think,about,the problem of cure,so the problem of hiv is that hiv,infects a cell type t cells of which is,a subset that have an incredibly long,lifespan infects central memory t cells,establishes latency in there and since,these cells live for 40 or 50 years the,virus in theory could live a very long,time,but hiv a even does a worse thing it,actually inserts itself into the,chromosomes here,and and puts itself into the chromosomes,called integration so the virus puts,itself into this and essentially becomes,a part of the infected individual,through these,central memory t cells and this,combination of integration,into,a very very long-lived cell type,essentially makes this a lifelong,incurable infection there's no way you,can wipe out all those cells there's no,way you can go into those chromosomes,and find the viral nucleic acid and do,anything very specifically about it an,incurable disease,now this is how we've thought about the,problem for a long time in fact this was,the only way you were really allowed to,think about this problem for a very long,time,but the case i want to make today is,that the cure of hiv or other,chronic related viral infections indeed,may be possible and in fact i think it,should be a research priority so i'm,going to tell you some a a story really,and this is the story that made um,really brought this to the forefront and,said this is possible it's the story of,timothy brown,you've probably seen this guy in his,picture in the newspaper timothy brown,was infected by hiv he developed an,aids-associated malignancy and underwent,a,stem cell transplant for that he was,cured of his malignancy but the donor of,his transplant,had a specific,dna alteration such that their cells,were resistant to hiv so this,combination of all the things that we do,to people who get transplants wiping out,their own immune system and then,combined with,these resistant cells,cured this man of hiv,and so he is the only person that we,have a documented proof of cure,four years later he's offered,antiretrovirals he has no tumor and he,has no detectable hiv in his blood so,because of this case now we can at least,say it's theoretically possible to cure,hiv,so the point is the time is really right,to think about curative therapies and,there's really some enabling,technologies and these are what i'm,really going to talk about these are,novel dna cleaving proteins that i'm,going to show you can really find and,disable very specific sequences within,the human genome whether that sequence,would be an integrated virus or whether,that sequence would be the genes,encoding essential viral sep receptors,we can recognize them in and destroy,them and this raises then the,theoretical possibility of elimination,of the virus,and doing this i think really fulfills,what is a logical,triad of response to the hiv epidemic,for a long time we've been working on,prevention either through behavioral,modifications vaccines and so forth,we've certainly really made tremendous,advances in management through the,antiretrovirals that we have now but,really the third leg of that should be,the idea of curative therapies,so these things are all going to work,together as a part of a response to the,pandemic so here's the outline of the,talk we're going to go over viral,latency as a concept we'll talk about,dna targeting enzymes really the,enabling technology for us we'll talk,about how we want to use these for,targeting hiv and then i want to take a,little bit of aside and talk about sort,of the big efforts the big collaborative,work that we're doing that john sort of,alluded to in the martin delaney,collaboratory,you can't do that without talking about,targeting ccr5 really the key to curing,timothy brown and then at the end we'll,expand this then into some of the other,really critical chronic and latent viral,infections that are,affecting human health throughout the,world,so viral latency we have a few,virologists here,so,you know you can get virologists going,about what's latency what's persistence,and you know people will argue someone,have a kind of just a simple loose,conception of this and the idea is that,latency is a form by which,is a is a mechanism by which viruses,persist for a long time,in an infected individual and they do,that by only expressing a limited subset,of their viral transcripts and therefore,the genes and because they don't mak
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Macrophage Infection by HIV: Implications for Pathogenesis and Cure: Day Two
Macrophage Infection by HIV: Implications for Pathogenesis and Cure: Day Two
welcome to the second day of the nimh,sponsored a conference on macropod,infection by hiv and the strategies for,elimination,my name is kamel kalili and i will be,moderator of the session for this,morning,before we get to to the talks i want to,cover some uh housekeeping issues,uh,which as you see here,all participants will be muted and,listen only,in the listen only mode and the cameras,will be turned off,please submit your question uh by,a q an answer box anytime during the,presentation,if you have any technical difficulties,uh hearing or viewing the webinar please,note this in the qa box,and,our technical as a personnel will take,care of that,uh you can also send,an email to,events as uh at the one,source events dot com,the most important thing here is,speakers so please stay on the 15,minutes uh,presentation time that was uh arranged,by their organizers,so uh with that notion,i would like to,introduce you to our speakers,we have a great lineup of the six talks,and the first talks will be,presented by morgan uh bombsells,from institute,and then the second talk is by the,james termini from university of miami,the third one is by rebecca peters,university of miami and then the the,next one is by the aitau who,from the university of texas medical,branch and then next is howard,kendallman from university of nebraska,medical centers and final talk will be,delivered by the rafale kaminsky from,temple university thank you very much,good morning to all of you thank you for,inviting me to this great meeting,today i will tell you about two things,how hiv,can infect mucosal macrophages and,establish latency in vitro,and,how replication competent,hiv reservoir form in macrophages of,hiv-infected individual under,suppressive cr,hiv is mainly transmitted at the genital,mucosa and what we have,tried to do in the lab for the last past,year is to understand how circumcision,can protect,hiv entering the male genitals by 50,and using x-vivo,x-plant infection as well as,reconstruction infection because of the,construction infected,we have shown that hiv can penetrate by,two pathways to penetrate the penile,tissue first through the foreskin where,hiv target,langerhans cells prior to trans infect,cd4 t cell,second hiv penetrates the eureka which,will be,our topic of today and target directly,macrophages but not t cell,importantly have infected cell present,in all fluid vectorizing the infection,such as semen or cervical vaginal,secretion mediate efficiently efficient,hiv penile entry whereas cell free,viruses is not efficient,we recently asked whether hiv reservoir,formed in mucosal macrophage,following infection,therefore we reconstructed a urethral,mucosa made of fibroblasts macrophages,overlaid by urethral epithelial cell and,after 17 days the,reconstruction polarized was inserted in,the macro microscopic device and,inoculated in situ with gag gfp,hiv-infected t-cell producing gfp,viruses or with cell-free viruses,when the reconstruction was observed by,a spinning disk live in live imaging as,you can see here t-cell adhere to the,surface of the epithelium forming,virological cyanides able to shed bursts,of viral particles that penetrate inside,the tissue,next,by uh observing uh,live imaging recording first,we could uh,measure that the the time required for,the infected t-cell to form perform,productive synapse with epithelium,which lasts,approximately half an hour before the,t-cell is able to shed virus for another,hour and leave the uh,each site of adherence as you just,show,what happens to the virus produced at,this viral synapse we could follow the,virus through the epithelium as you can,see here,and,the virus translocate by transcytosis,before to infect,macrophage we found,hiv dna,positive,in the stroma of the reconstruction,this macrophage also contains,hiv protein concentrate in a circular,structure reminiscent of virus,containing compartments that are the,hallmark of hiv-infected,macrophages,furthermore we found that macrophage,infection establishes below the site,where the viral synapse form both in,video and by,electron microscopy as you can see here,we next,quantify the virus,produced,by this infected reconstruction and as,you can see here the virus is produced,for approximately two weeks before to,stop,its production uh suggesting that the,macrophage big,enter latency,furthermore these,macrophages could be reactivated to,produce a viral,particle,a,stimulation by lps that targets,specifically tlr4 on macro futures,suggests as you can see here in pink,suggesting that following mucusal entry,hiv not only infects macrophages but,also establishes a lateral replication,competent infection,which is a definition of an hiv,reservoir,we next ask whether replication,competent hiv reservoir could form in,tissue macrophages in vivo,i,will,not,repeat the nice introduction rebecca,venus,made yesterday on the crucial,role of hiv reservoir to prove,as a barrier to eradication but will,more concentrate on the differences,between
After seeing the fifth section, I believe you have a general understanding of this enzyme functions to generate functional viral protein products encoded by the hiv genome.
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Human Immunodeficiency Virus (HIV)
Human Immunodeficiency Virus (HIV)
HIV is one of the best-known viruses in existence.,Despite this, compared to some of the other viruses we’ve covered, our knowledge about,HIV is relatively new.,Human immunodeficiency virus began circulating and infecting humans long before we knew what,it was and where it came from, as with most diseases in human history.,But HIV in particular is considered to be one of the most devastating infectious agents,to emerge in recent history.,The story begins in the early 1980s when a mysterious disease popped up quite suddenly.,This was recognized due to increasing numbers of unusual opportunistic infections and rare,cancers that could be transmitted sexually, through injection drug use, from pregnant,women to their babies, or through blood transfusion.,CDC identified the disease as “acquired immunodeficiency syndrome”, or AIDS, but,it wasn’t until several years later that scientists figured out that a retrovirus was,causing AIDS.,It took years, a few name changes, many lost lives, and a mountain of hard work from many,researchers, but we now know that human immunodeficiency virus is a retrovirus that attacks the body’s,immune system, and can lead to AIDS if not treated.,Now we have heard the term retrovirus before, but what are they exactly?,These viruses are enveloped, positive-strand RNA viruses, and they tend to have unusual,morphology and replication strategies.,More specifically, retroviruses have a capsid containing two copies of a positive-strand,RNA genome.,Back in the 1970s, scientists David Baltimore and Howard Temin showed that the retroviruses,encode an RNA-dependent DNA polymerase, which is also called reverse transcriptase.,Essentially, this reverse transcriptase enzyme allows the virus to make copies of DNA from,RNA.,At the time, the “central dogma” of molecular biology as it is sometimes colorfully referred,to, was the idea that genetic information is passed only from DNA to RNA, and then from,RNA to protein, just as we learned when we studied transcription and translation in the,biochemistry series.,Baltimore and Temin’s finding demonstrated that this was not exclusively the case, and,their discovery ended up earning them a Nobel Prize.,Among the human retroviruses, there are three subfamilies: Oncovirinae, which is associated,with cancer and neurologic disorders, Lentivirinae, which includes HIV-1 and HIV-2, and Spumavirinae,,which doesn’t cause clinical disease, but does cause visible changes in infected cells.,The retroviruses are classified by a few factors: the disease they cause, host range, tissue,tropism, virion morphology, and genetic complexity.,But let’s focus specifically on HIV.,Human immunodeficiency virus primarily infects CD4 T cells, which are white blood cells that,fight infection, but the virus can also infect macrophages, which are another type of white,blood cell.,The envelope of HIV-1 has proteins that form spikes on the virion’s surface, and it’s,these glycoproteins and transmembrane proteins that attach to a host cell and help the virus,get inside.,In the case of CD4 T cells, the virus causes lytic infection.,With macrophages, the virus causes persistent low-level productive infection.,Since the virus is killing one type of host cell altogether, the CD4 T cells, in order,to make more copies of itself, it dramatically affects the immune response and ultimately,leads to immunosuppression.,There are multiple different pathways that the virus can take to trigger disease, depending,on what cells it infects and where they are, and they are all very, very complicated.,But the overall gist is this: HIV is very skilled at hiding from different components,of the immune system, and one of the major factors contributing to this is its ability,to repeatedly undergo mutation.,Let’s talk about the actual disease HIV causes.,Stage 1 of HIV is an acute HIV infection, where an infected person might have flu-like,symptoms, or might not show symptoms at all.,During Stage 1, there is a very large amount of virus in the blood, and an infected person,is very contagious.,Stage 2 is chronic HIV infection, which is sometimes called clinical latency or asymptomatic,HIV infection.,By the end of Stage 2, the amount of HIV in the blood, or the viral load, goes way up,,while the CD4 cell count goes down.,The most severe phase of HIV infection is Stage 3: Acquired Immunodeficiency Syndrome,,or AIDS.,By this point in the disease progression, someone infected with HIV has such a badly,damaged immune system that they are more likely to get severe cases of opportunistic infections,,and without treatment, people with AIDS typically survive about three years.,Even though there is no cure, there are medications available to keep infections from developing,to Stage 3.,So where did HIV come from?,Scientists have determined that HIV infection in humans originated from a type of chimpanzee,in Central Africa.,The chimpanzee version of the virus, called simian immunodeficiency virus, or SIV, got,passed to humans a
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Genetic Approaches and Host Targets to Inhibit Influenza Virus Pathogenesis
Genetic Approaches and Host Targets to Inhibit Influenza Virus Pathogenesis
thank you everyone for joining my name's,nick heaton my lab is at duke university,and what i'm going to talk to you about,today,are some genetic approaches that we've,been taking to identify host factors we,think that can be targeted to prevent,influenza virus disease,so if the goal is to better control,influenza virus infection there are,really two ways that we can go about,this,the first is to target the virus,directly and the second is to target,something about the host cell,so the virus can no longer replicate,now in this first approach this is i,think probably,most more intuitive to most people this,is what we've done historically develop,small molecules that inhibit viral,enzymes or functionality of virus,proteins so the virus just really can't,replicate,tamiflu or also tamavir for example is a,small molecule that inhibits,the neuramidase protein of virus which,is required for the virus to leave cells,and go on to infect,neighboring cells,the second approach is targeting the,host cell and this is,interest has increased in kind of this,this second option,recently,and again the idea is to change,something about,the host response,essentially leaving the virus alone but,making the host less permissive for,infection,so again different ways one can go about,this the first is to try and enhance the,natural immune response to infection,we recognize that cells already have,ways to detect the virus and respond to,that virus and so one school of thought,is that we simply just,might find ways to help the immune,system just function a little better and,in this way better control virus,infection,the other approach is to directly,prevent viral infection or replication,the actual target cells where the virus,needs to replicate,and one can do this by eliminating a,necessary host factor so all viruses,require,co-opting proteins in the host cell to,complete their replication cycle so if,you can find a host protein that is,absolutely essential for the virus and,get rid of that now the virus can no,longer replicate or alternatively,cells can upregulate genes,that encode for proteins that,intrinsically restrict virus infection,going back to this kind of immune,activation idea a lot of these cytokines,that are made after a cell detects virus,infection talk to neighboring cells tell,them to turn on these genes,and if these genes are turned on before,it's exposed to a virus that cell is now,non-permissive for infection,and so at least at a high level,these various options are at least,theoretical approaches for waves,that influenza virus could be controlled,and we've been interested in the,host side of things what i'm going to,tell you about today are two kind of,shorter stories,that relate to enhancing the immune,response to infection or identifying,virus restriction factors and i'm going,to start with the restriction factor,story,so for any host directed therapeutic,the first thing you have to have is the,target what is the actual host protein,that you want to change expression of,and so to find those targets we and many,other groups have taken high throughput,genetic approaches to identify such,such factors and one approach that can,be used is crispr casting-based,technology,i think most people are more aware of,the technology in the context of,knocking out changes that diagrams here,on the left,and essentially how this works,is a catalytically active cas9 protein,can be targeted to a specific genomic,locus,by virtue of the sequence of the guide,rna,and when this is targeted to an exon,cas9 can make a cut,in the dna a double-stranded break which,the host cell then,fixes imperfectly,and frequently leads to frame shifts,and the knockout of that protein,and so you can do screens with this,technology and what that gives you,are the factors that are necessary for,viral replication when they're lost the,virus can no longer replicate,the slight permutation of that,technology,i'm showing here on the right this is,called dcas9 activation,which again is using cas9 protein but,now cast 9 is catalytically inactive can,no longer cut dna,the guide rna still targets it to a,locus but now it's targeting it to,promoters instead of the middle of the,gene,and finally and importantly cast 9 and,the rna,work in such a way that transcriptional,activators are are dragged to these,promoters and it actually turns on genes,it actually increases expression rather,than knocking them out,what you get when you use that kind of,technology are factors that are,sufficient for viral control,um,factors that all by themselves are able,to stop viral infection,and,the the two stories i'm going to tell,you about today are using that,technology,now we wanted to find,uh cellular factors that when they were,up regulated would make the cell,completely resistant to infection,so we decided to use a reporter system,which i've diagrammed here on the left,so instead of just taking,regular cells and infecting them with a,virus and seeing,you know what cells live and whic
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