WEBVTT 00:00:16.790 --> 00:00:18.640 BARBARA IMPERIALI: OK, I want to walk us 00:00:18.640 --> 00:00:23.200 through a bit of an exercise to understand 00:00:23.200 --> 00:00:28.120 what happens when people become resistant to an antibiotic. 00:00:28.120 --> 00:00:31.180 What's the molecular basis for resistance? 00:00:31.180 --> 00:00:33.170 It's nothing magical. 00:00:33.170 --> 00:00:35.080 It's really things that you can understand 00:00:35.080 --> 00:00:38.350 based on what you've learned during various parts 00:00:38.350 --> 00:00:39.290 of the course. 00:00:39.290 --> 00:00:42.790 But I just want to remind you about this dreadful schematic 00:00:42.790 --> 00:00:46.750 here, which shows how rapidly resistance 00:00:46.750 --> 00:00:51.670 emerges to different antibiotics by showing you the year 00:00:51.670 --> 00:00:55.810 that the drugs are introduced and the year that resistances 00:00:55.810 --> 00:00:56.930 develop. 00:00:56.930 --> 00:01:01.475 One of the newest antibiotics to be introduced-- 00:01:01.475 --> 00:01:03.850 people thought, oh, it's a different mechanism of action. 00:01:03.850 --> 00:01:05.680 It should be pretty resilient. 00:01:05.680 --> 00:01:06.880 It should last for a while. 00:01:06.880 --> 00:01:08.380 It should be useful with daptomycin. 00:01:08.380 --> 00:01:13.060 It's a cyclic peptide antibiotic, 00:01:13.060 --> 00:01:15.280 which has a particular structure that doesn't 00:01:15.280 --> 00:01:16.900 look like a lot of the others. 00:01:16.900 --> 00:01:19.300 And honestly, it was two to three years 00:01:19.300 --> 00:01:21.190 before resistance emerged. 00:01:21.190 --> 00:01:24.160 So what I want to do is think together 00:01:24.160 --> 00:01:29.440 about what are the ways in which a bacterium could evolve 00:01:29.440 --> 00:01:32.870 to develop resistance against an antibiotic? 00:01:32.870 --> 00:01:36.430 So here we've got the target. 00:01:36.430 --> 00:01:38.770 We know that the antibiotic is very 00:01:38.770 --> 00:01:41.260 effective against the target. 00:01:41.260 --> 00:01:44.350 What types of things could happen in the bacterium 00:01:44.350 --> 00:01:48.330 to make it manage to just ignore the antibiotic 00:01:48.330 --> 00:01:50.320 and resist the antibiotic? 00:01:50.320 --> 00:01:51.850 Any suggestions? 00:01:51.850 --> 00:01:53.120 So it's very simple. 00:01:53.120 --> 00:01:55.030 There's a molecular target. 00:01:55.030 --> 00:01:57.190 It could be topoisomerase. 00:02:01.730 --> 00:02:05.480 It could be in fact the ribosome and the machinery 00:02:05.480 --> 00:02:07.850 for synthesizing proteins. 00:02:07.850 --> 00:02:12.270 It could be the machinery that cross-links peptidoglycan. 00:02:16.340 --> 00:02:20.090 What sorts of approaches and what sorts of strategies 00:02:20.090 --> 00:02:23.840 might evolve to make that antibiotic stop working? 00:02:23.840 --> 00:02:25.520 OK, fire. 00:02:25.520 --> 00:02:26.420 Yes. 00:02:26.420 --> 00:02:28.340 AUDIENCE: When two hydrogen-holding enzymes 00:02:28.340 --> 00:02:31.692 at-- create things that are not [INAUDIBLE] absorbing. 00:02:31.692 --> 00:02:32.900 BARBARA IMPERIALI: OK, right. 00:02:32.900 --> 00:02:35.000 So antibiotic gets in. 00:02:38.670 --> 00:02:46.230 The enzyme breaks up the antibiotic, so evolution 00:02:46.230 --> 00:02:48.580 to destroy the antibiotic. 00:02:52.810 --> 00:02:56.160 And that's very much what happens with penicillin. 00:02:56.160 --> 00:02:59.460 The key aspect of the structure that's so useful 00:02:59.460 --> 00:03:03.300 suddenly becomes invalidated through a degradation 00:03:03.300 --> 00:03:04.710 of the beta-lactam bond. 00:03:04.710 --> 00:03:05.690 So that's one of them. 00:03:05.690 --> 00:03:07.180 What's next? 00:03:07.180 --> 00:03:07.680 Yeah. 00:03:07.680 --> 00:03:10.015 AUDIENCE: [INAUDIBLE] 00:03:12.350 --> 00:03:13.950 BARBARA IMPERIALI: Ah, so maybe there 00:03:13.950 --> 00:03:25.050 could be uptake decreased, so that's quite hard, 00:03:25.050 --> 00:03:30.360 but there could be some evolution of the cell wall 00:03:30.360 --> 00:03:34.320 to make it less permeable to the antibiotic 00:03:34.320 --> 00:03:38.550 because we're usually relying on antibiotics to diffuse 00:03:38.550 --> 00:03:39.810 in passively. 00:03:44.690 --> 00:03:46.830 So if the membrane-- 00:03:46.830 --> 00:03:50.740 this could be in a membrane of a Gram-negative bacterium, 00:03:50.740 --> 00:03:53.930 or the outer membrane of a Gram-negative bacterium that 00:03:53.930 --> 00:03:55.820 has a slightly different composition, 00:03:55.820 --> 00:03:58.110 could physically change its structure. 00:03:58.110 --> 00:04:00.810 These are tough things to evolve all at once, 00:04:00.810 --> 00:04:02.840 but it's certainly a possibility. 00:04:02.840 --> 00:04:04.160 We've talked about uptake. 00:04:04.160 --> 00:04:05.660 What about-- what else could happen? 00:04:05.660 --> 00:04:06.160 Yes. 00:04:06.160 --> 00:04:08.325 AUDIENCE: When you get a [INAUDIBLE] out, 00:04:08.325 --> 00:04:12.063 such that they have oxygen [INAUDIBLE].. 00:04:12.063 --> 00:04:12.980 BARBARA IMPERIALI: OK. 00:04:12.980 --> 00:04:15.530 So this guy could just-- 00:04:15.530 --> 00:04:18.470 we've got a circular antibiotic usually, 00:04:18.470 --> 00:04:21.410 but this just changes-- 00:04:21.410 --> 00:04:22.910 the target just changes. 00:04:22.910 --> 00:04:25.380 It can't bind anymore, through mutation, 00:04:25.380 --> 00:04:28.090 so that the antibiotic simply doesn't bind. 00:04:28.090 --> 00:04:31.850 It gets in, but it's changed, and that happens a lot. 00:04:31.850 --> 00:04:34.460 It also happens a lot-- 00:04:34.460 --> 00:04:36.860 one can think of antibiotic resistance 00:04:36.860 --> 00:04:40.340 very much along the same veins as one thinks of resistance 00:04:40.340 --> 00:04:42.590 to chemotherapeutic agents. 00:04:42.590 --> 00:04:44.540 You're targeting a kinase. 00:04:44.540 --> 00:04:46.460 Your drug works great. 00:04:46.460 --> 00:04:48.800 A year later, the cancer comes back 00:04:48.800 --> 00:04:51.530 because there's a single mutation in your target. 00:04:51.530 --> 00:04:57.380 This happens a lot with the EGF, kinase, RAS's and so on. 00:04:57.380 --> 00:04:59.360 There's a dramatic change. 00:04:59.360 --> 00:05:02.030 So this change would be a change in the target. 00:05:02.030 --> 00:05:04.250 You mentioned two things, right? 00:05:04.250 --> 00:05:04.820 I thought. 00:05:04.820 --> 00:05:05.950 Maybe not. 00:05:05.950 --> 00:05:07.367 AUDIENCE: Well, like I said, there 00:05:07.367 --> 00:05:08.659 were some for that [INAUDIBLE]. 00:05:08.659 --> 00:05:09.600 BARBARA IMPERIALI: Ah. 00:05:09.600 --> 00:05:10.230 On the surface. 00:05:10.230 --> 00:05:12.030 AUDIENCE: A couple of days you're going back, so. 00:05:12.030 --> 00:05:13.697 BARBARA IMPERIALI: OK, so there could be 00:05:13.697 --> 00:05:16.600 some kind of import strategy. 00:05:16.600 --> 00:05:19.320 So some antibiotics just diffuse. 00:05:19.320 --> 00:05:22.010 Some go in through targeted import, 00:05:22.010 --> 00:05:24.780 and that might change so that the antibiotic can't 00:05:24.780 --> 00:05:26.075 get in anymore. 00:05:26.075 --> 00:05:26.700 Other thoughts? 00:05:29.370 --> 00:05:32.230 There's a couple of other sneaky ways. 00:05:32.230 --> 00:05:34.660 I mean, you've got to sort of give these bacteria credit 00:05:34.660 --> 00:05:38.210 for maximum sneakiness. 00:05:38.210 --> 00:05:42.110 So if influx is an issue, what about efflux? 00:05:45.350 --> 00:05:48.320 The biggest problem with antibiotics 00:05:48.320 --> 00:05:52.550 against Gram-negatives is that they way upregulate 00:05:52.550 --> 00:05:54.050 efflux pumps. 00:05:54.050 --> 00:05:57.267 They just, like, cover their cells with pumps that just go, 00:05:57.267 --> 00:05:58.850 you're going to give me an antibiotic? 00:05:58.850 --> 00:06:01.400 I'm just going to lob it straight back out to you. 00:06:01.400 --> 00:06:08.630 So the efflux pumps increase. 00:06:08.630 --> 00:06:12.860 So their molecules, we have a lot of efflux pumps 00:06:12.860 --> 00:06:16.240 to just kick out things that are not-- 00:06:16.240 --> 00:06:18.500 that we don't want in our cells. 00:06:18.500 --> 00:06:20.940 The bacteria have similar things. 00:06:20.940 --> 00:06:23.900 They will-- they're fairly promiscuous, 00:06:23.900 --> 00:06:26.450 exporting pumps that will bind to things 00:06:26.450 --> 00:06:29.150 that don't look like things that should be in a cell, 00:06:29.150 --> 00:06:32.170 and literally bind to them on the inside of the membrane, 00:06:32.170 --> 00:06:33.680 [MAKES SQUIRT SOUND] send them back 00:06:33.680 --> 00:06:35.580 to the outside of the membrane. 00:06:35.580 --> 00:06:38.450 So Gram-negative bacteria can massively 00:06:38.450 --> 00:06:40.520 upregulate the production of a pump 00:06:40.520 --> 00:06:44.640 that they already have, but they just make much more of them. 00:06:44.640 --> 00:06:48.080 So in many cases, you can hardly test a new compound 00:06:48.080 --> 00:06:51.530 because it's getting pumped out as fast as it gets pumped in. 00:06:51.530 --> 00:06:55.790 What could be a strategy when this happens? 00:06:55.790 --> 00:06:59.050 Because people are doing this. 00:06:59.050 --> 00:07:00.650 You inhibit the pump. 00:07:00.650 --> 00:07:02.500 So you make your antibiotic-- 00:07:02.500 --> 00:07:05.440 it works great, but you stop the pump working. 00:07:05.440 --> 00:07:09.190 So you have to give two drugs, the drug that's 00:07:09.190 --> 00:07:12.430 the antibiotic to the target and the drug that inhibits 00:07:12.430 --> 00:07:14.980 the pump, and that happens. 00:07:14.980 --> 00:07:19.480 Similarly, with this mechanism, where the antibiotic gets 00:07:19.480 --> 00:07:24.610 destroyed, you can recover from this 00:07:24.610 --> 00:07:29.850 by inhibiting the destroying enzyme, 00:07:29.850 --> 00:07:32.200 and then your antibiotic doesn't get destroyed 00:07:32.200 --> 00:07:34.130 when it gets into the cells. 00:07:34.130 --> 00:07:36.910 So there's one extremely important formulation 00:07:36.910 --> 00:07:38.980 of antibiotic that is used. 00:07:38.980 --> 00:07:40.285 It's called Augmentin. 00:07:46.190 --> 00:07:52.350 And what it is is a penicillin plus 00:07:52.350 --> 00:07:54.550 a beta-lactamase inhibitor. 00:07:54.550 --> 00:07:58.950 It's the drug that works plus a drug that 00:07:58.950 --> 00:08:01.890 inhibits the enzyme that destroys the drug. 00:08:01.890 --> 00:08:03.420 People get this all the time. 00:08:03.420 --> 00:08:06.340 Every day of the week, this stuff is prescribed. 00:08:06.340 --> 00:08:09.510 It's a two-compound cocktail that 00:08:09.510 --> 00:08:12.480 has something to overcome the resistance so that your drug 00:08:12.480 --> 00:08:13.950 still works in a cell. 00:08:13.950 --> 00:08:14.790 All right? 00:08:14.790 --> 00:08:17.130 And there's one more key mechanism, 00:08:17.130 --> 00:08:20.370 and what bacteria will just do is they say, well, you know, 00:08:20.370 --> 00:08:23.430 I'm getting dosed with this much antibiotic. 00:08:23.430 --> 00:08:29.920 What's a good way around it is to massively upregulate 00:08:29.920 --> 00:08:33.520 the biosynthesis of the target to a state where you just 00:08:33.520 --> 00:08:35.320 can't saturate it all. 00:08:35.320 --> 00:08:39.440 So upregulation of the target is a very, very common thing. 00:08:39.440 --> 00:08:41.770 So you-- this should have just increased the number 00:08:41.770 --> 00:08:43.419 of transcripts being made. 00:08:43.419 --> 00:08:46.960 You increase the amount of target being made so 00:08:46.960 --> 00:08:51.370 that, even if antibiotics are flooding into cells, 00:08:51.370 --> 00:08:55.120 there's just not enough to inhibit all of the target 00:08:55.120 --> 00:08:59.270 because it's been upregulated by 10 or 100-fold. 00:08:59.270 --> 00:09:02.050 So what I think is cool about all these mechanisms 00:09:02.050 --> 00:09:03.143 is they all make sense. 00:09:03.143 --> 00:09:04.810 You just kind of have to think of them-- 00:09:04.810 --> 00:09:06.280 do I stop the drug getting in? 00:09:06.280 --> 00:09:08.350 Do I stop it getting pumped out? 00:09:08.350 --> 00:09:10.420 Do I stop it getting degraded? 00:09:10.420 --> 00:09:12.340 Do I make more target? 00:09:12.340 --> 00:09:14.380 All of those things are very viable, 00:09:14.380 --> 00:09:17.380 and they are strategies that are used quite commonly. 00:09:17.380 --> 00:09:23.710 So very commonly, both in bacteria and in viruses, 00:09:23.710 --> 00:09:25.960 we seldom give one compound. 00:09:25.960 --> 00:09:29.820 We commonly give multiple compounds 00:09:29.820 --> 00:09:32.740 to sort of hit multiple targets, because if you 00:09:32.740 --> 00:09:36.790 gave a two-drug cocktail to a bacterium, 00:09:36.790 --> 00:09:40.030 but you knew there was going to be upregulation of a target, 00:09:40.030 --> 00:09:43.540 you could hope that the other enzyme is still a target. 00:09:43.540 --> 00:09:48.150 So you give cocktails of drugs, as opposed to single drugs. 00:09:48.150 --> 00:09:50.590 And you're going to see that very relevantly when 00:09:50.590 --> 00:09:54.430 we talk about the HIV virus because it's only 00:09:54.430 --> 00:09:57.880 been that HIV has become-- 00:09:57.880 --> 00:10:01.450 HIV-AIDS has become a treatable condition 00:10:01.450 --> 00:10:04.750 because of drug cocktails, not because of singular drugs that 00:10:04.750 --> 00:10:06.280 inhibit one step. 00:10:06.280 --> 00:10:08.470 And you'll see it very, very commonly there. 00:10:08.470 --> 00:10:11.240 Any questions about this stuff? 00:10:11.240 --> 00:10:11.803 OK. 00:10:11.803 --> 00:10:13.345 So we're going to move on to viruses. 00:10:26.530 --> 00:10:31.330 And so I will actually update the slides that are on the web 00:10:31.330 --> 00:10:33.790 to give you this set of information 00:10:33.790 --> 00:10:36.520 so you can see it in one place. 00:10:36.520 --> 00:10:37.160 OK, viruses. 00:10:47.480 --> 00:10:51.350 Viruses are fascinating organisms. 00:10:51.350 --> 00:10:53.300 They don't have the right to be alive 00:10:53.300 --> 00:10:56.720 because they don't have the machinery to be alive, 00:10:56.720 --> 00:10:59.690 but they exploit the host's mechanisms 00:10:59.690 --> 00:11:01.950 for completing their viability. 00:11:01.950 --> 00:11:05.030 So viruses, more or less, I think 00:11:05.030 --> 00:11:11.120 we like to think of them as living a borrowed life. 00:11:14.900 --> 00:11:23.000 And they only survive if they have spent 00:11:23.000 --> 00:11:25.430 some time inside a host cell. 00:11:45.090 --> 00:11:48.440 So we will see with viruses, some viruses specifically 00:11:48.440 --> 00:11:50.510 target humans. 00:11:50.510 --> 00:11:54.050 Other viruses may spend some time in different organisms, 00:11:54.050 --> 00:11:56.960 and then target humans, and be carried around 00:11:56.960 --> 00:11:59.430 amongst different organisms. 00:11:59.430 --> 00:12:02.270 But the key thing is that viruses can only 00:12:02.270 --> 00:12:05.750 actually replicate once they're inside a host cell 00:12:05.750 --> 00:12:08.780 because they basically exploit all of the host cell's 00:12:08.780 --> 00:12:10.520 machinery to do that. 00:12:10.520 --> 00:12:13.850 So viruses don't make many of their own enzymes. 00:12:13.850 --> 00:12:16.670 They don't have their own amino acid supplies 00:12:16.670 --> 00:12:19.520 or all the metabolic enzymes that 00:12:19.520 --> 00:12:23.550 are required for life, all the replication, transcription, 00:12:23.550 --> 00:12:25.370 translation machinery. 00:12:25.370 --> 00:12:27.590 They just borrow the host's machinery, 00:12:27.590 --> 00:12:31.160 but there are occasionally individual components 00:12:31.160 --> 00:12:33.960 that the virus will bring along with it 00:12:33.960 --> 00:12:37.850 to cover certain things that are not provided by the hosts. 00:12:37.850 --> 00:12:39.890 But viral genomes are tiny. 00:12:39.890 --> 00:12:43.130 They may comprise maybe eight genes. 00:12:43.130 --> 00:12:45.010 Some of them are a lot-- are bigger, 00:12:45.010 --> 00:12:48.000 but they are very, very small genomes. 00:12:48.000 --> 00:12:51.890 They're very, what we call, parsimonious genomes, 00:12:51.890 --> 00:12:54.320 so there's overlapping genes, so you can keep 00:12:54.320 --> 00:12:56.960 the genome tiny by having-- 00:12:56.960 --> 00:12:59.720 compacting the size of the genome. 00:12:59.720 --> 00:13:01.890 And then there are bigger viruses. 00:13:01.890 --> 00:13:05.570 Some of the biggest viruses approach the sizes of bacteria, 00:13:05.570 --> 00:13:07.820 like the mimiviruses, and they may 00:13:07.820 --> 00:13:11.150 have been an intermediate step from virus 00:13:11.150 --> 00:13:14.420 to more elaborated organisms. 00:13:14.420 --> 00:13:17.240 And those viruses have a bit more machinery 00:13:17.240 --> 00:13:18.740 within their contexts. 00:13:18.740 --> 00:13:23.720 People-- obviously, there's no fossil record for viruses. 00:13:23.720 --> 00:13:27.800 It's not like we can go, you know, go exploring 00:13:27.800 --> 00:13:29.690 and find a fossil record. 00:13:29.690 --> 00:13:31.580 But where these viruses are being found 00:13:31.580 --> 00:13:34.310 is in the permafrost, so they're frozen. 00:13:34.310 --> 00:13:37.160 They've been frozen there for centuries. 00:13:37.160 --> 00:13:39.740 So people are finding really sort of scary things 00:13:39.740 --> 00:13:42.680 in the Siberian permafrost because the viruses are 00:13:42.680 --> 00:13:44.300 preserved there. 00:13:44.300 --> 00:13:47.000 And some of these giant viruses are being 00:13:47.000 --> 00:13:49.130 discovered in those locations. 00:13:49.130 --> 00:13:53.120 And if that's not the subject for wonderful sci-fi books, 00:13:53.120 --> 00:13:56.060 I don't know what is, because there are-- and I 00:13:56.060 --> 00:13:58.850 tend to read those things because my favorite thing is 00:13:58.850 --> 00:14:01.610 finding mistakes in them. 00:14:01.610 --> 00:14:04.620 So there's a lot out there about those kinds of things. 00:14:04.620 --> 00:14:08.642 So let me just show you a tiny bit about-- 00:14:08.642 --> 00:14:11.710 you know, this is that boring old "learn genetics" thing 00:14:11.710 --> 00:14:15.280 right from the beginning, but what I want to take you back to 00:14:15.280 --> 00:14:16.210 is sizes. 00:14:16.210 --> 00:14:17.380 So we know all this stuff. 00:14:17.380 --> 00:14:20.535 We've learned it to death, hemoglobin, antibodies, 00:14:20.535 --> 00:14:22.030 and ribosome. 00:14:22.030 --> 00:14:25.870 But what I really want to point out on this slide is that 00:14:25.870 --> 00:14:29.170 the smallest viruses, like the rhinovirus-- 00:14:29.170 --> 00:14:30.730 that's the common cold-- 00:14:30.730 --> 00:14:34.120 or the hepatitis virus are not barely any bigger 00:14:34.120 --> 00:14:36.250 than the ribosome. 00:14:36.250 --> 00:14:39.370 So obviously, there's not much in the virus, 00:14:39.370 --> 00:14:41.680 but all the components of the virus 00:14:41.680 --> 00:14:48.130 have evolved to enable them to sneakily get into host cells, 00:14:48.130 --> 00:14:52.030 exploit the host cell machinery, and then replicate 00:14:52.030 --> 00:14:55.330 inside host cell, and then get out of the host cell 00:14:55.330 --> 00:14:58.940 and ready to infect another host cell. 00:14:58.940 --> 00:15:02.030 So I want you to really notice these sizes. 00:15:02.030 --> 00:15:05.650 So the rhinovirus is similar to a ribosome, 00:15:05.650 --> 00:15:08.980 but some viruses, which we will talk about, 00:15:08.980 --> 00:15:13.840 the influenza virus and the HIV virus are a little bigger, 00:15:13.840 --> 00:15:17.820 but none of them compete up to the size of a bacterium. 00:15:17.820 --> 00:15:22.900 And just to get you into that mode, there are the bacteria, 00:15:22.900 --> 00:15:25.030 and there's the mitochondria, and remember 00:15:25.030 --> 00:15:28.690 endosymbiotic theory, bacteria, similar size to mitochondria, 00:15:28.690 --> 00:15:32.880 and much, much bigger than any typical virus. 00:15:32.880 --> 00:15:37.060 But giant viruses approach some of these bigger sizes. 00:15:37.060 --> 00:15:38.790 They're a different ballgame altogether. 00:15:38.790 --> 00:15:41.890 And we won't talk about them, apart from the fact 00:15:41.890 --> 00:15:44.396 that they're really cool, and they're in the permafrost. 00:15:53.080 --> 00:15:56.680 All right, so another impressive thing 00:15:56.680 --> 00:16:01.300 about viruses, as they look-- some of them like this. 00:16:01.300 --> 00:16:05.110 Phage, a bacterial virus, they look like things, 00:16:05.110 --> 00:16:09.530 lunar landers, for example, or sort of other kinds of things. 00:16:09.530 --> 00:16:11.110 Some of them are linear. 00:16:11.110 --> 00:16:13.510 Some of them are different kinds of shapes. 00:16:13.510 --> 00:16:15.760 A lot of viruses are icosahedra. 00:16:15.760 --> 00:16:19.320 We'll talk about that in a moment. 00:16:19.320 --> 00:16:22.330 But the fact sheet about viruses is first of all sizes. 00:16:26.230 --> 00:16:29.980 And the typical viral size, if there is something typical, 00:16:29.980 --> 00:16:35.710 expand from 20 to 400 nanometers in diameter. 00:16:39.080 --> 00:16:41.810 So remember, the ribosome sits right 00:16:41.810 --> 00:16:47.030 at this end with respect to size, but bacteria-- 00:16:47.030 --> 00:16:52.090 oh, yellow, I can't do a yellow lecture here-- 00:16:55.130 --> 00:16:59.060 remember, are 1 to 10 micrometers in length, 00:16:59.060 --> 00:17:01.730 depending on what dimension you're measuring, 00:17:01.730 --> 00:17:05.030 so considerably smaller, nanometer scale, 00:17:05.030 --> 00:17:07.589 micrometer scale for bacteria. 00:17:07.589 --> 00:17:10.910 So that's the first thing that it's important to know. 00:17:10.910 --> 00:17:13.760 They're very small. 00:17:13.760 --> 00:17:17.420 The next critical thing is what's in a virus? 00:17:17.420 --> 00:17:21.109 What is its-- what's the blood and guts of a virus? 00:17:21.109 --> 00:17:28.860 And it's either DNA or RNA, and it 00:17:28.860 --> 00:17:32.940 can be single-stranded or double-stranded. 00:17:32.940 --> 00:17:35.690 So it has its genetic material. 00:17:35.690 --> 00:17:38.910 Its genetic material is usually dedicated 00:17:38.910 --> 00:17:41.170 to making more copies of itself. 00:17:41.170 --> 00:17:45.180 So if the virus has a coat, a coat of proteins, 00:17:45.180 --> 00:17:47.460 the virus has to have a gene for that 00:17:47.460 --> 00:17:50.460 because the host isn't going to have a coat for a virus. 00:17:50.460 --> 00:17:53.820 So the virus has to have certain specialized things that 00:17:53.820 --> 00:17:58.950 complete itself that can't be borrowed from the host cell. 00:17:58.950 --> 00:18:02.280 And they can be-- 00:18:02.280 --> 00:18:07.420 let's see-- they can be what are called capsid viruses 00:18:07.420 --> 00:18:08.350 or enveloped. 00:18:12.730 --> 00:18:16.480 Capsid viruses just have a protein coat. 00:18:16.480 --> 00:18:20.260 The enveloped viruses have a membrane surrounding them 00:18:20.260 --> 00:18:22.420 with proteins stuck into them. 00:18:22.420 --> 00:18:31.400 So the enveloped viruses have an outer membrane 00:18:31.400 --> 00:18:32.995 which is studded with proteins. 00:18:35.860 --> 00:18:37.570 But what is cool about the virus is 00:18:37.570 --> 00:18:39.100 it never makes its own membranes. 00:18:39.100 --> 00:18:41.320 It doesn't make its phospholipids. 00:18:41.320 --> 00:18:44.470 It just, as it emerges from a host cell, 00:18:44.470 --> 00:18:47.690 pinches a piece of the cell surface. 00:18:47.690 --> 00:18:50.500 It steals the cellular membrane with it, 00:18:50.500 --> 00:18:52.660 as it's emerging from a cell. 00:18:52.660 --> 00:18:55.630 And you'll see this in a video, how cool that 00:18:55.630 --> 00:18:59.890 is, all the proteins that-- all the components of the virus 00:18:59.890 --> 00:19:02.500 cluster near the surface of a membrane, 00:19:02.500 --> 00:19:05.560 and then you have this wonderful endocytosis 00:19:05.560 --> 00:19:07.190 using the host membrane. 00:19:07.190 --> 00:19:11.232 So the virus never has to make it own membrane. 00:19:11.232 --> 00:19:14.960 And not all viruses are enveloped, just some of them, 00:19:14.960 --> 00:19:17.540 and you'll see examples of each. 00:19:17.540 --> 00:19:19.400 So the definition really is that they're 00:19:19.400 --> 00:19:22.270 small, infectious agents, that they only 00:19:22.270 --> 00:19:25.870 replicate inside living cells because they 00:19:25.870 --> 00:19:30.040 have to exploit a lot of the machinery of living cells. 00:19:30.040 --> 00:19:34.150 And they can infect humans, other animals. 00:19:34.150 --> 00:19:35.860 There are plant viruses. 00:19:35.860 --> 00:19:37.450 Bacteria have viruses. 00:19:37.450 --> 00:19:42.100 So all living organisms have viruses that infect them. 00:19:42.100 --> 00:19:46.630 But viruses are usually targeted very specifically to the cells 00:19:46.630 --> 00:19:47.950 that they infect. 00:19:47.950 --> 00:19:50.530 And, in fact, you will see with HIV, 00:19:50.530 --> 00:19:54.100 it's not just a virus that infects a human host. 00:19:54.100 --> 00:19:56.140 It infects specifically, and that 00:19:56.140 --> 00:20:00.830 was why it was so terrifying, this-- actually T cells. 00:20:00.830 --> 00:20:04.720 That's the one cell type in the host that it goes after. 00:20:04.720 --> 00:20:10.210 So viruses very often target to particular organs 00:20:10.210 --> 00:20:13.810 within their hosts, and that's why 00:20:13.810 --> 00:20:15.250 we know some of the viruses. 00:20:15.250 --> 00:20:17.770 And you'll see that the names of the viruses 00:20:17.770 --> 00:20:22.300 are related to the organs that they may infect. 00:20:22.300 --> 00:20:24.970 So I want to just briefly describe the terms. 00:20:24.970 --> 00:20:30.100 We talk about these with all infectious diseases, 00:20:30.100 --> 00:20:35.440 that they may be endemic, epidemic, and pandemic. 00:20:35.440 --> 00:20:38.710 Endemic is the term that we use for, there's 00:20:38.710 --> 00:20:41.830 a very low level of an infectious agent 00:20:41.830 --> 00:20:43.420 in the population. 00:20:43.420 --> 00:20:45.760 It's completely out of-- 00:20:45.760 --> 00:20:47.230 within control. 00:20:47.230 --> 00:20:49.710 There's a few cases, but there's not 00:20:49.710 --> 00:20:53.200 a transfer from person to person or animal to animal. 00:20:53.200 --> 00:20:57.550 We would call that endemic, a very, very low level of virus 00:20:57.550 --> 00:20:59.920 that doesn't cause any threat. 00:20:59.920 --> 00:21:04.390 As soon as the virus or bacterial infectious agents 00:21:04.390 --> 00:21:08.390 starts spreading amongst a local population, 00:21:08.390 --> 00:21:11.920 we would call that a local epidemic, so 00:21:11.920 --> 00:21:15.280 all of a community, all of a country, 00:21:15.280 --> 00:21:17.890 so very much defined geographically 00:21:17.890 --> 00:21:22.660 into a particular space where there's transmission of viruses 00:21:22.660 --> 00:21:26.980 from person to person or animal to person within a community. 00:21:26.980 --> 00:21:29.530 There has to be direct contact. 00:21:29.530 --> 00:21:34.480 But now, with travel, many viruses 00:21:34.480 --> 00:21:38.170 reach pandemic stages, which means worldwide. 00:21:38.170 --> 00:21:42.220 So plane travel really caused enormous trouble 00:21:42.220 --> 00:21:48.220 because you can have a virus in Africa or Asia. 00:21:48.220 --> 00:21:51.280 Somebody gets on a plane and ends up somewhere else, 00:21:51.280 --> 00:21:55.210 and the virus has been moved to a new country. 00:21:55.210 --> 00:22:00.430 I made the terrible mistake of reading Hot Zone on a plane one 00:22:00.430 --> 00:22:03.550 time, which is about Marburg virus, which 00:22:03.550 --> 00:22:07.820 is where people basically just start bleeding out in the spot. 00:22:07.820 --> 00:22:09.430 And I'm reading this book, and it's 00:22:09.430 --> 00:22:12.010 describing the steps of someone who 00:22:12.010 --> 00:22:15.310 had Marburg and was just sort of bleeding out next to them 00:22:15.310 --> 00:22:16.090 on the plane. 00:22:16.090 --> 00:22:19.450 And I'm like, are you crazy, reading this book on a plane? 00:22:19.450 --> 00:22:22.360 Because they were describing how Marburg was just 00:22:22.360 --> 00:22:26.770 moved from its country of origin to New York City, 00:22:26.770 --> 00:22:28.240 or something like that. 00:22:28.240 --> 00:22:32.410 So you remember when we had the Ebola concerns. 00:22:32.410 --> 00:22:35.260 There was a real, genuine worry that Ebola 00:22:35.260 --> 00:22:38.400 would jump through flight travel, 00:22:38.400 --> 00:22:40.590 through people coming in at airports, 00:22:40.590 --> 00:22:43.740 and end up with a pandemic of Ebola. 00:22:43.740 --> 00:22:50.070 When there was a real problem with the avian flu in Asia, 00:22:50.070 --> 00:22:54.030 Singapore, that's very, very protective of its territory, 00:22:54.030 --> 00:22:57.930 had sensors that would-- you would go into Singapore, 00:22:57.930 --> 00:23:00.960 and you'd go down these two huge escalators. 00:23:00.960 --> 00:23:03.750 And they had sensors measuring people's temperature 00:23:03.750 --> 00:23:08.220 at a distance as they came down the escalator, and hauling 00:23:08.220 --> 00:23:11.880 people over, and sort of interrogating them, 00:23:11.880 --> 00:23:13.140 where have you been?-- 00:23:13.140 --> 00:23:16.260 to see whether they would be allowed to enter Singapore, 00:23:16.260 --> 00:23:19.500 because the flight travel, people getting on planes, 00:23:19.500 --> 00:23:22.230 spreading a very contagious virus to a new country 00:23:22.230 --> 00:23:24.780 is very, very realistic. 00:23:24.780 --> 00:23:29.460 The issue with spreading to pandemic situations 00:23:29.460 --> 00:23:33.600 is very, very important when one thinks of history, 00:23:33.600 --> 00:23:39.030 because when the Europeans were conquering the Americas, 00:23:39.030 --> 00:23:42.210 in particular South America and Central America, 00:23:42.210 --> 00:23:45.070 they brought with them a lot of viruses. 00:23:45.070 --> 00:23:47.220 But there was an innate sort of resistance 00:23:47.220 --> 00:23:50.220 to-- because of years and years of exposure. 00:23:50.220 --> 00:23:53.520 But these communities have never seen these viruses, 00:23:53.520 --> 00:23:56.910 so millions of people died because they were suddenly 00:23:56.910 --> 00:24:01.110 exposed to a human virus that they had never seen before, 00:24:01.110 --> 00:24:04.650 through transmission from a country where there wasn't 00:24:04.650 --> 00:24:06.700 such a problem with the virus. 00:24:06.700 --> 00:24:11.430 So the indigenous peoples of the Americas, Australia, 00:24:11.430 --> 00:24:15.810 and New Zealand had terrible consequences there. 00:24:15.810 --> 00:24:18.690 Some of you have probably heard of the Spanish flu, 00:24:18.690 --> 00:24:23.460 and that was towards the tail end of World War I 00:24:23.460 --> 00:24:27.010 and is thought to have killed as many as 100 million people. 00:24:27.010 --> 00:24:29.760 And that, in fact, is quite interesting. 00:24:29.760 --> 00:24:32.910 It's called the Spanish flu, but there's some evidence 00:24:32.910 --> 00:24:35.670 that it might have originated in the Americas, 00:24:35.670 --> 00:24:39.300 in the boats that took troops over to Europe 00:24:39.300 --> 00:24:41.740 to help at the tail end of the First World War. 00:24:41.740 --> 00:24:45.330 And there's a really interesting book about that whole story, 00:24:45.330 --> 00:24:48.780 that the Spanish flu may not have originated in Spain. 00:24:48.780 --> 00:24:51.510 And that's a-- it's definitely a worthwhile read. 00:24:51.510 --> 00:24:56.370 So that tells you a lot about the statistics of viruses. 00:24:56.370 --> 00:25:01.050 I just want to highlight here, we talk about HIV 00:25:01.050 --> 00:25:03.420 as a very serious virus. 00:25:03.420 --> 00:25:08.790 It emerged in the early '80s to this current-- 00:25:08.790 --> 00:25:13.320 well, in 2011, there were 35 million people infected. 00:25:13.320 --> 00:25:17.040 There's about 2 and 1/2 million new cases a year. 00:25:17.040 --> 00:25:20.190 But what's fascinating about HIV-- 00:25:20.190 --> 00:25:23.010 there was a stage before the really good antivirals 00:25:23.010 --> 00:25:26.520 were available that, if the mother had HIV, 00:25:26.520 --> 00:25:28.920 the baby would get HIV. 00:25:28.920 --> 00:25:31.950 But now, if there's treatment of the mother, 00:25:31.950 --> 00:25:36.330 and the baby is delivered, often by a Caesarean section, 00:25:36.330 --> 00:25:39.390 the baby can escape being infected 00:25:39.390 --> 00:25:41.760 with the virus due to the new antivirals. 00:25:41.760 --> 00:25:44.220 So that's really important, that the-- 00:25:44.220 --> 00:25:46.920 originally, there were a lot of cases of newborns who 00:25:46.920 --> 00:25:50.280 simply got HIV during birth. 00:25:50.280 --> 00:25:53.520 But now that can be-- there's escape from that, 00:25:53.520 --> 00:25:54.840 which is really, really cool. 00:25:54.840 --> 00:25:57.450 The viral load can be brought really low 00:25:57.450 --> 00:26:00.570 with the common antivirals against HIV, 00:26:00.570 --> 00:26:05.700 and that next generation doesn't have that sentence. 00:26:05.700 --> 00:26:08.310 So I mentioned to you that a lot of viruses 00:26:08.310 --> 00:26:12.720 are basically named after the organs that they hit. 00:26:12.720 --> 00:26:14.820 So I've just got a human being here 00:26:14.820 --> 00:26:18.020 with a lot of different viruses that hit different places, 00:26:18.020 --> 00:26:21.480 and I just want to point out a few points. 00:26:21.480 --> 00:26:26.520 Viruses may be targets nowadays of childhood vaccinations, 00:26:26.520 --> 00:26:27.450 and many of you-- 00:26:27.450 --> 00:26:29.280 I hope all of you-- 00:26:29.280 --> 00:26:33.540 have had vaccinations to many of these common viruses. 00:26:33.540 --> 00:26:37.980 There is a concern now with communities that are deciding 00:26:37.980 --> 00:26:41.700 not to vaccinate children. 00:26:41.700 --> 00:26:45.960 That's a huge social problem that may, initially, sort of, 00:26:45.960 --> 00:26:48.750 people can get away with it because there's 00:26:48.750 --> 00:26:50.820 community vaccination. 00:26:50.820 --> 00:26:53.130 You're in a community where a lot of people 00:26:53.130 --> 00:27:00.420 have a resistance or some sort of immunity to a virus. 00:27:00.420 --> 00:27:04.440 But as communities become less and less vaccinated, 00:27:04.440 --> 00:27:06.390 than later generations will start 00:27:06.390 --> 00:27:08.400 to get the disease seriously. 00:27:08.400 --> 00:27:10.860 And that's actually happening in parts of the world where 00:27:10.860 --> 00:27:11.440 there's-- 00:27:11.440 --> 00:27:14.280 there used to be no polio, and now there's 00:27:14.280 --> 00:27:18.630 polio emerging because the community immunity has 00:27:18.630 --> 00:27:20.280 been-- is fading away. 00:27:20.280 --> 00:27:25.530 So we hope that people get vaccinated. 00:27:25.530 --> 00:27:26.970 That's for sure. 00:27:26.970 --> 00:27:28.800 The vaccinations work. 00:27:28.800 --> 00:27:32.310 Several vaccinations-- several viruses 00:27:32.310 --> 00:27:34.410 were pretty much eradicated. 00:27:34.410 --> 00:27:39.360 Smallpox and polio were two of the real poster examples 00:27:39.360 --> 00:27:42.300 of childhood vaccinations that worked 00:27:42.300 --> 00:27:44.400 and worked amazingly well. 00:27:44.400 --> 00:27:46.590 But now, there's a problem with failure 00:27:46.590 --> 00:27:49.900 to vaccinate in certain parts of the world. 00:27:49.900 --> 00:27:51.420 So that's a concern. 00:27:51.420 --> 00:27:55.080 And then, another interesting thing is that some viruses-- 00:27:55.080 --> 00:27:58.070 whoops, oops, go back. 00:27:58.070 --> 00:27:58.570 Sorry. 00:27:58.570 --> 00:27:59.690 Go back, back, back, back. 00:27:59.690 --> 00:28:01.023 Don't now-- that's all a secret. 00:28:01.023 --> 00:28:02.560 You can't see that just yet. 00:28:02.560 --> 00:28:06.910 Some viruses lead to cancer, so human papilloma virus, 00:28:06.910 --> 00:28:11.800 where there is a vaccine, the people who have HIV-- 00:28:11.800 --> 00:28:15.730 some of the types of hepatitis and Epstein-Barr 00:28:15.730 --> 00:28:19.630 are all associated with later cases of cancer. 00:28:19.630 --> 00:28:21.040 That's important to know. 00:28:21.040 --> 00:28:25.090 So often cancers are named by the organ that they attach, 00:28:25.090 --> 00:28:27.100 so even though the three-- 00:28:27.100 --> 00:28:32.020 the five hepatitises all attack the liver, they're not related. 00:28:32.020 --> 00:28:35.210 They're just five viruses that go off to the liver. 00:28:35.210 --> 00:28:38.060 So if you've had a vaccination against Hep A, 00:28:38.060 --> 00:28:41.892 It doesn't protect you from Hep B or C by a relationship. 00:28:41.892 --> 00:28:43.600 They're very, very different, so you have 00:28:43.600 --> 00:28:45.860 to have different vaccinations. 00:28:45.860 --> 00:28:49.610 So this just gives you a nice view of human viruses, 00:28:49.610 --> 00:28:52.510 what their names are, what organs they may attack, 00:28:52.510 --> 00:28:55.450 what sorts of things they might be associated with. 00:28:55.450 --> 00:28:58.360 But the trouble is, this nomenclature doesn't get you 00:28:58.360 --> 00:29:02.780 anywhere towards understanding the mechanism of a virus. 00:29:02.780 --> 00:29:07.210 So what we will focus on is a much better system 00:29:07.210 --> 00:29:10.060 for describing viruses that's based 00:29:10.060 --> 00:29:15.010 on whether they have DNA or RNA within the genomes 00:29:15.010 --> 00:29:17.430 that they import into host cells, 00:29:17.430 --> 00:29:20.980 and whether that DNA or RNA is single-stranded or 00:29:20.980 --> 00:29:24.100 double-stranded, because that truly tells us 00:29:24.100 --> 00:29:27.280 a lot more about the virus and maybe the steps that 00:29:27.280 --> 00:29:30.880 could be inhibited to prevent the viral infections. 00:29:30.880 --> 00:29:33.050 But first of all, just a few pictures-- 00:29:33.050 --> 00:29:36.350 here's some-- so viruses can be rod-shaped. 00:29:36.350 --> 00:29:37.510 They can look like-- 00:29:37.510 --> 00:29:39.640 they can be icosahedra. 00:29:39.640 --> 00:29:41.860 They can just have a capsid. 00:29:41.860 --> 00:29:44.380 So I mentioned they may just have a protein 00:29:44.380 --> 00:29:49.600 coat, the sets of repeating proteins that 00:29:49.600 --> 00:29:54.010 pack into a beautiful structure, very commonly an icosahedron, 00:29:54.010 --> 00:29:56.290 and I'll show you why that is. 00:29:56.290 --> 00:29:59.290 Or they may be enveloped viruses, 00:29:59.290 --> 00:30:04.180 like, influenza has a membranous surface around where 00:30:04.180 --> 00:30:05.560 the DNA is packaged. 00:30:05.560 --> 00:30:08.800 All of these have nucleic acids packaged within them, 00:30:08.800 --> 00:30:12.070 DNA or RNA, single or double-stranded. 00:30:12.070 --> 00:30:15.240 And in the case of the enveloped viruses, 00:30:15.240 --> 00:30:18.070 that membrane-- it's a normal membrane. 00:30:18.070 --> 00:30:19.600 It's just like your membrane. 00:30:19.600 --> 00:30:22.070 In fact, it is your membrane-- 00:30:22.070 --> 00:30:24.730 will have proteins dotted within it 00:30:24.730 --> 00:30:28.750 that's actually-- serve as recognition to the host cells. 00:30:28.750 --> 00:30:32.680 They'll grab onto host cells and be the source of the infection 00:30:32.680 --> 00:30:34.405 into the host cells. 00:30:34.405 --> 00:30:39.037 And this is a bacterial virus, and as I said, 00:30:39.037 --> 00:30:40.120 I just love the way they-- 00:30:40.120 --> 00:30:41.650 I mean, they really look like this. 00:30:41.650 --> 00:30:43.748 You know, the cartoon is really the cartoon 00:30:43.748 --> 00:30:45.790 of what the thing looks like, and they're sort of 00:30:45.790 --> 00:30:46.810 pretty amazing. 00:30:46.810 --> 00:30:48.220 And they kind of-- 00:30:48.220 --> 00:30:51.970 they keep their nucleic acid in the head here. 00:30:51.970 --> 00:30:56.320 They land on their sort of feet, and they shoot the nucleic acid 00:30:56.320 --> 00:30:58.580 material into the host cells. 00:30:58.580 --> 00:31:00.590 So that's very interesting. 00:31:00.590 --> 00:31:02.330 Of course, this thing is-- 00:31:02.330 --> 00:31:02.830 OK. 00:31:02.830 --> 00:31:08.450 So why are many viruses that are capsid viruses icosahedra? 00:31:08.450 --> 00:31:13.120 So it ends up being a problem of geometry. 00:31:13.120 --> 00:31:18.640 So how can you make a perfect coat around something 00:31:18.640 --> 00:31:21.820 with very, very few building blocks of different types? 00:31:21.820 --> 00:31:25.220 Like, if every building block in that coat was different, 00:31:25.220 --> 00:31:28.150 the virus would have to have genes for all of them. 00:31:28.150 --> 00:31:30.370 What viruses can do is they can have 00:31:30.370 --> 00:31:34.540 genes for, like, three pieces of a module of the virus. 00:31:34.540 --> 00:31:38.020 So I'm going to show you how these capsid viruses get 00:31:38.020 --> 00:31:39.640 assembled. 00:31:39.640 --> 00:31:44.260 So here, color-coded, is an icosahedral virus, 00:31:44.260 --> 00:31:49.330 where I've coded in the red, green, and blue, 00:31:49.330 --> 00:31:52.510 a triangular component-- this is really cool-- 00:31:52.510 --> 00:31:57.970 that is a single sort of panel on that icosahedral virus that 00:31:57.970 --> 00:32:00.310 comes together as a triangle through 00:32:00.310 --> 00:32:05.110 noncovalent interactions between three proteins. 00:32:05.110 --> 00:32:07.210 You see that panel there. 00:32:07.210 --> 00:32:10.510 What you can then do is see how that panel would 00:32:10.510 --> 00:32:14.920 fit into a pentagon with an extra triangle stuck onto it, 00:32:14.920 --> 00:32:20.290 and you can fit that triangle into the pentagon 00:32:20.290 --> 00:32:22.700 and also into the additional piece. 00:32:22.700 --> 00:32:24.850 And then you can start to visualize 00:32:24.850 --> 00:32:29.200 how you could build an icosahedron from those pieces 00:32:29.200 --> 00:32:34.120 because they represent each of those faces within the virus. 00:32:34.120 --> 00:32:40.210 So you can go from this, which is a set of building blocks 00:32:40.210 --> 00:32:41.660 that I just showed you-- 00:32:41.660 --> 00:32:43.840 then you can assemble them like this. 00:32:43.840 --> 00:32:48.070 And one of these would be this part of the icosahedron, 00:32:48.070 --> 00:32:52.570 and then you just have a bunch of copies of it. 00:32:52.570 --> 00:32:54.810 And you can see how you would assemble that. 00:32:54.810 --> 00:32:58.710 And years ago, I decided to decorate my Christmas tree 00:32:58.710 --> 00:33:00.370 with icosahedra. 00:33:00.370 --> 00:33:03.450 So I went through this geometrical thing, 00:33:03.450 --> 00:33:05.320 and believe me, it works really nicely. 00:33:05.320 --> 00:33:08.220 You can put together an icosahedron 00:33:08.220 --> 00:33:09.880 and build an icosahedron. 00:33:09.880 --> 00:33:12.330 You could spray it gold and put it on your Christmas tree. 00:33:12.330 --> 00:33:14.550 It's kind of fanatical, but it really-- it's 00:33:14.550 --> 00:33:17.670 highly recommended. 00:33:17.670 --> 00:33:20.670 All right, so let's now get down to something a little bit more 00:33:20.670 --> 00:33:23.820 serious than Christmas trees and things. 00:33:23.820 --> 00:33:30.450 All right, so I told you that the classification of viruses 00:33:30.450 --> 00:33:35.240 by what organ they attack or who discovered them or anything 00:33:35.240 --> 00:33:36.060 is just-- 00:33:36.060 --> 00:33:39.960 is a vagary that's not so useful to the non-physicians 00:33:39.960 --> 00:33:41.950 because you can't immediately know, 00:33:41.950 --> 00:33:45.300 oh, this is how the virus gets into the host cell. 00:33:45.300 --> 00:33:48.930 This is how the virus uses its genetic material 00:33:48.930 --> 00:33:50.760 to make new viruses. 00:33:50.760 --> 00:33:53.280 So what was developed by Baltimore-- 00:33:53.280 --> 00:33:55.540 David Baltimore used to be at-- 00:33:55.540 --> 00:33:56.880 it was kind of interesting. 00:33:56.880 --> 00:34:00.220 David Baltimore, a very famous person and Nobel laureate, 00:34:00.220 --> 00:34:04.020 used to be at MIT when I was at Caltech, 00:34:04.020 --> 00:34:05.880 and we moved in opposite directions. 00:34:05.880 --> 00:34:07.830 I'm not sure it was a great trade for MIT, 00:34:07.830 --> 00:34:10.150 but it was a great trade for Caltech. 00:34:10.150 --> 00:34:13.409 So I ended up with David Baltimore's labs in Building 68 00:34:13.409 --> 00:34:18.270 because we did that swap in 1999 or something like that. 00:34:18.270 --> 00:34:20.219 So I thought that was pretty interesting. 00:34:20.219 --> 00:34:23.310 Anyway, so what Baltimore decided 00:34:23.310 --> 00:34:26.940 is-- was much better to classify viruses 00:34:26.940 --> 00:34:31.568 by the type of genetic material, like, are they DNA or RNA? 00:34:31.568 --> 00:34:34.530 Is that DNA or RNA single-stranded or 00:34:34.530 --> 00:34:35.850 double-stranded? 00:34:35.850 --> 00:34:39.989 Because, depending on what the genetic material in the virus 00:34:39.989 --> 00:34:44.370 is, once that gets unloaded into a host cell, 00:34:44.370 --> 00:34:47.219 certain steps have to happen in order for the virus 00:34:47.219 --> 00:34:50.159 to be able to replicate that genetic material, 00:34:50.159 --> 00:34:53.310 to convert it ultimately into the proteins 00:34:53.310 --> 00:34:59.340 it needs, and then to package up new viral genetic material 00:34:59.340 --> 00:35:02.940 into viral capsids so that they can then 00:35:02.940 --> 00:35:06.760 be sprung out of the cell and go infect another cell. 00:35:06.760 --> 00:35:11.050 So the classification basically went this way. 00:35:11.050 --> 00:35:17.070 So if you think of it, what the major goal in the infected cell 00:35:17.070 --> 00:35:20.850 is to get the virus to a stage where the virus has 00:35:20.850 --> 00:35:22.920 plus-messenger RNA. 00:35:22.920 --> 00:35:27.960 It has RNA that can be read by the host's ribosomes 00:35:27.960 --> 00:35:29.950 and convert it into proteins. 00:35:29.950 --> 00:35:32.130 So the overall goal of the virus, 00:35:32.130 --> 00:35:36.930 if we give it sort of some conscience, shall we say, 00:35:36.930 --> 00:35:41.710 is to make its viral material into messenger RNA. 00:35:41.710 --> 00:35:44.580 Now, the virus doesn't include messenger RNA. 00:35:44.580 --> 00:35:47.070 That's just what is made transiently, 00:35:47.070 --> 00:35:50.550 but the virus may have single-stranded DNA. 00:35:50.550 --> 00:35:53.490 It may have plus-sense RNA. 00:35:53.490 --> 00:35:55.890 It may have negative-sense RNA. 00:35:55.890 --> 00:35:58.440 It could have double-stranded DNA, 00:35:58.440 --> 00:36:01.560 or it could even have double-stranded RNA. 00:36:01.560 --> 00:36:04.290 And depending on what that genetic material, 00:36:04.290 --> 00:36:07.170 is what the Baltimore classification of a virus 00:36:07.170 --> 00:36:07.920 would be. 00:36:07.920 --> 00:36:10.200 So depending on what's inside the virus, 00:36:10.200 --> 00:36:12.090 then they can be classified. 00:36:12.090 --> 00:36:15.540 And what we're going to go through today and on Friday 00:36:15.540 --> 00:36:22.020 is examples of class I, class V, and class VI viruses, 00:36:22.020 --> 00:36:26.130 so we can see how that genetic material ultimately 00:36:26.130 --> 00:36:28.310 becomes a new viral-- 00:36:28.310 --> 00:36:32.160 a new virus within a host cell, or at least the components 00:36:32.160 --> 00:36:36.070 thereof ready to be sprung out of a virus. 00:36:36.070 --> 00:36:44.040 And there's one important point that I want to also address-- 00:36:44.040 --> 00:36:49.740 oops-- budding or lytic. 00:36:49.740 --> 00:36:52.890 All right, there are two ways in which 00:36:52.890 --> 00:36:56.160 viruses escape their host cell. 00:36:56.160 --> 00:36:59.190 They may be budding. 00:36:59.190 --> 00:37:02.280 So here you have a host cell. 00:37:02.280 --> 00:37:04.740 The viral components all congregate 00:37:04.740 --> 00:37:08.970 near the surface of the membrane from the inside, 00:37:08.970 --> 00:37:12.710 and then the host cell buds off. 00:37:12.710 --> 00:37:17.790 The viral components go with it, and the bud splits off. 00:37:17.790 --> 00:37:20.370 So the host cell has its nucleus. 00:37:20.370 --> 00:37:21.840 It's still intact. 00:37:21.840 --> 00:37:23.970 HIV is such a virus. 00:37:23.970 --> 00:37:26.190 HIV doesn't kill its hosts. 00:37:26.190 --> 00:37:27.820 That's the best sign of a parasite. 00:37:27.820 --> 00:37:31.650 It wants the host to stick around, so it just buds off. 00:37:31.650 --> 00:37:37.410 The other types of viruses are lytic, 00:37:37.410 --> 00:37:42.720 and, basically, the cell just bursts open and throws out 00:37:42.720 --> 00:37:43.260 the virus. 00:37:43.260 --> 00:37:45.290 So they're in two categories. 00:37:45.290 --> 00:37:48.413 Some of them are budding, though the enveloped viruses 00:37:48.413 --> 00:37:49.830 have to be budding because they're 00:37:49.830 --> 00:37:53.250 going to take with them the membrane of the host cell. 00:37:53.250 --> 00:37:53.910 All right? 00:37:53.910 --> 00:37:56.980 So that's another important difference. 00:37:56.980 --> 00:37:59.350 So what have we got here? 00:37:59.350 --> 00:38:04.050 So ultimately, the goal is to be able to make a plus-strand mRNA 00:38:04.050 --> 00:38:06.010 for protein synthesis. 00:38:06.010 --> 00:38:10.320 So we really need to have the appropriate sense of the RNA 00:38:10.320 --> 00:38:13.420 that will dictate the protein synthesis. 00:38:13.420 --> 00:38:16.520 So let's first of all look at one of the simple versions, 00:38:16.520 --> 00:38:18.930 a double-stranded DNA virus. 00:38:18.930 --> 00:38:23.280 And this is represented by the smallpox virus. 00:38:23.280 --> 00:38:27.900 So everybody's heard of that, and herpes simplex. 00:38:27.900 --> 00:38:30.090 And these are both enveloped viruses, 00:38:30.090 --> 00:38:33.305 so that means they have a membrane shell. 00:38:33.305 --> 00:38:34.680 And so I'm just going to walk you 00:38:34.680 --> 00:38:37.920 through the steps of going from the double-stranded DNA 00:38:37.920 --> 00:38:39.420 to make a new virus. 00:38:39.420 --> 00:38:40.950 So here's the virus. 00:38:40.950 --> 00:38:46.500 It has a capsid, as well as a membrane envelope. 00:38:46.500 --> 00:38:50.310 And there's recognition between the virus and the host cell. 00:38:50.310 --> 00:38:54.090 And we'll talk very specifically about what that recognition is 00:38:54.090 --> 00:38:58.530 when we talk about HIV, because that's very well categorized. 00:38:58.530 --> 00:39:01.380 Once the virus gets into the host cell, 00:39:01.380 --> 00:39:05.340 it sort of spills off all the coat and dumps 00:39:05.340 --> 00:39:10.140 out its double-stranded DNA, the viral DNA, into the host cell. 00:39:10.140 --> 00:39:12.750 And then that DNA can-- 00:39:12.750 --> 00:39:15.570 in the nucleus, can replicate into more copies 00:39:15.570 --> 00:39:20.880 of the viral DNA, or it can be transcribed 00:39:20.880 --> 00:39:24.000 into messenger RNA, which is then 00:39:24.000 --> 00:39:28.830 the coat for all those capsid proteins that the virus needs. 00:39:28.830 --> 00:39:32.550 And then these start to self-assemble within the host 00:39:32.550 --> 00:39:37.170 cell where the capsid proteins wrap around 00:39:37.170 --> 00:39:39.450 the viral genetic material. 00:39:39.450 --> 00:39:42.870 They accumulate near the surface of the cell, 00:39:42.870 --> 00:39:45.520 and then they bud off from the cell. 00:39:45.520 --> 00:39:48.120 So that's how you go from simple DNA. 00:39:48.120 --> 00:39:51.450 So these processes are completely 00:39:51.450 --> 00:39:56.790 based on the human enzymes that do those processes. 00:39:56.790 --> 00:39:59.400 Replication, we've got to replicate DNA. 00:39:59.400 --> 00:40:01.553 We're going to have to do that in the nucleus. 00:40:01.553 --> 00:40:02.970 Transcription, we're going to have 00:40:02.970 --> 00:40:07.650 to ship out part of the DNA from the nucleus to the cytoplasm 00:40:07.650 --> 00:40:09.300 and make-- 00:40:09.300 --> 00:40:12.240 we're going to have to make a copy of the messenger RNA 00:40:12.240 --> 00:40:14.010 and ship it out to the nucleus. 00:40:14.010 --> 00:40:17.520 And then we're going to use the host ribosomes, the host's 00:40:17.520 --> 00:40:20.130 amino acids, the building blocks in everything, 00:40:20.130 --> 00:40:24.850 to make a new protein that is not a host's cell protein. 00:40:24.850 --> 00:40:26.610 It's the capsid protein. 00:40:26.610 --> 00:40:28.230 Obviously, the human cell isn't going 00:40:28.230 --> 00:40:30.310 to be making a capsid protein. 00:40:30.310 --> 00:40:34.050 So that's the main thing that the virus had to encode. 00:40:34.050 --> 00:40:36.300 It had to have the DNA to make that. 00:40:36.300 --> 00:40:38.460 So that all looks sort of fairly simple, 00:40:38.460 --> 00:40:40.240 and the steps make sense. 00:40:40.240 --> 00:40:43.710 This is why we cover this virus first because it really-- 00:40:43.710 --> 00:40:46.790 it's kind of the most transparent to understand, 00:40:46.790 --> 00:40:50.470 so this transient stage of sort of borrowing machinery. 00:40:50.470 --> 00:40:53.730 And as I mentioned here, the virus 00:40:53.730 --> 00:40:55.710 can spring out of the host cell. 00:40:55.710 --> 00:40:57.396 Yes. 00:40:57.396 --> 00:41:00.584 AUDIENCE: So all it means is-- one's that don't kill the host 00:41:00.584 --> 00:41:05.513 cells, how do they, like, on the body, or the cells that they-- 00:41:05.513 --> 00:41:08.055 BARBARA IMPERIALI: They start to just be too much of a burden 00:41:08.055 --> 00:41:10.080 onto the body, so they're just-- 00:41:10.080 --> 00:41:13.650 you know, if they're inside cells and exploiting 00:41:13.650 --> 00:41:17.040 the resources of the cell, they're basically-- 00:41:17.040 --> 00:41:19.830 they're harming it, but they're not destroying it instantly 00:41:19.830 --> 00:41:20.980 every life cycle. 00:41:20.980 --> 00:41:25.860 They're just using resources to replicate, and then go-- 00:41:25.860 --> 00:41:28.140 get spread to another cell, and another cell, 00:41:28.140 --> 00:41:29.710 where they'll keep using resources. 00:41:29.710 --> 00:41:31.890 So it's really just an overload of the system. 00:41:31.890 --> 00:41:34.050 It's a very good point. 00:41:34.050 --> 00:41:36.670 But they can stick around a long time, 00:41:36.670 --> 00:41:38.610 and with HIV, you're going to see 00:41:38.610 --> 00:41:40.380 what really sneaky thing they do is 00:41:40.380 --> 00:41:43.420 because they put their genome into the host genome. 00:41:43.420 --> 00:41:46.860 And that's sort of really pretty terrifying. 00:41:46.860 --> 00:41:49.560 I always ask this question, but it's kind of a silly one. 00:41:49.560 --> 00:41:51.570 You know, what is life? 00:41:51.570 --> 00:41:53.280 A virus is alive. 00:41:53.280 --> 00:41:56.040 Well, they're kind of alive, but they're not really alive 00:41:56.040 --> 00:41:58.110 unless they have some place to live. 00:41:58.110 --> 00:41:59.850 But aren't we all like that? 00:41:59.850 --> 00:42:01.290 So that's very philosophical. 00:42:01.290 --> 00:42:03.660 So we'll move right on here. 00:42:03.660 --> 00:42:05.940 So when you think of a virus, this 00:42:05.940 --> 00:42:08.310 is the original central dogma, all 00:42:08.310 --> 00:42:10.920 the moving parts of the central dogma. 00:42:10.920 --> 00:42:13.230 And note-- so that when you think of a virus, 00:42:13.230 --> 00:42:17.190 what double-- what does double-stranded DNA need 00:42:17.190 --> 00:42:19.440 from the host? 00:42:19.440 --> 00:42:21.060 It's got all of these things. 00:42:21.060 --> 00:42:24.090 It's got the-- the host has the polymerase. 00:42:24.090 --> 00:42:27.400 It has the DNA-dependent RNA polymerase. 00:42:27.400 --> 00:42:29.580 It's got all the ribosomal machinery. 00:42:29.580 --> 00:42:31.920 So the only thing that the virus needs 00:42:31.920 --> 00:42:35.010 is the gene for its capsid proteins. 00:42:35.010 --> 00:42:38.060 So you can peel out from that entire life cycle 00:42:38.060 --> 00:42:40.630 the one unique thing about the virus. 00:42:40.630 --> 00:42:43.380 So that's a double-stranded DNA. 00:42:43.380 --> 00:42:46.650 Let's now move to a different type of V, 00:42:46.650 --> 00:42:50.370 which is a negative-stranded RNA virus. 00:42:50.370 --> 00:42:52.560 And these are quite important because these 00:42:52.560 --> 00:42:55.020 form the basis for-- 00:42:55.020 --> 00:42:56.950 let me just go to the diseases. 00:42:56.950 --> 00:42:59.940 This is the influenza virus, and I'm 00:42:59.940 --> 00:43:01.770 going to mention some very important points 00:43:01.770 --> 00:43:04.290 relative to influenza virus. 00:43:04.290 --> 00:43:10.395 So influenza virus is what's known as a segmented virus. 00:43:17.480 --> 00:43:20.470 And what that means is that its genome-- 00:43:20.470 --> 00:43:24.630 in this case, it's negative-stranded RNA-- 00:43:24.630 --> 00:43:25.375 is in pieces. 00:43:36.730 --> 00:43:45.280 A lot of other viruses just have a single strand of genome, 00:43:45.280 --> 00:43:49.240 a single nucleic acid strand. 00:43:52.130 --> 00:44:00.740 So it's just one piece, where portions of that nucleic acid 00:44:00.740 --> 00:44:03.830 code for different proteins, and they'll often 00:44:03.830 --> 00:44:07.710 code for initially polyproteins that get broken up. 00:44:07.710 --> 00:44:10.400 And we'll see a virus with a single strand 00:44:10.400 --> 00:44:12.140 when we look at HIV. 00:44:12.140 --> 00:44:17.630 But the influenza virus has a segmented genome. 00:44:17.630 --> 00:44:20.270 And that's very relevant for its lifestyle 00:44:20.270 --> 00:44:24.980 because we'll see in a moment how influenza virus can cause 00:44:24.980 --> 00:44:28.820 more damage than we anticipate because of recombination 00:44:28.820 --> 00:44:31.580 of different copies of the segmented virus 00:44:31.580 --> 00:44:32.610 through differences. 00:44:32.610 --> 00:44:34.610 But let's first of all take a look 00:44:34.610 --> 00:44:36.830 at the life cycle of this virus, and then we'll 00:44:36.830 --> 00:44:40.550 move on to dealing with the issue of the segmentation. 00:44:40.550 --> 00:44:45.740 So here's a typical enveloped virus with a capsid. 00:44:45.740 --> 00:44:50.300 Inside, there's the negative-stranded RNA that gets 00:44:50.300 --> 00:44:52.850 into the host cell, and you make-- 00:44:52.850 --> 00:44:58.130 and you dump into the host cell the viral genomic RNA. 00:44:58.130 --> 00:45:00.230 That can get copied. 00:45:00.230 --> 00:45:04.700 The minus-strand RNA gets copied to the plus-strand RNA, 00:45:04.700 --> 00:45:09.120 which becomes the messenger for protein synthesis in the cell. 00:45:09.120 --> 00:45:10.700 So you've gone in with minus strand. 00:45:10.700 --> 00:45:13.090 You've made the plus strand, which is the messenger, 00:45:13.090 --> 00:45:16.430 and that encodes all the proteins that 00:45:16.430 --> 00:45:19.170 are needed for a new virus. 00:45:19.170 --> 00:45:23.900 And some of those proteins may have signal sequences. 00:45:23.900 --> 00:45:26.900 They may be shipped to the surface of the cell, 00:45:26.900 --> 00:45:30.980 and they may be planted in the outside cellular membrane 00:45:30.980 --> 00:45:32.420 of the host cells. 00:45:32.420 --> 00:45:36.050 And what you see here is copies of those proteins 00:45:36.050 --> 00:45:38.970 actually in the surface of a cell. 00:45:38.970 --> 00:45:42.170 So what happens with this virus is, once all the moving 00:45:42.170 --> 00:45:46.490 parts are made, they congregate at the surface of a cell, 00:45:46.490 --> 00:45:50.010 get packaged, and then bud off from the cell. 00:45:50.010 --> 00:45:53.990 So remember all the rules you learned about where proteins 00:45:53.990 --> 00:45:57.110 end up in the cell are all good still here 00:45:57.110 --> 00:46:01.580 because the capsid proteins have to get to a cell membrane, 00:46:01.580 --> 00:46:04.220 so they're translated with a signal sequence. 00:46:04.220 --> 00:46:08.150 They congregate-- I don't know how this self-assembly occurs, 00:46:08.150 --> 00:46:12.020 but it's a fascinating process, so that ultimately you 00:46:12.020 --> 00:46:16.370 bud off an intact virion from the host cell. 00:46:16.370 --> 00:46:19.220 But the key thing that the virus has to have 00:46:19.220 --> 00:46:23.930 is something that will copy negative-stranded RNA 00:46:23.930 --> 00:46:27.840 to plus-stranded RNA, which is going to be the messenger. 00:46:27.840 --> 00:46:31.760 So the virus also has to code for a particular protein that's 00:46:31.760 --> 00:46:33.890 unique to its lifestyle. 00:46:33.890 --> 00:46:38.360 So it has an RA-dependent RNA polymerase. 00:46:38.360 --> 00:46:41.900 We don't use an RNA-dependent RNA polymerase, 00:46:41.900 --> 00:46:45.890 but the virus needs it to take its negative-strand RNA 00:46:45.890 --> 00:46:48.590 to a plus-strand RNA, which will be the messenger. 00:46:48.590 --> 00:46:49.760 So does that make sense? 00:46:49.760 --> 00:46:51.920 So obviously, that's a moving part 00:46:51.920 --> 00:46:54.690 that it needs to provide to the host. 00:46:54.690 --> 00:46:58.700 Now, what's this about segmented viruses that's quite important? 00:47:01.220 --> 00:47:03.740 Oh, and I just want to underscore here, 00:47:03.740 --> 00:47:06.500 what defines the destination of these proteins, 00:47:06.500 --> 00:47:09.380 whether they're capsid proteins or proteins that 00:47:09.380 --> 00:47:11.930 are going to be packaged within the virus, 00:47:11.930 --> 00:47:14.210 is basically just the same rules that 00:47:14.210 --> 00:47:16.460 apply that we talked about when we talked 00:47:16.460 --> 00:47:19.790 about protein trafficking. 00:47:19.790 --> 00:47:22.820 So every year, there's a whole panic. 00:47:22.820 --> 00:47:24.480 Did you get your flu shot? 00:47:24.480 --> 00:47:26.000 Is it going to work this year? 00:47:26.000 --> 00:47:28.370 Oh my god, millions of people are going to get sick. 00:47:28.370 --> 00:47:29.390 Go get your flu shot. 00:47:29.390 --> 00:47:32.490 It's tetravalent, it's trivalent, and so on. 00:47:32.490 --> 00:47:35.300 So what we're trying to do every year 00:47:35.300 --> 00:47:38.430 is predict what the virus is going to look like. 00:47:38.430 --> 00:47:39.440 So we have to-- 00:47:39.440 --> 00:47:42.770 there are teams of people, who sometimes get it wrong, 00:47:42.770 --> 00:47:47.170 who predict the variation in these genes. 00:47:47.170 --> 00:47:50.780 And they look at winter in the Southern Hemisphere, 00:47:50.780 --> 00:47:52.610 because that precedes us, and try 00:47:52.610 --> 00:47:55.520 to guess what's going to happen in winter in the Northern 00:47:55.520 --> 00:47:56.420 Hemisphere. 00:47:56.420 --> 00:48:01.190 And we get to try and put together a vaccination package. 00:48:01.190 --> 00:48:04.940 But the problem with the viral influenza virus 00:48:04.940 --> 00:48:10.190 is that there can be not just a drift, like mutations, 00:48:10.190 --> 00:48:13.100 small mutations happening a little bit at a time, 00:48:13.100 --> 00:48:16.850 but there can be recombination of the genes, 00:48:16.850 --> 00:48:21.770 because they are segmented, into totally new virus particles 00:48:21.770 --> 00:48:23.960 that have different properties. 00:48:23.960 --> 00:48:28.700 So viruses don't just drift in their genomic sequence. 00:48:28.700 --> 00:48:33.130 They can have dramatic shifts in their sequences that occur-- 00:48:33.130 --> 00:48:37.310 whoops-- through combinations of viruses that come-- that 00:48:37.310 --> 00:48:39.450 have infected different animals. 00:48:39.450 --> 00:48:41.300 So some of the common strains, when 00:48:41.300 --> 00:48:44.360 we talk about certain strains that have been very, very 00:48:44.360 --> 00:48:48.710 troublesome to humans, may result from such a combination. 00:48:48.710 --> 00:48:54.170 So this would be the Eurasian pig flu, the classic pig flu, 00:48:54.170 --> 00:48:56.810 the human flu, the bird flu. 00:48:56.810 --> 00:49:00.370 If, in certain communities where people often 00:49:00.370 --> 00:49:03.040 live with their livestock, a cell 00:49:03.040 --> 00:49:06.430 gets infected with viruses, a human virus 00:49:06.430 --> 00:49:11.200 and the swine virus, they can mix and match together. 00:49:11.200 --> 00:49:14.620 And you can make a totally different viral composition, 00:49:14.620 --> 00:49:18.520 where you've got one piece of genetic information 00:49:18.520 --> 00:49:22.880 from the swine flu and seven more from the human flu. 00:49:22.880 --> 00:49:24.910 And what that can suddenly mean is 00:49:24.910 --> 00:49:28.630 that the-- first of all, the vaccines don't work at all, 00:49:28.630 --> 00:49:31.690 but that they may have very, very different properties 00:49:31.690 --> 00:49:33.910 for infectivity. 00:49:33.910 --> 00:49:37.780 The protein that is expressed that may cause 00:49:37.780 --> 00:49:40.870 that very first attack of the virus on your cells 00:49:40.870 --> 00:49:44.440 in the upper lungs may be very different to the type-- 00:49:44.440 --> 00:49:46.720 to the protein that comes from the swine flu 00:49:46.720 --> 00:49:50.590 and may give you much more serious lung infections 00:49:50.590 --> 00:49:52.870 because they can go deeper into the lungs. 00:49:52.870 --> 00:49:56.050 So it can be very small changes by pulling 00:49:56.050 --> 00:50:00.840 an enzyme, a piece of gene, from a completely different organism 00:50:00.840 --> 00:50:03.640 and matching it up with the rest of the genes 00:50:03.640 --> 00:50:07.480 from the human virus that makes for dramatic shifts 00:50:07.480 --> 00:50:10.990 in viral infections that cause these sorts 00:50:10.990 --> 00:50:13.870 of sudden tectonic shifts where we've really 00:50:13.870 --> 00:50:15.880 got to deal with a virus. 00:50:15.880 --> 00:50:17.560 There are two terms up here. 00:50:17.560 --> 00:50:20.740 There's H and N. These are hemagglutinin and 00:50:20.740 --> 00:50:22.120 neuraminidase. 00:50:22.120 --> 00:50:25.240 They are two proteins that are in the viral coat, 00:50:25.240 --> 00:50:30.400 so you'll often hear viruses referred to as H1N1, H3N3, 00:50:30.400 --> 00:50:33.430 and it's just the variant of those proteins that 00:50:33.430 --> 00:50:34.330 are in the viruses. 00:50:34.330 --> 00:50:35.980 See these little terms here-- 00:50:35.980 --> 00:50:39.370 that's what that means, what type of hemagglutinin, 00:50:39.370 --> 00:50:42.790 what type of neuraminidase, is on the surface of the virus. 00:50:42.790 --> 00:50:45.700 So I am done for today, and next class 00:50:45.700 --> 00:50:49.660 will be exclusively about the AIDS-HIV virus, where we'll 00:50:49.660 --> 00:50:52.450 go into that life cycle and also talk 00:50:52.450 --> 00:50:55.780 about resistance to therapeutic agents and combination 00:50:55.780 --> 00:50:57.630 therapies.