1 00:00:01 --> 00:00:04 It comes acquainted with different antigens. 2 00:00:04 --> 00:00:09 And recall that what we were talking 3 00:00:09 --> 00:00:13 about was the following, that there were several kinds of 4 00:00:13 --> 00:00:18 phagocytic cells. Phagocytic cells are cells that 5 00:00:18 --> 00:00:23 chew up other things, both macrophages and even more 6 00:00:23 --> 00:00:27 frequently, dendritic cells, many of which hang around lymph 7 00:00:27 --> 00:00:33 nodes by the way. They process antigens into 8 00:00:33 --> 00:00:41 oligopeptides. The oligopeptides get presented on 9 00:00:41 --> 00:00:48 the surface of these cells. Let's say, here's a macrophage, 10 00:00:48 --> 00:00:56 in the form of through the class 2 MHC molecules which are displayed on 11 00:00:56 --> 00:01:02 the surfaces of the cells. And, here's a typical oligopeptide 12 00:01:02 --> 00:01:07 that has been chewed up from one of the antigens that was previously 13 00:01:07 --> 00:01:12 internalized, eaten up by the macrophage, a dendritic cell, 14 00:01:12 --> 00:01:16 and then presented on the surface. Recall, then, we have an itinerant 15 00:01:16 --> 00:01:21 macrophage or dendritic cell. Could we turn up the sound just a 16 00:01:21 --> 00:01:26 little, just a notch? Thank you. And this dendritic cell 17 00:01:26 --> 00:01:31 or macrophage, I'll just call it a macrophage for 18 00:01:31 --> 00:01:36 the moment, is then moving largely through the lymph nodes, 19 00:01:36 --> 00:01:41 but wherever it moves, it's carrying along this oligopeptide. 20 00:01:41 --> 00:01:45 And recall that we liken this voyage of it to a Middle Eastern market 21 00:01:45 --> 00:01:49 where there's a lot of bazaar stalls on either side of the road, 22 00:01:49 --> 00:01:53 and where instead of the usual male merchants, there's a lot of female 23 00:01:53 --> 00:01:57 merchants hanging out. And these females are called T 24 00:01:57 --> 00:02:02 helper cells. They're a kind of T lymphocyte or T 25 00:02:02 --> 00:02:07 cell. TH refers to their function. And here, all of these T helper 26 00:02:07 --> 00:02:12 cells, I'll indicate each of them here as a pink circle. 27 00:02:12 --> 00:02:17 And these T helper cells display on their surface to blow them up to a 28 00:02:17 --> 00:02:22 large size a T cell receptor that is organized much the way 29 00:02:22 --> 00:02:27 immunoglobulin molecule and antibody molecule's organized. 30 00:02:27 --> 00:02:33 That is to say, it has variable and constant regions. 31 00:02:33 --> 00:02:38 It's generated through the rearrangement of antibody-like genes. 32 00:02:38 --> 00:02:43 But it only functions, this T cell receptor or as it's 33 00:02:43 --> 00:02:48 called in the trade the TCR, only functions to sense the presence 34 00:02:48 --> 00:02:53 of antigens in the extracellular space. In fact, 35 00:02:53 --> 00:02:58 it senses antigens in the context of the MHC class 2. 36 00:02:58 --> 00:03:02 So here's an MHC class 2 molecule. We can think of the MHC class 2 as 37 00:03:02 --> 00:03:07 being a hand, which is presenting this oligopeptide. 38 00:03:07 --> 00:03:12 I haven't drawn a hand, but you can pretend it's a hand. 39 00:03:12 --> 00:03:17 And this MHC class 2 is being presented by either a macrophage or 40 00:03:17 --> 00:03:21 a dendritic cell. And recall, we talked about the 41 00:03:21 --> 00:03:26 voyage of this macrophage or dendritic cell through this street 42 00:03:26 --> 00:03:31 here, and all these T helper cells are kind of lazily waiting along on 43 00:03:31 --> 00:03:36 the sidelines looking at what this phagocytic cell is hocking. 44 00:03:36 --> 00:03:40 Most of the T helper cells are totally uninterested in what he's 45 00:03:40 --> 00:03:45 hocking. But one of them is struck. It's love at first sight, this one 46 00:03:45 --> 00:03:50 over here, let's say, because her T cell receptor 47 00:03:50 --> 00:03:55 precisely recognizes this oligopeptide in the context of the 48 00:03:55 --> 00:04:00 MHC class 2 molecule. And, obviously I would like to draw 49 00:04:00 --> 00:04:04 thousands of these T helper cells here, each of which bears a 50 00:04:04 --> 00:04:08 different T cell receptor on her surface. I'm only showing one. 51 00:04:08 --> 00:04:12 And recall that after they make this encounter, 52 00:04:12 --> 00:04:16 the T helper cell gets all excited because she says, 53 00:04:16 --> 00:04:20 oh, I can't believe it, you have exactly the oligopeptide 54 00:04:20 --> 00:04:24 that's recognized by my receptor. And so, she gets all excited, and 55 00:04:24 --> 00:04:28 what she does is she proliferates because that's about all that 56 00:04:28 --> 00:04:32 excited cells can do. Well, they can do other things, 57 00:04:32 --> 00:04:37 but again, we don't want to talk about it. Anyhow, 58 00:04:37 --> 00:04:42 so this particular T helper cell undergoes a clonal expansion, 59 00:04:42 --> 00:04:47 and is now activated, i.e. activated not only psychologically but 60 00:04:47 --> 00:04:52 physiologically by having encountered the antigen-presenting 61 00:04:52 --> 00:04:57 cell. The MHC class 2, the macrophage is called an 62 00:04:57 --> 00:05:02 antigen-presenting cell. It's using its MHC class 2 molecules 63 00:05:02 --> 00:05:07 to do so. Macrophages and dendritic cells are pretty much similar in 64 00:05:07 --> 00:05:13 this respect. Macrophages go all over the body in the tissues. 65 00:05:13 --> 00:05:18 Dendritic cells tend to inhabit the lymph nodes. But from the point of 66 00:05:18 --> 00:05:23 view of our discussion today, we can imagine that they're 67 00:05:23 --> 00:05:28 functionally essentially equivalent. And having said that, now these T 68 00:05:28 --> 00:05:34 helper cells go looking for a congenial B cell. 69 00:05:34 --> 00:05:39 So, now we have a third actor in the drama, and the congenial B cell 70 00:05:39 --> 00:05:44 looks like this. And, the B cell has the following 71 00:05:44 --> 00:05:49 thing. The B cell has also on its surface, MHC class 2 molecules, 72 00:05:49 --> 00:05:55 which can be used in antigen presentation. But the B cell has an 73 00:05:55 --> 00:06:00 addition as we said last time, already, on its surface, IGM 74 00:06:00 --> 00:06:05 molecules. An IGM is a brand of antibody. 75 00:06:05 --> 00:06:10 Keep in mind that really one of the paradoxes that we haven't really 76 00:06:10 --> 00:06:14 fully settled on is the following question or the following issue. 77 00:06:14 --> 00:06:19 How is it that when a B cell sees a cognate antigen, 78 00:06:19 --> 00:06:24 why does it get stimulated? In other words, what is it that 79 00:06:24 --> 00:06:29 induces the B cell to start proliferating? 80 00:06:29 --> 00:06:32 Here's another version of what I showed you last time, 81 00:06:32 --> 00:06:36 where a B cell which makes the right antibody gets stimulated, 82 00:06:36 --> 00:06:40 but a B cell that doesn't does not get stimulated. 83 00:06:40 --> 00:06:44 And that's the issue we're wrestling with right now. 84 00:06:44 --> 00:06:48 So here on the surface of this B cell is an IGM molecule. 85 00:06:48 --> 00:06:52 Keep in mind an IGM molecule is an antibody molecule. 86 00:06:52 --> 00:06:56 Immunoglobulin means IG. It's the earliest form of antibody 87 00:06:56 --> 00:07:00 that's made. Once again, it is antigen specific. 88 00:07:00 --> 00:07:05 Its variable region has been rearranged through the fusion of 89 00:07:05 --> 00:07:10 different VDJ segments and somatic hypermutation. 90 00:07:10 --> 00:07:15 And, this B cell has a very interesting property. 91 00:07:15 --> 00:07:20 This is a naïve cell, and what this B cell does is as 92 00:07:20 --> 00:07:25 follows. It moves around the body, and if this B cell happens to find 93 00:07:25 --> 00:07:30 an antigen, which is recognized by its antibody, the IGM antibody. 94 00:07:30 --> 00:07:36 Then the B cell will bind this antigen using its IGM molecule to do 95 00:07:36 --> 00:07:42 so. More importantly, it will then internalize this 96 00:07:42 --> 00:07:48 antigen and chew it up into little pieces, and then present it on it 97 00:07:48 --> 00:07:54 surface via the MHC class 2 molecule. So, let's just review what 98 00:07:54 --> 00:07:59 we've been saying. Before, we were talking about 99 00:07:59 --> 00:08:03 macrophages and dendritic cells, which gobbled up whatever they could, 100 00:08:03 --> 00:08:07 processed whatever they gobbled up, and put it on the surface again as 101 00:08:07 --> 00:08:11 MHC class 2, and therefore the macrophages and the dendritic cells 102 00:08:11 --> 00:08:15 are really like sewer rates. They'll just chew on anything and 103 00:08:15 --> 00:08:19 they'll put it on their surface. They're totally promiscuous in what 104 00:08:19 --> 00:08:23 they present on their surface. But here, the B cell is doing 105 00:08:23 --> 00:08:27 something rather similar. But the B cell isn't presenting 106 00:08:27 --> 00:08:31 whatever it happens to stumble across on its surface. 107 00:08:31 --> 00:08:35 The B cell is extraordinarily selective at what it presents on its 108 00:08:35 --> 00:08:39 surface. It only presents on its surface those antigens which are 109 00:08:39 --> 00:08:44 recognized by its IGM molecule. So here, it uses its IGM molecule 110 00:08:44 --> 00:08:48 to grab hold of this antigen. It internalizes the antigen, and 111 00:08:48 --> 00:08:53 then presents it back on the surface as an MHC class 2 molecule. 112 00:08:53 --> 00:08:57 So, there's a profound contrast in the behavior of these two kinds of 113 00:08:57 --> 00:09:02 antigen-presenting cells. The macrophages and dendritic cells, 114 00:09:02 --> 00:09:06 they just gobble up everything, and whatever they find, 115 00:09:06 --> 00:09:10 they put on their surface. They don't care with MHC class 2. 116 00:09:10 --> 00:09:14 The B cell is extraordinarily selective and specific. 117 00:09:14 --> 00:09:18 It will pull in not through regular phagocytosis. It will pull in using 118 00:09:18 --> 00:09:22 its IGM receptor, specific antigens that are 119 00:09:22 --> 00:09:26 recognized by its IGM molecule, and then externalize it using its 120 00:09:26 --> 00:09:30 MHC class 2 molecule to do so. Let's go back to the drama of the 121 00:09:30 --> 00:09:34 activated T helper cell, and here's the activated T helper 122 00:09:34 --> 00:09:39 cell. We'll draw her in pink. The T helper cell has just had an 123 00:09:39 --> 00:09:43 encounter with a macrophage, or dendritic cell. And, she's just 124 00:09:43 --> 00:09:48 left this marketplace. And now, she's very excited. 125 00:09:48 --> 00:09:53 So here is her T cell receptor. And she's very excited. She's 126 00:09:53 --> 00:09:57 putting out all kinds of growth factors and multiplying 127 00:09:57 --> 00:10:02 all over the place. And she starts looking again now for 128 00:10:02 --> 00:10:06 a B cell with which he can react. Now, most of the B cells in the 129 00:10:06 --> 00:10:10 body will not have an epitope that she recognizes. 130 00:10:10 --> 00:10:15 Most of the B cells in the body will have picked up other kinds of 131 00:10:15 --> 00:10:19 things that happen to recognize by their T cell receptor, 132 00:10:19 --> 00:10:24 and will present it on the surface. A rare B cell will happen to 133 00:10:24 --> 00:10:28 internalize an antigen, and put on the surface, which is the 134 00:10:28 --> 00:10:32 same antigen that was recognized previously in the previous 135 00:10:32 --> 00:10:37 encounter. And so, now this T helper cell goes 136 00:10:37 --> 00:10:42 around looking for an attractive male. What's an attractive male for 137 00:10:42 --> 00:10:47 her? An attractive male for her is one whose MHC class 2 molecule is 138 00:10:47 --> 00:10:52 recognized directly in the context, and this oligopeptide is recognized 139 00:10:52 --> 00:10:57 by her T cell receptor. And so, she'll come over here and 140 00:10:57 --> 00:11:02 she'll say excitedly to the B cell, you can't believe what just happened. 141 00:11:02 --> 00:11:05 She will say, I was just there. I just went through the market. 142 00:11:05 --> 00:11:09 I was sitting there in the marketplace, and along came a 143 00:11:09 --> 00:11:13 macrophage, and presented me with an oligopeptide that exactly fit in my 144 00:11:13 --> 00:11:17 T cell receptor. And now, she says excitedly, 145 00:11:17 --> 00:11:21 here I find a B cell has exactly the same oligopeptide presenting it to 146 00:11:21 --> 00:11:25 me. Isn't that a coincidence? And the B cell says, come on lady, 147 00:11:25 --> 00:11:29 get to the point. And she says, I just had an encounter with a 148 00:11:29 --> 00:11:33 macrophage dendritic cell. I recognized the same oligopeptide 149 00:11:33 --> 00:11:37 in the macrophage dendritic cell that you have. 150 00:11:37 --> 00:11:42 And, the B cell says, well, I guess this must be some kind 151 00:11:42 --> 00:11:46 of meaningful encounter, and so these two cells get together. 152 00:11:46 --> 00:11:51 And what happens now is that the T cell, having recognized the 153 00:11:51 --> 00:11:55 oligopeptide, presented on the surface of the B cell now begins to 154 00:11:55 --> 00:12:00 send out signals to stimulate the B cell to proliferate. 155 00:12:00 --> 00:12:03 And this B cell now begins to proliferate. And this B cell now 156 00:12:03 --> 00:12:07 begins to proliferate, as is indicated on this overhead, 157 00:12:07 --> 00:12:11 and eventually it starts making IGM molecules. It makes more of them, 158 00:12:11 --> 00:12:15 and then through the class switching that we talked about last time, 159 00:12:15 --> 00:12:19 it'll make eventually IGG secreted antibody gamma globulin molecules. 160 00:12:19 --> 00:12:22 So you see here the three essential cell types that participate in this. 161 00:12:22 --> 00:12:26 And why is it so complicated? Because it's extraordinarily 162 00:12:26 --> 00:12:30 important that the immune system doesn't inadvertently make 163 00:12:30 --> 00:12:34 antibodies that are inappropriate to express, because as we said before, 164 00:12:34 --> 00:12:38 if a certain of those antibodies and indeed possibly many of them could 165 00:12:38 --> 00:12:42 be autoreactive. And what do I mean by autoreactive? 166 00:12:42 --> 00:12:47 I mean reactive with self. They could be antibodies that react with 167 00:12:47 --> 00:12:52 one's own tissues. And in so doing, they could create 168 00:12:52 --> 00:12:57 series kinds of autoimmune diseases. So, we have this sequence of 169 00:12:57 --> 00:13:02 failsafe reactions. So, when finally the decision for 170 00:13:02 --> 00:13:06 the B cell to get activated depends on a previous encounter with the 171 00:13:06 --> 00:13:11 same oligopeptide by a macrophage or dendritic cell, 172 00:13:11 --> 00:13:15 the T helper cell acting as an intermediary and now activating the 173 00:13:15 --> 00:13:20 B cell, once the T cell tells the B cell that the T cell has had a 174 00:13:20 --> 00:13:24 previous encounter with exactly the same oligopeptide, 175 00:13:24 --> 00:13:29 on that occasion being presented by a macrophage or dendritic cell. 176 00:13:29 --> 00:13:32 And that is actually the mechanism by which we get this clonal 177 00:13:32 --> 00:13:36 expansion of B cells in the immune system, and ultimately how we get 178 00:13:36 --> 00:13:40 the productive antibody molecules. I mean, this is the image I showed 179 00:13:40 --> 00:13:44 you earlier, but I never really explained to you what the biology 180 00:13:44 --> 00:13:48 behind that is. I just said that antigen encounter 181 00:13:48 --> 00:13:52 on the part of the B cell causes that B cell to enjoy clonal 182 00:13:52 --> 00:13:56 expansion. And now, we've gone through the detail of 183 00:13:56 --> 00:14:00 deciding how three different cell types interact, 184 00:14:00 --> 00:14:04 collaborate with one another to create the antibody response because 185 00:14:04 --> 00:14:08 this B cell then goes on to produce IGM as it already is doing, 186 00:14:08 --> 00:14:12 and then eventually IGG, and possibly a series of other 187 00:14:12 --> 00:14:17 immunoglobulins, IGE and IGA which have other 188 00:14:17 --> 00:14:21 purposes. Now, all of this actually is an important 189 00:14:21 --> 00:14:25 prelude to our main topic of discussion today, which is 190 00:14:25 --> 00:14:30 the disease of AIDS. And, let me just add one other 191 00:14:30 --> 00:14:35 detail to this because the ability of a T helper cell to recognize MHC 192 00:14:35 --> 00:14:39 class 2 molecules depends on another cell surface molecule expressed by 193 00:14:39 --> 00:14:44 the T helper cell. And this other T cell surface 194 00:14:44 --> 00:14:49 molecule is called CD4. CD4, we don't have to worry of what 195 00:14:49 --> 00:14:54 it stands for. CD4 is not an antigen specific 196 00:14:54 --> 00:14:59 receptor. CD4, instead, only recognizes MHC class 2 197 00:14:59 --> 00:15:04 molecules no matter what they're carrying. 198 00:15:04 --> 00:15:09 So, there are MHC class 2 molecules which I've implied to you can carry 199 00:15:09 --> 00:15:14 thousands of different oligopeptides. CD4 doesn't care what's being 200 00:15:14 --> 00:15:20 carried by the MHC class 2. It just binds to MHC class 2 201 00:15:20 --> 00:15:25 molecules, thereby telling the T helper cell that an encounter has 202 00:15:25 --> 00:15:31 been made with an antigen-presenting cell. 203 00:15:31 --> 00:15:36 So, the ligand for CD4 is part of the MHC class 2 molecule. 204 00:15:36 --> 00:15:42 Now, that all leaves us in a very nice segue to the whole disease of 205 00:15:42 --> 00:15:47 AIDS. Let's just remember how the disease of AIDS was discovered. 206 00:15:47 --> 00:15:53 In 1981, there were a group of five young men who were all subsequently 207 00:15:53 --> 00:15:58 determined to be gay, be homosexual, who were discovered 208 00:15:58 --> 00:16:04 in San Francisco to have a very unusual kind of immunodeficiency. 209 00:16:04 --> 00:16:08 They all had night sweats. They got different kinds of 210 00:16:08 --> 00:16:12 otherwise unusual diseases. For example one of the things they 211 00:16:12 --> 00:16:17 got was a disease called Kaposi's sarcoma, which was otherwise known 212 00:16:17 --> 00:16:21 only in old southern Italian and Jewish men, Kaposi's sarcoma. 213 00:16:21 --> 00:16:25 But these were young men, and they were neither southern Italian 214 00:16:25 --> 00:16:31 nor Jewish. They got pneumocystis carinii, 215 00:16:31 --> 00:16:37 which is a microbial infection of the lung. And, 216 00:16:37 --> 00:16:44 in fact, they got all kinds of herpes virus infections. 217 00:16:44 --> 00:16:50 And they were all seen in a cluster by an alert physician who saw 218 00:16:50 --> 00:16:57 something very unusual, and therefore said, perhaps 219 00:16:57 --> 00:17:04 correctly, that they had acquired immunodeficiency. 220 00:17:04 --> 00:17:05 Now, this acquired immunodeficiency is a syndrome. 221 00:17:05 --> 00:17:07 A syndrome, by the way, for your information, is a whole 222 00:17:07 --> 00:17:09 collection of symptoms that appear together. That's what a syndrome 223 00:17:09 --> 00:17:11 means. So, this term AIDS came from the fact that they had a whole 224 00:17:11 --> 00:17:13 series of symptoms. And, this was an acquired 225 00:17:13 --> 00:17:15 immunodeficiency rather than a congenital immunodeficiency rather 226 00:17:15 --> 00:17:17 than a congenital immunodeficiency because given the complexity of the 227 00:17:17 --> 00:17:19 immune system, you can imagine correctly that there 228 00:17:19 --> 00:17:21 are a lot of people in the world who were born with congenitally 229 00:17:21 --> 00:17:23 defective immune systems that are immunodeficient from birth because 230 00:17:23 --> 00:17:25 there's so many different proteins involved in regulating all of these 231 00:17:25 --> 00:17:27 different immune responses. But this was really different. 232 00:17:27 --> 00:17:29 It was an acquired immunodeficiency. It was seen in a very special 233 00:17:29 --> 00:17:31 subgroup, and so the race was on over the next two years to figure 234 00:17:31 --> 00:18:02 out what was going on. 235 00:18:02 --> 00:18:06 Now, by coincidence, starting in 1970-'71, 236 00:18:06 --> 00:18:10 retrovirus research had begun. And as it turned out, retrovirus 237 00:18:10 --> 00:18:14 search, President Nixon's war on cancer, retrovirus research was 238 00:18:14 --> 00:18:18 motivated largely by the notion that human cancers are caused by 239 00:18:18 --> 00:18:22 retrovirus infections. And, that led to the war on cancer. 240 00:18:22 --> 00:18:26 And the notion behind the war on cancer was totally wrong because it 241 00:18:26 --> 00:18:30 turns out that only a minute fraction of human cancers have 242 00:18:30 --> 00:18:34 anything to do with retrovirus infections, although as we've said 243 00:18:34 --> 00:18:38 earlier, retroviruses proved to be very important tools experimentally 244 00:18:38 --> 00:18:43 for discovering proto-oncogenes and oncogenes in the genome. 245 00:18:43 --> 00:18:47 But if you ask, what fraction of human cancers are 246 00:18:47 --> 00:18:51 actually due to a human being infected by a retrovirus? 247 00:18:51 --> 00:18:55 It's almost zero. It's a small fraction of a percent. 248 00:18:55 --> 00:18:59 Nonetheless, in the 1970s, there was an enormous effort made in 249 00:18:59 --> 00:19:03 trying to figure out all of the biology of retroviruses. 250 00:19:03 --> 00:19:08 And by the late 1970s, people concluded this was very 251 00:19:08 --> 00:19:13 interesting science. Indeed, proto-oncogenes and 252 00:19:13 --> 00:19:18 oncogenes were discovered, but that it was pretty irrelevant to 253 00:19:18 --> 00:19:23 understanding directly how human cancer arose, which human cancers 254 00:19:23 --> 00:19:28 could be explained rather by somatic mutations in the genome. 255 00:19:28 --> 00:19:33 In 1981, the AIDS infection arose. And, what happened subsequently is 256 00:19:33 --> 00:19:37 that there was a race on to try to find out what the infectious agent 257 00:19:37 --> 00:19:41 was because it seemed to be an infectious agent. 258 00:19:41 --> 00:19:45 It was being spread from one gay young man to another that was used 259 00:19:45 --> 00:19:49 to induce this. And within two years, 260 00:19:49 --> 00:19:53 by 1983, the culprit retrovirus had been found. I'm telling you this 261 00:19:53 --> 00:19:57 long song and dance to give you the following insight. 262 00:19:57 --> 00:20:00 If there had not been a decade of earlier retrovirus research, 263 00:20:00 --> 00:20:04 it could have taken the scientific community many, 264 00:20:04 --> 00:20:07 many years to figure out what was causing AIDS. But through 265 00:20:07 --> 00:20:11 happenstance, through a sheer stroke of luck, by the time the first 266 00:20:11 --> 00:20:15 individuals suffering from AIDS were encountered in '81, 267 00:20:15 --> 00:20:18 there was already a backlog of a decade's worth of detailed 268 00:20:18 --> 00:20:22 retrovirus research, which made it possible to discover, 269 00:20:22 --> 00:20:26 to discern almost within months what was causing it. 270 00:20:26 --> 00:20:30 And, the agent that was causing it was a retrovirus. 271 00:20:30 --> 00:20:33 The retrovirus here has indicated, very schematically, these artists' 272 00:20:33 --> 00:20:37 drawings never have any resemblance of what things really look like. 273 00:20:37 --> 00:20:41 And if they do, it's only by coincidence. Let me borrow your 274 00:20:41 --> 00:20:45 laser pointer here for a second. So here, and this is what a 275 00:20:45 --> 00:20:48 retrovirus looks like just to give you a feeling. 276 00:20:48 --> 00:20:52 In the center, there are two single stranded RNA 277 00:20:52 --> 00:20:56 molecules. The virus is diploid. There's two copies of the genome 278 00:20:56 --> 00:21:00 for reasons we still don't understand. 279 00:21:00 --> 00:21:03 Surrounding it is a so-called nucleocapsid, which is responsible 280 00:21:03 --> 00:21:07 for protecting the RNA molecules. These two pink dots are 281 00:21:07 --> 00:21:10 reverse-transcriptase molecules because as you'll recall, 282 00:21:10 --> 00:21:14 when retroviruses infect a cell, they carry the enzyme with them into 283 00:21:14 --> 00:21:18 the cell. You could say, why don't they make it after they 284 00:21:18 --> 00:21:21 get into the cell? And it's not totally obvious why, 285 00:21:21 --> 00:21:25 but this is what they do. There's another shell of proteins out here. 286 00:21:25 --> 00:21:29 And then, beyond that is a lipid bilayer. And this lipid bilayer is, 287 00:21:29 --> 00:21:33 as you may recall, stolen from cell from which the 288 00:21:33 --> 00:21:37 virus is protruding because if you look at retrovirus-infected cells, 289 00:21:37 --> 00:21:41 here's the plasma membrane of a retrovirus-infected cell. 290 00:21:41 --> 00:21:45 Here you can see a nucleo-capsid forming with the RNA molecules. 291 00:21:45 --> 00:21:49 And this shoves its way, protrudes its way through the plasma membrane, 292 00:21:49 --> 00:21:53 stealing a patch of plasma membrane from the infected cell, 293 00:21:53 --> 00:21:57 and at the same time this part of the plasma membrane carries with it 294 00:21:57 --> 00:22:02 viral glycoproteins. And viral glycoproteins, 295 00:22:02 --> 00:22:06 they're obviously glycosylated, as are many other extracellular 296 00:22:06 --> 00:22:10 proteins. And in this case, they're indicated with these yellow 297 00:22:10 --> 00:22:14 ovals, and these viral glycoproteins are used to attach to subsequently 298 00:22:14 --> 00:22:18 infected cells so what happens is that when the retrovirus gets out of 299 00:22:18 --> 00:22:22 the cell, I'll draw it again schematically here, 300 00:22:22 --> 00:22:26 it has this glycoproteins coat on it with the plasma membrane, 301 00:22:26 --> 00:22:30 and it uses these glycoproteins spikes. 302 00:22:30 --> 00:22:34 I just won't put the yellow ovals on them, to attach to cells which need 303 00:22:34 --> 00:22:39 to be infected. So, here's a target cell that needs 304 00:22:39 --> 00:22:44 to be infected. So, the target cell, 305 00:22:44 --> 00:22:49 and how does this virus know how to attach to this cell and not to other 306 00:22:49 --> 00:22:54 cells? Because on the surface of the target cell are certain cellular 307 00:22:54 --> 00:22:58 proteins, which are used for normal cell physiology, 308 00:22:58 --> 00:23:03 which are there, and which the virus has opportunistically developed 309 00:23:03 --> 00:23:08 an affinity for. So here on the surface of a target 310 00:23:08 --> 00:23:13 cell might be a normal cellular protein to which the viral 311 00:23:13 --> 00:23:18 glycoprotein combined. Or, if you want to get technical, 312 00:23:18 --> 00:23:23 this enables the virus particle to adsorb, to attach to. 313 00:23:23 --> 00:23:28 Notice the D here rather than the B, to adsorb to the surface of the 314 00:23:28 --> 00:23:33 target cell. Importantly, what's the cell surface protein of 315 00:23:33 --> 00:23:38 the target cell to which HIV virus adsorbs? It's our old friend CD4. 316 00:23:38 --> 00:23:42 I.e. the HIV particle likes to adsorb, preferentially adsorbs to 317 00:23:42 --> 00:23:47 the surface of cells that express the CD4 molecule on the surface. 318 00:23:47 --> 00:23:52 Note, by the way, that just five minutes ago, we described a totally 319 00:23:52 --> 00:23:57 different function of CD4. CD4 over here was said to represent 320 00:23:57 --> 00:24:01 the means by which the T helper cell can recognize MHC molecules being 321 00:24:01 --> 00:24:06 displayed on the surface of either of these dendritic 322 00:24:06 --> 00:24:11 cells or B cells. But here we see CD4 in a totally 323 00:24:11 --> 00:24:16 different context. Here, the CD4 represents the 324 00:24:16 --> 00:24:22 docking site to which the viral glycoprotein can attach, 325 00:24:22 --> 00:24:27 enabling the virus, which came to be called human immunodeficiency 326 00:24:27 --> 00:24:32 virus. In fact, the virus was discovered by 327 00:24:32 --> 00:24:36 two groups simultaneously, one of them called HDLV-3, the other 328 00:24:36 --> 00:24:41 called lymphadenopathy virus. The first group was American. 329 00:24:41 --> 00:24:45 The second group was French, and they allowed Herald Varmus, 330 00:24:45 --> 00:24:50 one of the co-discoverers of the proto-oncogene to act as sort of the 331 00:24:50 --> 00:24:54 judge to see what it would be called because there was great political 332 00:24:54 --> 00:24:59 tension. Would it get the American or the French name depending on 333 00:24:59 --> 00:25:03 which of the two warring scientists, and they were warring, could claim 334 00:25:03 --> 00:25:08 discovery? So, he had a Solomonic decision. 335 00:25:08 --> 00:25:12 He decided to name it human immunodeficiency virus. 336 00:25:12 --> 00:25:16 That was a compromise. And by the way, some people in less than 337 00:25:16 --> 00:25:21 charitable mood say, well, of course he named it human 338 00:25:21 --> 00:25:25 immunodeficiency virus because those are almost his own initials. 339 00:25:25 --> 00:25:30 But, I think that's unfair. These were his initials. 340 00:25:30 --> 00:25:34 Here's human immunodeficiency virus. He named it for a perfectly good 341 00:25:34 --> 00:25:38 reason. Anyhow, that broke the Franco-American 342 00:25:38 --> 00:25:42 diplomatic tension, and now one began to realize that 343 00:25:42 --> 00:25:46 HIV or human immunodeficiency virus attacked T helper cells and 344 00:25:46 --> 00:25:50 preferentially infected T helper cells by virtue of the ability of 345 00:25:50 --> 00:25:54 the virus particle to dock itself to the CD4 molecules presented on the 346 00:25:54 --> 00:25:58 surface of these cells. By the way, what happens afterwards, 347 00:25:58 --> 00:26:02 after the virus becomes adsorbed to the surface of an infectable cell 348 00:26:02 --> 00:26:07 such as a T helper cell. So, here's the virus particle. 349 00:26:07 --> 00:26:13 Here's the surface of a T helper cell. What happens then is these 350 00:26:13 --> 00:26:19 two lipid bilayers fuse with one another so that now they became one, 351 00:26:19 --> 00:26:25 and now the internal contents, the nucleocapsid which contains the RNA 352 00:26:25 --> 00:26:31 and the reverse transcriptase now has direct topological access into 353 00:26:31 --> 00:26:36 the cytoplasm of the cell. In fact, the glycoprotein, 354 00:26:36 --> 00:26:40 the yellow ovals there of human immunodeficiency virus actually had 355 00:26:40 --> 00:26:44 two functions. First, it specifically recognizes 356 00:26:44 --> 00:26:48 the CD4 molecules to which it then anchors or adsorbs the virus 357 00:26:48 --> 00:26:52 particle. And secondly, it also has fusing functions, 358 00:26:52 --> 00:26:56 i.e. it's capable of causing the lipid bilayer of the virion, 359 00:26:56 --> 00:27:00 or the virus particle, to fuse with that of the plasma membrane of the 360 00:27:00 --> 00:27:05 infected target cell. And, once it's in there, 361 00:27:05 --> 00:27:10 then the virus can begin to do its replication. Now, 362 00:27:10 --> 00:27:15 the replication of the HIV virus was already pretty well understood by 363 00:27:15 --> 00:27:20 the time that HIV was discovered in 1982-'83 because of this backlog of 364 00:27:20 --> 00:27:25 retrovirus research. And just to review for you how 365 00:27:25 --> 00:27:30 retroviruses replicate, RNA is put into the cell, 366 00:27:30 --> 00:27:35 single stranded RNA. It's called plus strand RNA because 367 00:27:35 --> 00:27:40 it is of the same polarity of the same strandedness as messenger RNA. 368 00:27:40 --> 00:27:45 If it were complementary to messenger RNA, 369 00:27:45 --> 00:27:51 then it would be called minus strand RNA. This is reverse transcribed by 370 00:27:51 --> 00:27:56 the reverse transcriptase, which is carried into the cell. 371 00:27:56 --> 00:28:01 RT stands for reverse transcriptase. And now, one gets a double stranded 372 00:28:01 --> 00:28:06 DNA molecule, a copy of the virus. And this DNA copy is sometimes 373 00:28:06 --> 00:28:11 called a provirus. And just to review, 374 00:28:11 --> 00:28:15 this provirus is then subsequently integrated into the chromosomal DNA 375 00:28:15 --> 00:28:20 of the cell. So, here's the provirus. 376 00:28:20 --> 00:28:25 Here's the chromosomal DNA. And then, this integrated provirus 377 00:28:25 --> 00:28:30 then serves as a template for making progeny plus-stranded RNA. 378 00:28:30 --> 00:28:34 And this progeny plus-stranded RNA, which is, by the way, forward 379 00:28:34 --> 00:28:39 transcribed by RNA polymerase too, which does the bulk of the heavy 380 00:28:39 --> 00:28:43 lifting in terms of making RNA in the nucleus, this plus-stranded RNA 381 00:28:43 --> 00:28:48 can have two functions recall. One, it can serve as a template on 382 00:28:48 --> 00:28:53 ribosomes for making viral proteins such as the viral capsid proteins. 383 00:28:53 --> 00:28:57 And two, the plus stranded RNA can in turn be encapsidated, 384 00:28:57 --> 00:29:02 i.e. it can become packaged. Encapsidate equals, 385 00:29:02 --> 00:29:06 it can become packaged by the viral proteins to make progeny virus 386 00:29:06 --> 00:29:10 particles, which can then bud, as I've indicated here, from the 387 00:29:10 --> 00:29:14 surface of the infected cell. And in fact, we can imagine three 388 00:29:14 --> 00:29:18 classes of viral proteins that are required for replication. 389 00:29:18 --> 00:29:23 First is the reverse transcriptase, which is encoded by the viral RNA. 390 00:29:23 --> 00:29:27 Second are the capsid proteins which carry the RNA, 391 00:29:27 --> 00:29:31 and third are the viral glycoproteins up here which these 392 00:29:31 --> 00:29:35 glycoprotein spikes which are trans-membrane proteins that 393 00:29:35 --> 00:29:39 protrude from the virion, and allow the virion to adsorb to 394 00:29:39 --> 00:29:44 the surface of infected cells. It turns out that this virus has 395 00:29:44 --> 00:29:49 become an extremely difficult virus to deal with. For most viruses that 396 00:29:49 --> 00:29:54 we have encountered over the last 100 years, one has had great success 397 00:29:54 --> 00:29:59 in making vaccines against these viruses including, 398 00:29:59 --> 00:30:04 as we discussed in great detail, poliovirus. 399 00:30:04 --> 00:30:09 In fact, for smallpox, another virus, the vaccine effort 400 00:30:09 --> 00:30:14 was so successful that about 20 years ago, the last case of smallpox 401 00:30:14 --> 00:30:19 finally occurred in Eritrea in northeast African when some herdsmen 402 00:30:19 --> 00:30:24 had the last documented case. And since that time, there have 403 00:30:24 --> 00:30:29 been no documented cases of smallpox in the wild, and there's only two or 404 00:30:29 --> 00:30:34 three stocks of smallpox virus surviving. 405 00:30:34 --> 00:30:37 One of them is in some type of research center is Moscow, 406 00:30:37 --> 00:30:41 and the other is probably in the Communicable Disease Center in 407 00:30:41 --> 00:30:44 Atlanta, Georgia. And, there's been great debate, 408 00:30:44 --> 00:30:48 by the way. Should one get rid of those surviving stalks, 409 00:30:48 --> 00:30:51 or should one keep them for research? By now, you guys aren't vaccinated 410 00:30:51 --> 00:30:55 against smallpox because nobody gets it anymore, and there's a certain 411 00:30:55 --> 00:30:59 risk of getting a small pox vaccine. 412 00:30:59 --> 00:31:02 I am, so I'm not worried, but maybe you should be because 413 00:31:02 --> 00:31:06 starting about 20-25 years ago, one stopped vaccinating people 414 00:31:06 --> 00:31:10 against smallpox because it just doesn't seem to be necessary. 415 00:31:10 --> 00:31:14 Why give them the risk of having some disease which happens in one 416 00:31:14 --> 00:31:18 out of a million vaccinees (sic) instead of just leaving them 417 00:31:18 --> 00:31:22 unvaccinated? Well, I digress. Back to HIV, 418 00:31:22 --> 00:31:26 the fact is we've had enormous lack of success in making a good kind of 419 00:31:26 --> 00:31:30 vaccine against HIV, and why is that? 420 00:31:30 --> 00:31:34 Well, one of the critical things is that HIV is attacking and 421 00:31:34 --> 00:31:38 replicating in the T helper cells, and the T helper cells it turns out 422 00:31:38 --> 00:31:42 are the lynch pains of the immune response. Keep in mind that the T 423 00:31:42 --> 00:31:46 helper cells that I've shown you in this diagram over here represent 424 00:31:46 --> 00:31:50 these critical cellular messengers between the dendritic cells and the 425 00:31:50 --> 00:31:54 macrophages on the one hand, and the B cells on the other. 426 00:31:54 --> 00:31:58 You wipe them out, and the ability to make new antibodies is 427 00:31:58 --> 00:32:03 totally compromised. It turns out the T helper cells can 428 00:32:03 --> 00:32:09 also help to make another class of cells which are called cytotoxic T 429 00:32:09 --> 00:32:16 cells, another kind of T cell, cytotoxic, and these cytotoxic T 430 00:32:16 --> 00:32:23 cells have on their surfaces T cell receptors, which they can use to 431 00:32:23 --> 00:32:30 recognize infected cells, and kill infected cells. 432 00:32:30 --> 00:32:34 So, the cytotoxic T cells aren't involved in making antibody 433 00:32:34 --> 00:32:38 responses at all. The cytotoxic T cells are involved 434 00:32:38 --> 00:32:42 in recognizing cells that are expressing unusual or foreign 435 00:32:42 --> 00:32:46 antigens on their surface, and killing those cells. That's the 436 00:32:46 --> 00:32:50 function of the cytotoxic T cells. Obviously, it's quite different 437 00:32:50 --> 00:32:54 from the helper T cells. But once again, the activation of 438 00:32:54 --> 00:32:58 the cytotoxic T cells, and empowering them to make these 439 00:32:58 --> 00:33:02 attacks on abnormal cells depends on the helper T cells. 440 00:33:02 --> 00:33:06 Once again, the helper T cells represent the lynch pins, 441 00:33:06 --> 00:33:10 the keystones, of the immune response. But, 442 00:33:10 --> 00:33:14 because of this tropism, and when I use the word tropism, 443 00:33:14 --> 00:33:19 I mean because of the desire of the virus to phase towards and infect a 444 00:33:19 --> 00:33:23 certain subset of cells in the body, this tropism of HIV for infecting 445 00:33:23 --> 00:33:27 and killing helper T cells, the production of antibodies is 446 00:33:27 --> 00:33:31 strongly compromised on the one hand, and the production of cytotoxic T 447 00:33:31 --> 00:33:36 cells is compromised on the other. 448 00:33:36 --> 00:33:40 There's another aspect of HIV infection which is also very 449 00:33:40 --> 00:33:45 insidious, and that's the following. It turns out that the body can 450 00:33:45 --> 00:33:50 initially make an immune response against an infecting HIV particle. 451 00:33:50 --> 00:33:55 And here's kind of what things look like. I hope this shows up here. 452 00:33:55 --> 00:34:00 Who could lend me a laser pointer again? 453 00:34:00 --> 00:34:05 Excellent, thank you. OK, so here's what happens. 454 00:34:05 --> 00:34:10 And, there's two graphs here. On one hand are the cytotoxic T 455 00:34:10 --> 00:34:16 cells, and their level is shown on the solid line here. 456 00:34:16 --> 00:34:21 So, look at the course of infection. It's plotted here in weeks and 457 00:34:21 --> 00:34:26 years. If you see what happens in a primary HIV infection, 458 00:34:26 --> 00:34:32 and here on the right on this ordinate here is the viral titer 459 00:34:32 --> 00:34:37 indicated on a log scale. So, this is a semi-log graph for the 460 00:34:37 --> 00:34:41 viral titer. And what you see over here is that when you initially 461 00:34:41 --> 00:34:45 infected it, there's an enormous burst of viral titer. 462 00:34:45 --> 00:34:49 It goes up by four or five orders of magnitude, and then it falls down 463 00:34:49 --> 00:34:53 dramatically by two or three orders of magnitude. And it goes on, 464 00:34:53 --> 00:34:57 and it remains depressed by two or three orders of magnitude below its 465 00:34:57 --> 00:35:02 initial height for a number of years. 466 00:35:02 --> 00:35:06 What's going on then? The immune system has come to grips 467 00:35:06 --> 00:35:10 with the presence of the HIV virus, and begins successfully to try to 468 00:35:10 --> 00:35:14 eliminate it. How does the immune system eliminate HIV? 469 00:35:14 --> 00:35:18 By two mechanisms. First of all, the immune system makes neutralizing 470 00:35:18 --> 00:35:22 antibodies of the sort that float through the serum, 471 00:35:22 --> 00:35:26 and are able to glom onto the virus particle, attach to the virus 472 00:35:26 --> 00:35:30 particle, and thereby prevent it from being infectious. 473 00:35:30 --> 00:35:34 And secondly, as I mentioned last time, the immune system also can 474 00:35:34 --> 00:35:38 recognize virus-infected cells and kill them. And by killing a 475 00:35:38 --> 00:35:42 virus-infected cell, the immune system prevents that cell 476 00:35:42 --> 00:35:46 from continuing to function as a factory for putting out new virus 477 00:35:46 --> 00:35:50 particles. So, there's two ways by which virus 478 00:35:50 --> 00:35:54 particles are eliminated, but note here that the virus 479 00:35:54 --> 00:35:58 infected cell which is critically important among all the cell types 480 00:35:58 --> 00:36:02 in the body are the T helper cells. 481 00:36:02 --> 00:36:06 So, certain components of the immune system are killing the T helper 482 00:36:06 --> 00:36:10 cells that are involved in harboring and producing HIV virus. 483 00:36:10 --> 00:36:14 So, there's an auto destruction on the part of the immune system. 484 00:36:14 --> 00:36:19 Look, at the same time, at the titer, at the number of CD4 cells, 485 00:36:19 --> 00:36:23 and they're indicated here on the left ordinate, 486 00:36:23 --> 00:36:27 in this case, cells per microliter. CD4 cells originally started up 487 00:36:27 --> 00:36:32 here. They go down by a factor of two or 488 00:36:32 --> 00:36:36 three for the first weeks, and then over a period of years 489 00:36:36 --> 00:36:40 there's this ongoing struggle between the HIV particle and the 490 00:36:40 --> 00:36:44 immune system as the number of CD4 cells, and the CD4 cells we've said 491 00:36:44 --> 00:36:48 before, the CD4 positive cells are these T helper cells as the number 492 00:36:48 --> 00:36:52 of these cells per microliter of blood progressively declines further 493 00:36:52 --> 00:36:56 and further and further. And finally, the number of CD4 494 00:36:56 --> 00:37:00 positive cells, i.e. T helper cells, 495 00:37:00 --> 00:37:04 gets so low that the body is totally overwhelmed, and the patient then 496 00:37:04 --> 00:37:08 dies of an opportunistic infection. 497 00:37:08 --> 00:37:12 What do I mean by an opportunistic infection? Well, 498 00:37:12 --> 00:37:16 what I mean is that we are surrounded all the time by all kinds 499 00:37:16 --> 00:37:21 of microbes, which given the chance will kill us within a couple days. 500 00:37:21 --> 00:37:25 Keep in mind, I told you that there are in your gut, 501 00:37:25 --> 00:37:30 as many bacterial cells as there are the rest of your body. 502 00:37:30 --> 00:37:33 And some of these bacteria are really nasty. I remember, 503 00:37:33 --> 00:37:36 my grandfather got kicked in the belly by a horse, 504 00:37:36 --> 00:37:40 and three days later he was dead. Why? Because some of the bacteria 505 00:37:40 --> 00:37:43 got out of his gut, got into his peritoneal fluid cavity, 506 00:37:43 --> 00:37:47 and gone. This was the pre-antibiotic era, 507 00:37:47 --> 00:37:50 by the way, never new him very well because he died in 1916. 508 00:37:50 --> 00:37:54 I'm just telling you that your gut is full of all kinds of nasty thing 509 00:37:54 --> 00:37:57 on your skin. Not just on my skin, but on your skin there are billions 510 00:37:57 --> 00:38:01 of staph aureus bacteria. They're just waiting to cause you 511 00:38:01 --> 00:38:05 problems. Don't look. It's OK. 512 00:38:05 --> 00:38:09 Don't look too closely. They're just waiting to cause a 513 00:38:09 --> 00:38:13 nasty infection as well. Everyday we breathe in all kinds of 514 00:38:13 --> 00:38:17 awful microbes, fungi, and all these kinds of things 515 00:38:17 --> 00:38:21 including pneumocystis. And, rarely do we get sick because 516 00:38:21 --> 00:38:25 of the extraordinary competence of the immune system to respond to such 517 00:38:25 --> 00:38:30 a diversity of infectious agents, and to hold them at bay. 518 00:38:30 --> 00:38:34 In the 20th century, the percentage of people who die of 519 00:38:34 --> 00:38:38 infectious diseases has plummeted both because of the immune system 520 00:38:38 --> 00:38:42 and because we're eating healthier up to a point, 521 00:38:42 --> 00:38:46 and because of antibiotics and antifungals. But if the immune 522 00:38:46 --> 00:38:50 system is defective, all the antibiotics in the world, 523 00:38:50 --> 00:38:54 and all the antifungal agents can't save a patient if their CD4 cells 524 00:38:54 --> 00:38:58 get down very, very low because these antifungals 525 00:38:58 --> 00:39:03 always worked as collaborators with the immune system. 526 00:39:03 --> 00:39:07 They get rid of a bulk of the infection, but the immune system has 527 00:39:07 --> 00:39:11 to wipe out the residue. And what you see here is a struggle 528 00:39:11 --> 00:39:15 going on for a period of three, four, five, six years where the 529 00:39:15 --> 00:39:19 viral titer is successfully held low, and then all of a sudden as the 530 00:39:19 --> 00:39:23 immune system weakens the viral titer goes up to high levels, 531 00:39:23 --> 00:39:27 wipes out the residual T helper cells, and death invariably 532 00:39:27 --> 00:39:31 ensues. Now, I've given you one reason why 533 00:39:31 --> 00:39:34 the immune system can't deal with this virus, because virtually all 534 00:39:34 --> 00:39:38 other viruses attack various tissues throughout our body, 535 00:39:38 --> 00:39:41 but they don't attack the immune system itself. 536 00:39:41 --> 00:39:44 Here, we're having a virus which is attacking the defense of the body, 537 00:39:44 --> 00:39:48 that is to say, the immune system. So, one reason is the continuing 538 00:39:48 --> 00:39:51 depletion of the T helper cells. They can regenerate themselves for 539 00:39:51 --> 00:39:54 a period of time, very impressively long period of 540 00:39:54 --> 00:39:58 time, four, five, six, seven years. But ultimately, 541 00:39:58 --> 00:40:02 they get worn out, they die. Another reason is this is antigenic 542 00:40:02 --> 00:40:08 variation. Now, if you look at the retrovirus 543 00:40:08 --> 00:40:14 particle, what you see is on the surface the glycoprotein. 544 00:40:14 --> 00:40:19 It's right here. And, the glycoprotein is used by antibodies 545 00:40:19 --> 00:40:25 to recognize and bind to the virus particle and neutralize it, 546 00:40:25 --> 00:40:30 same as with poliovirus. But let's imagine, 547 00:40:30 --> 00:40:34 as happens to be the case, that the virus is highly error prone 548 00:40:34 --> 00:40:39 in replicating its genome. When I say error prone, I mean that 549 00:40:39 --> 00:40:44 instead of the host cell, polymerase, which makes ultimately 550 00:40:44 --> 00:40:48 one mistake out of a billion, the viral replication machinery 551 00:40:48 --> 00:40:53 makes mistakes all the time. It's quite defective in the 552 00:40:53 --> 00:40:58 fidelity and the faithfulness with which it replicates nucleic acid. 553 00:40:58 --> 00:41:02 That means that after each cycle of replication, there are in effect 554 00:41:02 --> 00:41:07 mutant viruses that have been produced, mutant progeny viruses, 555 00:41:07 --> 00:41:11 and where the mutation rate instead of being one in 10-9 might be one in 556 00:41:11 --> 00:41:16 10-2 or one in 10-3. And that means that there are 557 00:41:16 --> 00:41:20 continually novel variants of HIV being produced in a person's body. 558 00:41:20 --> 00:41:25 Let's imagine that that person has developed antibodies against the 559 00:41:25 --> 00:41:30 viral glycoprotein of the virus that initially infected him or her. 560 00:41:30 --> 00:41:34 Let's imagine that. And those antibodies are successful 561 00:41:34 --> 00:41:38 in eliminating most of the virus particles of the sort that initially 562 00:41:38 --> 00:41:42 infected that individual. But now we can imagine the 563 00:41:42 --> 00:41:46 possibility that in the imperative weeks or months, 564 00:41:46 --> 00:41:50 a new strain of HIV will arise within that individual's body a 565 00:41:50 --> 00:41:54 mutant strain in which the sequences that code the viral glycoprotein had 566 00:41:54 --> 00:41:58 been changed slightly. And now, the viral glycoprotein has 567 00:41:58 --> 00:42:02 changed slightly its epitopes. And the initially developed 568 00:42:02 --> 00:42:07 neutralizing antibody that recognized the initial cohort of 569 00:42:07 --> 00:42:12 virus coming into the cell in the individual no longer works because 570 00:42:12 --> 00:42:17 the virus has undertaken a strategy of immune evasion, 571 00:42:17 --> 00:42:22 sometimes it's called immunoevasion, in which now the viral glycoprotein, 572 00:42:22 --> 00:42:27 although it's still competent to affect a replication cycle to adsorb 573 00:42:27 --> 00:42:32 and fuse to the surface of an affected cell. 574 00:42:32 --> 00:42:36 Many of the epitopes, many of the oligopeptide antigens on 575 00:42:36 --> 00:42:40 the surface of the glycoprotein have been changed slightly through amino 576 00:42:40 --> 00:42:44 acid substitutions, through point mutations. 577 00:42:44 --> 00:42:48 And hence, the initially developed antibody, which previously was 578 00:42:48 --> 00:42:52 successful in glomming on and neutralizing this virus particle is 579 00:42:52 --> 00:42:56 rendered ineffective. And now, this second wave, 580 00:42:56 --> 00:43:00 this new strain of HIV will grow up and expand in that individual, 581 00:43:00 --> 00:43:04 and once again provoke a new immune response. 582 00:43:04 --> 00:43:07 And, the same cycle will repeat it. The second strain will now soon be 583 00:43:07 --> 00:43:11 eliminated, but while the elimination is going on, 584 00:43:11 --> 00:43:15 there's strong Darwinian selective pressure favoring the outgrowth of 585 00:43:15 --> 00:43:19 yet another mutant strain which is not recognized by either of the two 586 00:43:19 --> 00:43:23 initial antibody responses. And so, over this period of many 587 00:43:23 --> 00:43:27 years, what's happening is that the virus in the immune system are 588 00:43:27 --> 00:43:31 playing continual cat and mouse games with one another. 589 00:43:31 --> 00:43:34 The immune system goes after the virus; the virus moves over here; 590 00:43:34 --> 00:43:38 the immune system goes after that; and so you have a succession of 591 00:43:38 --> 00:43:42 antigenic variance. Here's one variant. 592 00:43:42 --> 00:43:45 Here's another variant. Here's another variant, and so 593 00:43:45 --> 00:43:49 forth. By the time the immune system succeeds in getting rid of 594 00:43:49 --> 00:43:53 the first variant, a new variant has appeared, 595 00:43:53 --> 00:43:57 and then the immune system ramps up its defenses and tries to get rid of 596 00:43:57 --> 00:44:00 that. And, it succeeds almost. But by the time that has happened, 597 00:44:00 --> 00:44:04 yet a third variant has appeared. And so, there are these continual 598 00:44:04 --> 00:44:08 clonal successions. A clonal succession represents a 599 00:44:08 --> 00:44:11 time where one clonal virus explodes, expands. It's soon eliminated, 600 00:44:11 --> 00:44:15 collapses, and then another clone comes up and expands. 601 00:44:15 --> 00:44:19 And this goes on. This works OK for about four, 602 00:44:19 --> 00:44:22 five, six years. But ultimately, the ability of the 603 00:44:22 --> 00:44:26 T helper cells to replenish themselves and to continue to mount 604 00:44:26 --> 00:44:30 an effective immune response fails. 605 00:44:30 --> 00:44:34 There's yet another aspect of HIV infection which is so insidious, 606 00:44:34 --> 00:44:38 and that's the following. Let's look at the viral life cycle right 607 00:44:38 --> 00:44:42 here, and the provirus, remember the provirus is this thing 608 00:44:42 --> 00:44:46 right here, which is integrated into the chromosomal DNA. 609 00:44:46 --> 00:44:50 And, we can assume that this provirus is transcribed by RNA 610 00:44:50 --> 00:44:54 polymerase too, and I will tell you that the 611 00:44:54 --> 00:44:58 promoter of the provirus is carried in by the proviral DNA, 612 00:44:58 --> 00:45:02 and actually depends on transcription factors that are 613 00:45:02 --> 00:45:07 present in the T helper cell. In fact, you'll recall that the T 614 00:45:07 --> 00:45:11 helper cell gets excited sometimes, and other times it's not excited. 615 00:45:11 --> 00:45:15 And she gets excited if I can attach gender to a T helper cell, 616 00:45:15 --> 00:45:20 when she encounters macrophages and dendritic cells, 617 00:45:20 --> 00:45:24 and/or when she encounters B cells. Other times, the T helper cell is 618 00:45:24 --> 00:45:28 kind of quiet and unactivated (sic). And, what happens when a T helper 619 00:45:28 --> 00:45:33 cell gets activated through these encounters? 620 00:45:33 --> 00:45:37 The T helper cell starts making her own transcription factors, 621 00:45:37 --> 00:45:41 which are used in order to facilitate these complex biological 622 00:45:41 --> 00:45:45 interactions with both antigen-presenting cells, 623 00:45:45 --> 00:45:49 macrophages and dendritic cells, and later on, B cells. And those 624 00:45:49 --> 00:45:53 same transcription factors that the T helper cell uses to turn on its 625 00:45:53 --> 00:45:57 own expression program are used by the provirus to transcribe 626 00:45:57 --> 00:46:01 its own DNA, i.e. HIV has evolved a proviral 627 00:46:01 --> 00:46:05 promoter sequence here which takes advantage of transcription factors 628 00:46:05 --> 00:46:09 that are present uniquely in an activated T cell. 629 00:46:09 --> 00:46:13 And when those transcription factors are available, 630 00:46:13 --> 00:46:17 not only does the T cell become activated, but the provirus becomes 631 00:46:17 --> 00:46:21 transcribed because these transcription factors now enable RNA 632 00:46:21 --> 00:46:25 polymerase 2 of the host to transcribe the provirus. 633 00:46:25 --> 00:46:29 But let's imagine now, if we follow that scenario to its conclusion, 634 00:46:29 --> 00:46:33 what happens when the T cell is not activated? 635 00:46:33 --> 00:46:37 When the T cell is quiescent, when it's quiet, these transcription 636 00:46:37 --> 00:46:41 factors are unavailable to attach to the promoter of the integrated 637 00:46:41 --> 00:46:45 provirus, and as a consequence the provirus will not be transcribed. 638 00:46:45 --> 00:46:49 It won't make RNA, and in that situation, how will anybody know 639 00:46:49 --> 00:46:53 that there's an integrated provirus in there? Well, 640 00:46:53 --> 00:46:57 the provirus is not being transcribed. The transcripts aren't 641 00:46:57 --> 00:47:02 being used to make viral protein. So in effect, the only evidence for 642 00:47:02 --> 00:47:06 the existence of HIV in the cell is this segment of DNA. 643 00:47:06 --> 00:47:10 In other words, this provirus can hide out in an unactivated quiescent 644 00:47:10 --> 00:47:14 T cell indefinitely. And, the immune system can't know 645 00:47:14 --> 00:47:18 that there's a provirus hiding out in this T helper cell because it's 646 00:47:18 --> 00:47:22 not being transcribed. And therefore, one can have a 647 00:47:22 --> 00:47:26 quiescent T helper cell, and several other cell types in the 648 00:47:26 --> 00:47:30 body, macrophages also, which aren't transcribing their 649 00:47:30 --> 00:47:34 proviruses. Well, you'll say, 650 00:47:34 --> 00:47:38 so what? It doesn't make any difference. If it's not being 651 00:47:38 --> 00:47:42 transcribed, it's not going to hurt the individual. 652 00:47:42 --> 00:47:46 But, keep in mind that the idea of getting rid of a viral infection is 653 00:47:46 --> 00:47:49 to eliminate all traces of a viral genome from an infected individual, 654 00:47:49 --> 00:47:53 and that's what happens with smallpox and with poliovirus, 655 00:47:53 --> 00:47:57 and with measles and virtually all the other infections we have. 656 00:47:57 --> 00:48:01 But here, we have a situation where the viral genome can hide out in a 657 00:48:01 --> 00:48:05 latent or inapparent (sic) configuration. 658 00:48:05 --> 00:48:09 There's no way to know it's there, and it may reemerge days, weeks, 659 00:48:09 --> 00:48:13 months, even years later because this previously transcriptionally 660 00:48:13 --> 00:48:17 silent provirus may suddenly be present in a cell which suddenly 661 00:48:17 --> 00:48:22 becomes activated. And now, an individual who 662 00:48:22 --> 00:48:26 "thought" quote unquote that he or she had gotten rid of HIV infection 663 00:48:26 --> 00:48:30 all of a sudden realizes there are viral genomes still hiding 664 00:48:30 --> 00:48:34 out in the body. And what that means is that in 665 00:48:34 --> 00:48:38 effect, it's absolutely impossible to rid the body of HIV infection 666 00:48:38 --> 00:48:42 ever. Once an individual is infected, in fact, 667 00:48:42 --> 00:48:46 that individual is infected for life. There's no way on Earth what we 668 00:48:46 --> 00:48:50 have at present of getting rid of the viral infection because the 669 00:48:50 --> 00:48:54 viral genome is always hiding out here or there in different 670 00:48:54 --> 00:48:58 interstices of the immune system, hiding out in transcriptionally 671 00:48:58 --> 00:49:02 silent state. Of course, we have very effective 672 00:49:02 --> 00:49:06 drugs against HIV now. Some drugs inhibit the reverse 673 00:49:06 --> 00:49:10 transcriptase. Others inhibit the processing of 674 00:49:10 --> 00:49:14 the capsid proteins, that is, the proteins which these 675 00:49:14 --> 00:49:19 capsid proteins happen to be cleaved from a large, high molecular-weight 676 00:49:19 --> 00:49:23 protein precursor into individual proteins, and there's an inhibitor 677 00:49:23 --> 00:49:27 of the protease that cleaves these proteins to the mature size. 678 00:49:27 --> 00:49:31 And, those drugs together hold the viral infection at bay for maybe 10, 679 00:49:31 --> 00:49:36 15, 20 years. But keep in mind that even though 680 00:49:36 --> 00:49:40 the viral infection is being stopped by these drugs, 681 00:49:40 --> 00:49:45 first of all, the virus is always hiding out in the bodies of such 682 00:49:45 --> 00:49:49 individuals in this latent, hidden form, and secondly, there may 683 00:49:49 --> 00:49:54 be a slow depletion of their T helper cells in spite of the 684 00:49:54 --> 00:49:58 effectiveness of these drugs. On that cheerful note, I wish you a 685 00:49:58 --> 50:03 good day.