nm0607: right then [0.4] okay that's great [0.8] yeah so i said in Finland [0.
8] about thirty per cent of cases are only thirty per cent of cases are 
acquired out of country and the rest acquired in country [1.5] so the next 
thing i want to show you is the [1.6] it says the situation in the U-K [0.6] er 
[0.5] current situation in the U-K [1.3] er that's a bit grim [2.8] er [1.5] i 
was just going to explain [6.5] you've got them in your handout [0.3] 
sm0608: yeah 
sf0609: u-huh 
nm0607: [4.7] now [1.7] i haven't put them on this copy i can't get onto my 
hard disk it's er [1.0] let's shut this off a minute and we'll talk about that 
when we move on 
nm0607: so if we look at the first table this this gives you the most up to 
date information for the U-K [0.4] okay [0.6] and what you can see is 
cumulatively [1.6] at the end of last year [1.4] about fifty-two-thousand 
people [0.8] had been diagnosed or fifty-three-thousand almost fifty-three-
thousand down in the bottom [0.3] right-hand corner [0.4] had been diagnosed 
with H-I-V [1.0] and of those roughly thirty-thousand [1.1] were homosexual 
spread [1.2] men-men [1.0] and roughly fifteen-thousand so 
slightly under a third [0.9] were [0.2] heterosexual spread [1.0] and then [0.
6] intravenous drug abuse comes next and then a relatively small number from 
blood products [0.6] about a thousand just under a thousand mother to infant 
transmission and then a couple of thousand where it's not quite clear how the 
transmission occurred [0.9] the thing that you should notice along the bottom 
[1.1] is that up until around about ninety-ninety-seven [1.0] the number of 
newly acquired infections each year is relatively stable [1.0] and then it 
starts to accelerate again [0.8] and in fact in the period September two-
thousand-and-one to September two-thousand-and-two [0.4] there's been some five-
thousand-three-hundred [0.4] new [0.6] infections diagnosed [1.4] so you can 
see that after a period of about ten years of relatively stable new infection 
rates [1.2] the epidemic is [0.4] in this country [0.3] is increasing again [0.
2] not dramatically but it is going up at the rate of [0.6] roughly [0.8] 
fifteen to twenty per cent increased incidence a year [2.8] and if you look at 
table 
two [2.3] what table two shows you is [0.9] diagnosis by [1.0] exposure 
category [2.0] for [0.6] just for one year just for the last year September [0.
5] two-thousand-and-one to September two-thousand-and-two [2.5] and you can see 
that [1.3] this sh-, this [0.8] table shows you two things it shows you [0.7] 
the distribution according to what type of category the infection was [0.6] in 
so men-men [0.6] and heterosexual spread and various subdivisions of 
heterosexual spread and you can see in there the figure that shows [1.0] for 
heterosexual er s-, er spread acquired abroad [0.7] no evidence of a high risk 
partner [0.9] okay [0.6] acquir-, U-K acquired no evidence of a high risk 
partner [0.7] and you can see it broken down by region [1.5] and the thing i 
want to come out of the broken down by region is you can see that both in terms 
of [0.5] the acquired infections last year and the total number of infections 
acquired [1.0] London is an epicentre [1.3] yeah [3.5] and then the final table 
i've given you [3.1] is [1.0] again [0.2] year is is more total figures this is 
[0.4] year of infectio-, [0.5] year of infection over 
the last ten years [1.5] and the area where the infection was acquired [0.3] or 
was diagnosed in fact not necessarily acquired [0.5] and again what emerges 
from that is you can see that across the total epidemic of the [0.3] fifty-odd-
thousand cases [0.8] some were over thirty-thousand thirty-two-thousand [0.4] 
were acquired in the London area [1.7] what that's telling you is [0.4] even in 
the epidemic in this country [0.7] the [0.2] the risk [0.3] varies according to 
where in the country you are [0.7] okay and that would be true in most 
countries [0.8] risk is not uniform [1.3] okay and it's it's a it's an 
important message to get across to you [2.7] okay [0.8] so you can see the 
situation globally [0.6] is we've got some forty-million people [1.5] infected 
[0.9] but actually the U-S-A the U-S the U-K's contribution to this forty-
million [0.5] is pretty small [0.7] it's only fifty-two-thousand [1.8] in fact 
it's less than fifty-two-thousand really because [0.5] you're talking about [0.
5] a significant fraction of the fifty-two-thousand diagnosed cases in this 
country will already be 
dead i can't remember [0.4] what the total is it's around about thirty-thousand 
of them have already died [0.8] so we're only contributing about twenty-
thousand [0.6] between twenty and thirty-thousand [0.2] to that forty-million 
figure [0.7] in this country [1.6] okay [1.4] all right that's all i'm going to 
say about the [1.0] the epidemic [0.8] okay [0.7] the important message you've 
got to take across about the epidemic is [1.1] it's a c-, huge global problem 
[1.5] it's still an escalating grobal problem [1.1] okay [0.2] the numbers are 
going up rapidly they are not stable or going down [0.7] okay [0.6] and it's 
predominantly a problem in the developing world [0.9] particularly sub-Saharan 
Africa [0.7] where you've seen from some of the incidence figures i showed you 
in the last lecture [0.5] that there are quite frightening consequences for 
social structures in some of those countries [0.9] you know [1.6] er [0.4] less 
of a problem in the developed world more under control in the developed world 
[1.1] more under more un-, control 
more under control still in this country [1.3] most of the spread in this 
country is still [0.3] homosexual spread although heterosexual spread [0.3] is 
the most rapidly growing [0.2] category [1.3] and most of that heterosexual 
spread [0.5] is [0.2] infection acquired [0.2] out of the country [1.0] so by 
somebody going from this country and having a sex partner [0.3] in a country 
where the generalized epidemic is a-, is going on [0.3] at a high level [0.8] 
rather than spread within the country [2.2] all right what i want to do now is 
move away from talking about the epidemic in a broad sense and start talking 
about [0.5] the virus [1.2] okay and the infection [0.7] so we have another [0.
4] chunk of handouts and i'll try and get [0.6] this up while you hand those 
around [2.6] if i can find me [0.2] pointer again [1.3] i've put the bally 
thing down [0.2] here we go 
nm0607: right [2.4] i hope you will already have seen a v-, [0.2] a version of 
this sort of slide maybe not a precisely [0.2] this but a version of this [0.8] 
so this is the virus we're talking about H-I-V [0.8] H-I-V [0.3] 
is a retrovirus to remind you [0.6] what that means is that is that unusually 
for a vir-, oops let me back up here [7.2] oh [0.2] bother [5.1] unusually for 
a virus it has a diploid genome [0.2] there are two pieces [0.6] of single 
strand [0.8] positive sense [0.5] R-N-A [0.4] contained within the virus 
particle [5.1] the R-N-A is approximately ten kilobases in length [0.6] just 
under ten kilobases in length [2.0] it is [0.5] it is surrounded [2.0] by a [0.
6] capsid structure [0.9] composed of [0.6] a number of proteins [0.6] P-twenty-
four being the major protein [0.9] and when H-I-V is diagnosed [0.9] it is in 
fact antibodies against P-twenty-four [1.2] that form the main basis of [0.3] 
diagnosis [2.8] so [0.2] the bulk of H-I-V diagnosis does not involve [0.3] 
looking directly for the agent itself for looking for the virus itself [0.6] 
that usually comes [0.3] as a confirmatory test [0.8] the bulk of diagnosis is 
looking [0.3] by looking for antibodies against this [0.4] major structural 
protein [0.9] P-twenty-four [0.5] that makes up the inner capsid shell [3.5] 
this [0.6] capsid shell has a 
toroid [0.2] type of structure a sort of [0.3] bit like a a flattened ended 
cone [2.8] m-, [0.7] on the R-N-A is the reverse transcriptase enzyme [1.1] 
this is a retrovirus so which group in the Baltimore classification scheme is 
this in [0.6] 
sm0610: six [2.2] 
nm0607: didn't hear it very loud [0.3] 
sm0610: six 
nm0607: six that's right six [0.7] so it goes through a D-N-A intermediate so 
the first thing that it's got to do when it gets inside the infected cell is 
convert its [0.5] single strand [0.4] positive sense R-N-A [0.5] into duplex D-
N-A [0.6] and it's transcription from that duplex D-N-A [0.6] that gives rise 
to the viral messenger R-N-A [2.5] the [1.1] toroidal [0.2] capsid is 
surrounded if i can ever find my pointer again there we go [0.4] is surrounded 
by matrix protein [0.7] shown here in green [1.4] that's then surrounded by a 
lipid envelope [0.3] so this is a lipid containing virus [1.3] and embedded in 
that lipid envelope [0.5] is the [0.6] envelope 
protein of the virus [1.1] and the envelope protein is synthesized as a 
precursor [3.7] called G-P- [1.4] one-sixty [1.5] the G-P standing for 
glycoprotein because this envelope [0.7] protein [0.5] is a glycoprotein [1.2] 
and after synthesis G-P-one-sixty is cleaved [0.8] to produce G-P-one-twenty [1.
0] which forms the head [2.4] of the [2.0] envelope protein sticking outside 
the lipid envelope [1.9] and G-P-forty-one which is kind of like the stalk [1.
3] that through non-covalent interactions [0.3] holds the [0.3] G-P-one-twenty 
in place [0.7] and the G-P-forty-one is a transmembrane protein it [0.2] it 
goes through the lipid bilayer membrane [2.0] okay [1.0] down here at the 
bottom [1.6] is the gene organization [0.3] of this virus [2.1] and [1.3] it's 
like any other retrovirus it [0.6] but has some additional genes what genes do 
normal retroviruses carry [1.9] 
sf0611: gag pol and env [1.0] 
sm0612: gag pol and env 
nm0607: gag pol and env and you can see here [0.9] gag [1.3] pol [1.1] and env 
[1.2] okay [0.7] but H-I-V is unusual 
in having a number of othe-, additional proteins usually referred to as 
accessory proteins [3.1] and the degree to which we understand what these 
accessory proteins actually do for the virus [0.5] varies according to which 
protein we are talking about [1.5] so for example you will already have heard 
in this lecture series quite extensively about tat and rev [1.0] tat and rev 
are involved in the regulation of gene expression by this virus [0.9] okay [0.
7] but you won't have heard anything yet for example [0.5] about vif [1.4] okay 
[0.8] vif is another accessory protein [0.4] that overlaps [0.3] the carboxy 
terminal end of the coding region of [0.9] the R-T gene the polymerase gene [0.
7] and the amino terminal region of the V-P-R gene [1.8] and vif stands for 
virus infectivity factor [4.5] it's the protein that m-, [0.3] of H-I-V that 
the limited amount of H-I-V work that i do that's the protein that we work on 
vif is an interesting protein [0.5] in that [1.7] as the name implies it's 
required [0.6] for virus infectivity [1.6] and if this protein is absent [0.9] 
and you try and grow 
virus in the [2.5] normal host cells for this virus [0.7] which are C-D-four-
positive lymphocytes [0.5] then the progeny virus that is produced is non-
infectious [4.5] it turns out [0.7] that vif [0.5] is actually required to 
overcome a normal cellular [0.4] protein that's an inhibitory factor [0.7] for 
H-I-V replication [0.9] and i don't have time to go into the detail and anyway 
the detail is not pertinent to [0.2] the rest of what i'm going to say [1.0] so 
there are a number of accessory proteins down here [1.4] and three [0.4] major 
normal retrovirus proteins gag which m-, [0.6] is a [0.4] er [1.2] is made as a 
polyprotein initially [1.3] called [3.2] er [3.0] P-R-fifty-five [1.3] 'cause 
of the fifty-five kilodalton [4.2] precursor [1.0] and that precursor is 
cleaved through the action of a [0.5] virion encoded protease gene [1.6] that 
undertakes the major cleavages necessary to convert [0.7] P-R-fifty-five [1.0] 
into [1.3] P-seventeen P-twenty-four P-six P-one P-seven a number of [0.8] 
structural proteins that make up this [0.3] capsid shell here that i'm 
pointing to [2.9] okay [1.5] so that's the virus we're talking about [1.3] 
let's move on then to look at the pattern of this infection [4.2] now you can 
divide H-I-V infection [0.8] into three broad stages [1.9] there's the primary 
infection [2.3] which occurs over a few weeks [2.6] there's a long period of 
what is usually called clinical latency [2.9] and then there's the [0.5] 
terminal stage of disease [0.4] which we usually refer to as AIDS [2.4] and the 
important point to see down here is the scale [1.9] you can see that the 
primary infection [0.7] occurs over a matter of weeks [2.8] the latent period 
[1.8] can be years [0.8] there are certainly people around who have [0.7] been 
well [0.5] for more than a dozen years [0.7] and then for some reason that's 
not entirely clear [0.4] gone into full-blown AIDS [2.5] the point about this 
[1.3] is [0.2] once you go into AIDS you are going to die [1.2] okay [1.7] you 
may you may be it may be possible to hold you [0.9] through [0.2] using 
antivirals that i'll talk about in a minute [1.0] in [0.2] in some sort of 
semblance of reasonable health for a period of time [1.4] but for example [0.5] 
when [0.5] 
A-Z-T zidovudine the main [0.3] R-T antiviral inhibitor was u-, used 
extensively in the United States in monotherapy [0.9] it improved your life 
expectancy as an AIDS victim from ten months to twenty months [2.1] so it had 
an effect [0.5] one shouldn't underestimate its effect [0.7] but [0.8] it 
didn't mean that you were going to survive [0.9] for [0.2] a long period of 
time and have a natural lifespan [1.4] okay i want to talk [0.8] a little bit 
about [0.4] the division of these different [0.6] er stages of the disease [0.
8] by symptomology [1.6] and [0.3] this really [2.3] deals with the [0.3] the 
clinical pattern of disease [0.9] okay [1.3] and i want to [0.3] keep referring 
back to this as i talk about the clinical pattern of disease [0.4] okay [1.7] 
now of course once [0.6] people started to diagnose H-I-V it became important 
[0.5] to have available to clinicians [0.4] some sort of definition [0.9] of 
what stage of this process [0.4] a particular patient that might present to 
them [0.5] was at [0.7] okay [0.8] and [0.4] two systems grew up [0.7] quite 
quickly [0.6] one was proposed by the C-D-C 
the Centre for Disease Control remember the place in Atlanta i said that is the 
sort of [0.3] American equivalent of the P-H-L-S [1.1] okay [1.3] and the other 
grew up [1.2] through [0.5] a major [0.2] hospital in the United States in 
Washington called the Walter Reed Hospital now the Walter Reed Hospital has a 
very long history of dealing with tropical diseases [1.4] okay [0.9] and these 
two [0.8] er organizations proposed a staging [0.9] system [0.4] to allow 
clinicians to [1.0] define when a patient presented to them what stage of 
disease that patient was in [1.5] the C-D-C system [2.1] defined people [0.7] 
as being in stage one [0.6] through [0.2] to four [1.3] and this was romanic 
one through to romanic four [4.2] the Walter Reed system [0.7] allowed you to 
divide people [0.3] in a stages zero to six [6.9] now it's important of course 
[0.4] when a new disease comes along [0.2] to have some sort of system of 
clinically defining the disease [0.5] why is that [belch] important excuse me 
[0.7] well it allows you to do surveillance studies that's the 
first thing it allows you to do it allows you to actually survey the disease [0.
8] particularly when you've got a disease that you know is going to [0.6] is 
going to develop over a long period of time [0.9] it allows you to survey its 
development [0.5] it allows you to do epidemiological studies what is the 
incidence of infection [1.5] and of course it will if you've got some sort of 
therapeutic intervention metha-, measur-, measure method [0.4] it will allow 
you to measure how how good that therapeutic intervention is [2.0] now these 
two schemes the C-D-C scheme [1.6] and the Walter Reed scheme [1.6] when they 
were first proposed [1.0] in the middle nineteen-eighties they were both used 
[3.1] they each have advantages and disadvantages [1.8] the C-D-C system [0.9] 
is largely based on clinical observation of the patient [3.0] so basic simple 
clinical observation of the patient [1.1] weight [1.1] er symptomology [1.1] 
okay [0.5] very little lab very little involvement of lab indicators 
or immune system indicators [1.2] by contrast the Walter Reed system [0.7] is 
ba-, is mainly based [0.4] on laboratory diagnostic assays [6.3] now on a 
global scale [0.6] the C-D-C system [0.7] took over relatively quickly [0.9] 
from the Walter Reed system and the main reason for that [0.2] was because [0.
6] the disease grew rapidly [0.4] in countries that were not well set up [0.5] 
to do the laboratory diagnostic assays that could easily be done in the United 
States [1.5] and so the C-D-C system is the system that you will most often 
hear about today and is the system that's broadly used [0.4] to define what 
stage someone is in [3.7] so [0.3] in this system then stage one [4.0] is the 
acute [0.4] phase of infection [6.6] and this acute primary infection [0.6] 
period [1.3] is most usually asymptomatic [2.2] so the person is infected [1.6] 
but most commonly they have no idea that they are infected they they exhibit no 
symptomology [1.0] if they do exhibtib-, er exhibit symptomology [0.7] it's 
basically a flu-like syndrome [2.1] they might get some fever they might get a 
bit of nausea they might 
be a little bit lethargic perhaps a little bit of diarrhoea [0.4] a sore throat 
et cetera [0.8] but nothing that's very specific i mean there are lots of 
things that would cause that [0.8] you know a bad night on the bevvy would 
cause most of those symptoms [0.3] okay so [0.6] in the acute phase there 
really er ev-, if there's any symptomology at all [0.8] it's nothing that you 
can kind of put your finger on and say ah you know i know this person is 
probably infected with H-I-V because they've got this symptom [1.1] okay [3.1] 
the only lab indicators you get in this acute phase [0.3] are a transient 
leukopenia and lympha-, [0.2] lymphopenia [1.2] so a transient drop leukope-, 
penia [0.5] means drop basically [1.0] so a transient drop in leukocyte numbers 
and lymphocyte numbers [5.7] you might get an inversion [0.9] of the ratio of C-
D-four to C-D-eight cells in the bloodstream [2.7] but it's important to 
realize that at this stage in the fect-, infection that is not due to a drop in 
C-D-four cells it's due actually to an increase in C-D-eight cells [6.9] okay 
[1.7] you may 
see some atypical lymphocytes in blood smears but you may not [1.7] okay [0.3] 
so the picture i'm painting then of stage one [0.6] is somebody who's infected 
[2.1] probably has no idea they're infected has no symptomology [1.7] okay [1.
4] and will take [0.5] somewhere between [1.6] a few days [1.2] and as long as 
three months [1.4] to seroconvert [2.9] now you remember i said to you that 
when people are diagnosed as being H-I-V positive [0.8] the main form of 
diagnosis is seroconversion the production of antibodies against one of the 
structural proteins of the virus [2.1] so in the period up to three months [0.
8] after the person has been infected [1.5] there are probably no indicators 
either to that individual [1.7] through symptomology or indeed [0.5] to the 
health authorities [0.6] through some sort of diagnostic assay [0.2] that 
they've actually been infected [2.8] unless [0.6] the diagnosis is looking 
specifically for virus [1.8] the reason for that is as you can see [0.5] from 
the virus count here in the blue line [0.7] it is 
during this period [1.4] that virus titres in the bloodstream [0.7] are 
probably at their highest level until you get right to the terminal stages of 
disease [3.3] okay [1.2] so what does that tell you about this individual [0.8] 
in terms of [0.4] societal risk [2.5] 
sm0613: they're at their most infectious [0.3] 
nm0607: yeah and [0.8] 
sm0613: they don't know [0.4] 
nm0607: and what does that mean for society [0.5] 
sm0613: that [0.2] you're going to get a lot of spread [0.4] 
nm0607: exactly [1.3] it's people in this phase here [1.0] that as far as 
society is concerned [0.3] are the greatest danger to society [1.5] okay [0.9] 
because these people [0.9] don't know they're ill [1.3] don't know that they've 
become infected [0.9] are probably con-, going to continue in the lifestyle 
that they had [0.3] prior to getting infected [1.0] and so are probably going 
to continue to do [0.8] the very acts that resulted in 
them being infected and so are very much more likely [0.5] to infect other 
people and they're particularly likely to infect other people [0.4] because 
they have the highest level of virus [0.3] in their bloodstream so they have 
the greatest chance at this point [0.4] of passing on the infection [2.5] okay 
[5.9] as far as seroconversion is concerned okay [0.8] what is the first 
antibody you would expect to detect after a seroconversion [3.3] what are the 
main classes of antibody that you get in the bloodstream [2.5] there are three 
[2.9] huh [0.9] 
sf0614: I-G-G [0.5] 
nm0607: I-G-G's one [0.9] 
sm0615: I-G-M [0.3] 
nm0607: I-G-M's two [2.6] what's the third one [1.6] 
sm0616: I-G-N [0.5] 
nm0607: I-G 
sm0616: N 
nm0607: okay so which out of these three then [0.5] are you most likely to 
detect [0.7] first [1.8] after 
infection [0.5] 
sf0617: I-G-M 
sm0618: I-G-M [0.9] 
nm0607: are we sure about that [0.3] 
sm0618: [0.9] 
nm0607: yeah [0.5] 
sf0617: yeah [1.5] 
nm0607: well you're right what happens with I-G-M remember [0.5] is I-G-M is 
the antibody that's initially produced to an infection [0.5] it rises very 
rapidly [1.0] you can often detect an I-G-M response [0.3] in [0.3] a few days 
[0.7] in the case of H-I-V you may un-, [0.2] you may intec-, detect an I-G-M 
response in as little as five days post-infection [0.6] if you go looking for 
it [2.2] it peaks [0.6] at about twenty-four days [0.3] plus or minus seventeen 
[2.4] and it disappears it goes back down again remember I-G-M drops away again 
[0.8] and it disappears by day eighty-one [0.2] plus or minus twenty-seven days 
[4.0] so [0.6] if you go looking for I-G-M [0.3] to H-I-V [0.3] four months 
after infection you won't find it right [0.5] it's gone [2.1] I-G-G [1.7] can 
be [0.3] most early detected about eleven days [0.6] so [0.4] almost two weeks 
after initial infection [1.8] it doesn't peak [0.7] to a hundred-and-thirty-
three days plus or minus sixty-three days [7.9] so it's about three months [0.
7] after the person's infected [0.9] that I-G-G the stable 
long term antibody response that you will see in a human [1.4] peaks [1.3] okay 
[1.1] so that's all i'm going to going to stay about stage one [1.5] other than 
to say that [1.7] you must [0.3] notice [0.3] that what happens at the end of 
stage one as far as the virus titre is concerned [1.0] is that it drops [2.1] 
and you should remember that this graph over here [0.6] the virus titre is a 
log scale [1.9] so it's a it's [0.2] it's a little bit misleading to look at 
this graph and think oh well it doesn't actually go down very much [1.9] it 
drops about a hundredfold [2.1] to a thousandfold in terms of titre [0.9] that 
means that at the end of the acute phase [0.6] the person is going to be [0.2] 
a hundred to a thousand times less likely [0.7] to transmit the virus [0.7] 
than they are at the peak of the acute phase [2.2] this drop in virus [0.5] is 
as a response of the immu-, is is [0.8] comes from the immune response [0.8] 
that has been activated against the virus both a [0.3] humoral and cell-
mediated immune response [0.7] that is able to some degree to get the virus 
under 
control and eliminate it [1.5] but the crucial thing is it's to some degree [1.
7] like all persistent virus infections [0.4] the immune response in this case 
is not able to completely eliminate the virus [2.9] it gets it under control 
but it doesn't eliminate it [3.1] okay [0.4] so that takes us from stage one 
then [0.5] into stage two [2.8] now stage two of infection [0.7] is this period 
of what is usually referred to as clinical latency [5.8] now what you can see 
in clinical latency [1.8] is that first of all it can be very long [2.1] okay 
[1.2] it can also be relatively short [3.0] so of course when it was realized 
[1.2] that this period [1.1] was of variable [1.2] and somewhat indeterminate 
length [1.1] the first thing that people started looking for [0.6] were 
prognostic indicators [2.0] was there any indicator during this period [0.7] 
that would tell you how long it's going to last [2.8] and why would that be 
important well it would be important because [0.4] during this period [0.5] the 
people are well [2.0] they're not a-, they're not exhibiting any disease 
symptoms [0.3] they are 
well [1.2] okay [0.8] if you acquire the infection [0.6] at twenty years of age 
[1.0] and somebody sells you well according to your prognostic indicator [0.4] 
you're not likely to go out of this [0.2] period of clinical latency for fifty 
years [0.9] you're not going to worry about it too much right 'cause you're 
probably going to be killed by something else before you get to seventy [0.6] 
yeah [0.7] but if somebody says to you [0.4] according to your prostic-, 
prognostic indicators your clinical peri-, period of clinical latency is going 
to be two years [1.2] then you're going to start [0.2] you know living life and 
spending money pretty quick because in five years you're going to be dead [0.4] 
probably in four years you're going to be dead [0.6] okay [1.5] i i've i've 
laid it out in a in a dramatic fashion [0.3] so that you realize that there was 
an enormous amount of pressure in the mid-eighties [0.4] to try and come up 
with prognostic indicators because that's what people were worried about [1.0] 
i am sick doctor you know [0.3] i am 
infected with something doctor when am i going to get sick is the question that 
was being asked [0.7] okay [1.9] now what you can see that is going on during 
this period [1.1] is [0.6] there is a very slow but almost imperceptible rise 
[0.6] in the viral load [2.7] the level of virus in the bloodstream [1.4] okay 
[3.4] but at the same time there is a clear drop going on [1.1] in the level of 
C-D-four-positive lymphocytes [1.3] in the bloodstream [4.8] and in fact the [0.
4] the first sort of indicator [1.3] that people started to use [4.3] were [2.
9] this level of C-D-four count [0.9] i should just back up a second and just 
[0.3] tell you a little bit about in the in the epidemic in the United States 
which was the e-, area where the long ter-, first long term studies were done 
[1.6] they started by looking at [0.6] about seven-thousand homosexuals [0.6] 
over a ten year period [0.9] yeah [0.4] so the first ten years from the [0.7] 
from the [0.3] early nineteen-eighties through to the early nineteen-nineties 
[0.6] and in that ten year period [2.3] thirty-six per cent of them [0.3] 
thirty-six per cent of 
the people had developed AIDS within that ten year period [4.2] forty-four per 
cent of them [1.0] were showing symptoms of going into AIDS by the end of the 
ten year period [0.7] so these were people who were recruited early they were 
already infected early in the [1.1] epidemic [0.5] and followed over ten years 
[1.4] so by the end of that ten years [0.5] somewhere close to eighty per cent 
of them [0.9] were already showing symptoms of going into disease [2.7] but 
twenty per cent of them one in five [0.4] were completely asymptomatic at the 
end of a ten year period [1.0] and this is in the period where there was really 
virtually no [1.1] er antiviral immuno-, er antiviral therapy going on [2.0] 
okay [3.2] now [0.3] prognostic indicator [1.3] C-D-four counts [3.4] people in 
the early phase [1.5] of [0.7] the next stage stage three [2.0] now stage three 
if you look at the recent literature [0.4] stage three has kind of fallen into 
disrepute [1.2] it used to be a period where [0.5] people were said to have 
what's called either ARC [0.5] AIDS Related Complex [1.9] or P-G-L Progressive 
Generalized Lymphoadenopathy [3.2] and in a sense what it was measuring was 
people starting to [0.4] tip over into AIDS [5.6] and [0.9] one study for 
example [0.6] looking at homosexual men who were already in P-G-L [0.5] so were 
already at the end of stage two beginning of stage three [1.3] followed them 
over twenty months so only two-and-a-half years [1.2] and if their C-D-four 
count at the beginning of that twenty months was less than two-hundred [1.1] 
per ml [1.9] by the end of the twenty month period sixty per cent of them had 
progressed to AIDS [3.7] by contrast [0.8] if their [1.5] C-D-four count was 
greater than three-hundred-and-fifty [1.8] per ml [2.0] only ten per cent of 
them [0.7] were in full-blown AIDS [2.3] 
sm0619: sorry what was the percentage of the first one 
nm0607: sixty [0.2] sixty per cent of the people after twenty months [0.4] were 
in full-blown AIDS if their C-D-four count at the beginning was this level [1.
8] and [1.0] only ten per cent if it was this level [1.9] 
it's important to point out to you that in these early studies there was a lot 
of controversy [0.6] because people were not used to measuring [0.5] C-D-four 
counts in humans [0.7] and it took a little while to realize that actually your 
C-D [0.2] your C-D-four count [0.5] actually has a daily rhythm [0.9] it goes 
up and down each day [0.7] so of course if you were mea-, er d-, the count you 
were getting would depend on when in the day you measured it so there was quite 
a lot of confusion in the literature [0.5] 'cause people were quoting different 
figures because they were measuring the counts at different times of the day [1.
0] okay [1.1] once that was figured out once the diurnal rhythm [0.5] of C-D-
four counts were was figured out of course they started measuring at the same 
time each day [0.3] so they could get comparative data [4.4] so what about [1.
1] so that's stages [0.2] one two and three and as i've said to you [0.6] three 
[0.5] has largely fallen into disrepute [2.6] that takes us on to stage four [2.
1] stage four [1.4] is [0.4] what is now 
commonly referred to [1.2] as full-blown AIDS [6.5] how do you define the entry 
into stage four [0.8] well three main criteria [3.1] have been used [1.3] the 
first is [1.1] fever for [0.3] persisting for more than a month [6.8] 
involuntary weight loss [0.2] at greater than ten per cent of baseline [2.3] so 
this is not somebody going on a diet and managing to lose one stone in ten [0.
7] because they're on a diet this is somebody losing [0.2] one stone in ten 
without trying [2.2] okay [1.5] and diarrhoea for more than a month [4.1] and 
you've got to have [1.6] all of these symptoms [1.6] without any other [0.4] 
concurrent reason other than the fact that you're infected with H-I-V [3.8] so 
it's not just that you've [0.3] kept on going to the same Indian restaurant and 
eaten you know a pretty [0.3] nasty meal that's been giving you a [0.2] you 
know [0.8] bad diarrhoea for a month and you've not learned you know you'd 
better change your restaurant i mean it's it's [0.4] you haven't got any other 
reason why this is happening to you other than that you're infected with H-I-V 
[4.0] okay let's ask 
something about then the viral dynamics that are going on during these 
different phases [4.3] if we look at the virus what's going on in in er [0.3] 
the primary infection phase [3.4] is the virus is growing flat out [0.2] 
there's no immune response there of a-, of any s-, consequence [0.5] the virus 
is just growing in a completely unrestricted fashion [0.5] it has a doubling 
time of about ten hours [1.4] peak viraemia will occur at about three weeks [1.
4] and each infected cell is going to [0.9] seed roughly twenty [1.8] new cells 
[0.8] to become infected [2.3] but the last sentence is quite important [0.4] 
the virus load starts to drop rapidly [0.5] as the immune response is activated 
[0.8] so you should not [0.4] be under the impression that [0.5] the immune 
response that we amount to H-I-V is completely useless [0.2] it's not [1.2] it 
does a pretty good job [0.5] at controlling the initial acute infection [1.6] 
it reduces the viral load between a hundred and a thousandfold [1.2] okay [0.8] 
the only problem is it doesn't completely eliminate the virus [2.1] during the 
asymptomatic phase [3.3] you have something like ten-to-the-ten virus particles 
being made every day [3.2] and you have something like ten-to-the-nine [0.4] C-
D-four-positive lymphocytes [0.5] being made and eliminated every day [1.5] so 
you can see that virus replication [1.2] and elimination because remember if a 
C-D-four is cell is eliminated you're going to eliminate the virus that's 
replicating in that cell [1.3] you have a rough balance here [0.9] and this is 
sometimes referred to as the steady state [4.3] what that means is that [2.0] 
the whole infection [0.7] is actually being sustained by only about ten-to-the-
six to ten-to-the-seven ce-, T-cells in the body [2.3] these are productively 
infected activated T-cells [4.2] the si-, the size of the latent H-I-V 
reservoir [2.1] okay [1.1] is mostly in resting T-cells [0.8] and it's about 
similar in size [8.8] it's important to point out to you [0.2] just to remind 
you [0.9] that when somebody goes into stage four [1.4] the immune system loses 
control of the virus replication again [0.8] and virus replication takes off [2.
8] and so 
in [0.4] stage four [0.5] there's again a s-, [0.2] the previo-, one of the 
previous slides showed you [0.4] a viraemia a strong viraemia [1.8] okay [1.4] 
a lot of virus in the bloodstream [1.4] a high chance [1.0] of [0.2] potential 
virus spread [0.9] if [1.6] the individual was indulging in activities that 
would be likely to spread the virus [2.0] but remember there's a big contrast 
[0.7] between somebody who's in the acute phase [0.5] and somebody who's in the 
symptomatic end phase [1.2] this is essentially a sexually transmitted disease 
[0.7] if you don't know you're infected [0.5] as will be the case in the acute 
phase [0.6] you will be undertaking your normal sexual activity be it [0.3] you 
know once a day once a week once a month once a year [0.6] okay [1.0] if you're 
in late stage AIDS [1.1] you're not interested in sex i mean sex is the last 
thing you've got on your mind you 
know [0.4] you've got on your mind coping with the symptomology [0.4] that 
you're suffering from [0.5] rapid weight loss [0.6] you've got diarrhoea you've 
got fever [0.4] as i explained to you on the first lecture you might have an 
opportusisti-, [0.2] opportunistic infection like athlete's foot up to the knee 
[0.4] it's sym-, in symptom terms [0.3] it's a very unpleasant er end stage 
infection [0.9] and so actually people in full-blown AIDS [0.3] are not a major 
risk [0.7] to society [1.3] they might be a risk to the people who are actually 
treating them [0.6] and the people who are treating them have to be careful [0.
4] that they don't come into contact with blood [0.9] remember these people may 
be bleeding from a number of orifices [1.0] but they they don't pose a large 
risk to society [1.5] okay my time's up i'll stop there and continue next [0.8] 
Tuesday [0.2] 
sf0620: mm-hmm [0.2] 
nm0607: tuesd-, Tuesday i think it is [2.5] okay