Omnium V3

TRANSCRIPT OF PROFESSOR JOHN KALDOR’S VISIT ON SATURDAY THE 24TH MAY
Dr. Kathy Takayama		Download PDF
The following document is a transcript of the live chat with Special Guest Tutor, internationally renowned epidemiologist Professor John Kaldor. Course participants can read the transcript below or download it as a PDF; however visitors to VSG do not have access to documents in this area.

mary: Dr. Kaldor has a paper on long-term resistance in 3 persons who have a virus witha nef gene deletion of 29 bp. That would be interesting to hear more about. kenneth: yeah, we also learnt about the nef gene in our course kathy: welcome back, john; we've gotten the ball rolling whilst you were having a read of the topics... john: Hi this is John sorry I had difficulty logging on samiran: I found an interesting statistic - apparently 1% of the caucasian population are homozygotes for mutant CCR5 receptors, making them resistant to HIV infection john: Kathy please tell me where we are up to in the discussion. anne: Samiran--actually I read an article today that suggested that the CCR5 mutation might have been selected for during the plague in the 1300's... Welcome Dr. Kalder and thank you so much for offering us some of your time!! amy: In those who are immune to HIV because they are homozygous for a mutation that affects the CCR5 receptor, I'm wondering what other effects on their overall health that mutation may have, if any. kathy: John, would you be happy for the students to start asking you questions, or would you have some comments to start off with? john: Lets go with questions kathy: Sam, would you like to start? samiran: Ok then - well the topic I wanted to discuss was HIV resistance - are there any on going studies to look at resistant indiviuals and explore the selection pressures that confer resistance? (thanks amy and anne) john: First let's clarify what we mean by resistance: we can distinguish resistance to getting infected in the first place, and then resistance to progression in people who are infected. From an epidemiological point of view, these are very different studies john: If we want to look at resistance to infection, this is where the African sex worker studies come in: Looking at the people who were exposed time after time, and did not become infected, and comparing to those who did become infected samiran: right, well I think I was talking mainly about people with CCR5 mutations ... john: CCR5 has been investigated from 2 points of view, first along the lines I just mentioned, and second, in studies we have done comparing people who are infected and progress slowly or not at all, to people who progress "normally". Of course these studies are now much harder to do, because people are getting effective treatment! In any case, CCR5 has been found to be associated with both forms of "resistance" in various studies anne: From a treatment standpoint, what can we learn about the CCR5 mutations that will promote our abilities to treat/prevent HIV infection? john: Epidemiological studies often throw up challenges that have to be picked up at a molecular level. For example, we observed over a decade ago that a group of blood transfusion recipients from a common donor in Sydney were all progressing very slowly, as was the donor, but no one knew why. Investigation of the virus found the nef deletion in common. We then established a large cohort of some 90 slow progressors from the community, and found that only 3 had the nef deletion, but it was not the same as the one in the blood recipients. So nef if important for progression. Sorry Anne I was writing this as your question came on...But it comes down to the same thing. If we know which part of the virus (nef) or which part of the host (CCR5 receptor) is critical to infection,, drug design or vaccines can be directed to these targets john: All of which sounds too easy but it is a big leap from observing a molecular association to translating into a drug that interacts appropriately with the relevant molecule amy: Are there any known adverse effects of CCR5 mutations on the overall health of the individual? mary: are any studies being done that may try to match the nef deletion with the CCR%? --or is the nef deletion too infrequent in the population? Does anything else characterize the nef delete people? john: I am not aware of any , but I would also be surprised if a comprehensive investigation has been done. HLA markers have been checked against almost every known disease but it is still early days for CCR. samiran: there are HLA associations with slower progression of HIV infection though john: (To mary) Looking at viral effects or host effects on their own is already a big epidemiological challenge (as evidenced by the small number of nef deletions in our cohort of 90). Interaction effects, unless very dramatic, are correspondingly harder to investigate. In any case the interaction would more likely be with a viral envelope protein, I guess (but dont forget I am but an epidemiologist here..!) john: (To Sam) indeed there are: HLA alleles have strong associations with both slow and fast progression. Some very clever work is being done at a few specialised labs to explain exactly how this works kathy: Capella group, you've been silent thus far; does your rep have a question to ask? kenneth: can i ask a question on SIV? john: Go, but dont forget your talking to a human epidemiologist .. kenneth: Seems like it can cause an immunodeficiency syndrome in rhesus macaque, but not in its natural host, which is the african green monkey. Has there been any research on this to see why? kenneth: There may be some similar mechanisms? kenneth: I mean similar with respect to HIV john: Kenneth there has been lots of SIV research looking at pathogenesis mechanisms but I am not the person to elaborate, sorry anne: Dr. Kalder just curious if there is a significant difference in the incidence of HIV and/or AIDS in aboriginal populations as compared to non-aboriginal populations. If there are differences, what might those be? Are they more attributable to cultural norms or to the actual biology of HIV in those populations, or perhaps a combination of the two. kenneth: That's absolutely ok. I was wondering whether it's appropriate too when I asked that question john: Anne: First, it is important to remember how hard it is to compare HIV incidence across populations: We are measuring the rate of acquisition of infection, and if we want to isolate an element like ethnicity, we have to assume everything else can be controlled for, including sexual behaviour and exposure levels! mary: Could you talk a bit about viral evolution? Do you think that this is being driven mainly by strain differences, or also by the host resistance/differences? john: Can I just complete my response to Anne: Having made that reservation, there have been considerable attempts from a public health perspective to see whether Aboriginal people in Australia (in Indigenous groups in other countries eg Canada) have different AIDS and HIV rates from non-Indigenous people. In Australia, rates have been similar overall, but with a higher proportion of heterosexual cases reported in Aboriginal people carlos: In the matter of epididemiology, once that all the mutations that confers to the humans selective advantage to a desease, and by that, today their part of the human gene patrimony, but in diferent locations in the globe, is the progression of the virus similar in different communitys that has an history of plages and infections completly different, and in the same group or population if its diferent in diferent ages and sexs? john: Anne, let me know in which direction you would like me to elaborate the Aboriginal answer. Mary, viral evolutions is being driven to some extent in the richer countries by treatment, but generally it is the host immune system and its variations that are probably the driving factor. As I said before, some fascinating work has been done on how the virus mutates to escape some specific T-cell responses anne: Thanks Dr. Kalder carlos: sorry.... response to the other questions first anne: I was wondering if there has been much in the way of behavioral surveys of Aboriginals to suggest this difference in heterosexuals? john: Carlos that is a huge question that can only be answered by mathematical modelling, not the observation science of epidemiology (unless we get sharper tools and huge population wide databases that run for decades!) anne: I ask that question, because I encountered your center's 2001 Annual Review today on the net, and there was mention of HIV increasing in homosexual male populations due, in part, to the treatment improvements. I anne: Meaning that as treatments improve, HIV is considered less of threat. john: Anne, research on sexual behaviour is also a great challenge: it involves "culturally appropriate" interactions whether whether Aboriginal people living in a remote setting or gay men living in central Sydney. Unsurprisingly, our experience and ability in this area has been greater with the gay men living in central Sydney. In this group there is convincing evidence of an increase in sexual risk behaviour (repeat annual surveys) but not yet of an HIV incidence increase. It is thought that perhaps HIV is seen a less of a threat than it was (improved treatment etc) john: Anne you wrote that just as I did the same! anne: Thanks for the elaboration. I must compliment you're handling of our "firing away" questions. I was very curious on how culture plays a role in disease progression in general...especially one that is of such a sensitive nature. Thanks again!! kathy: Yes, John, thank you for beig so gracious at 8 am on a Sat morning; does anyone else have further comments on the current thread, or any new questions? john: Thanks Anne, first time Ive done this and its getting to be fun just as the hour expires...Getting back to my response on Aboriginal communities: It is also important not to oversimplify: There are several hundred thousand people in Australia who would identify themselves as Aboriginal, and the cultural and behavioural variation is just as wide if not wider than the population of European origin john: No problems, I just got off the overnight plane from Perth so I am very fresh. samiran: can in vitro studies help in looking at racial differences in HIV infectivity rates? samiran: for example looking at infectivity in cell lines from different races in vitro? john: People who do in vitro studies might claim so...but the epidemiologist would not be convinced unless a difference could be observed in human populations. Which leads to a bit of a paradox, because as I said before such studies are really hard! amy: Quick question: Different sources have mentioned that the percentage of people infected with HIV increases with greater age. Is this trend simply due to the fact that the longer someone lives, the more chances of exposure to the vius, or does it have more to do with age-related deterioration of the immune response? john: Sam the other thing is dont forget how hard it is to define race, especially biolgically! john: Amy I dont know how good the evidence is that people get infected at a higher rate if they are older, but there is very strong and clear evidence that people who get infected when older PROGRESS much faster: Basically theire immune systems get overwhelmed more quickly kathy: John, as we have 5 minutes remaining, and we are appreciative of the fact that you've just arrived back in Sydney, would you like to start wrapping up the session, or is there any possibility of continuing for a bit longer (10 min or so?) john: Kathy I am happy to chat on for another 10 if people have further topics. I have tried to "wrap" each issue as we went along amy: That makes sense. Thanks for your time Dr. Kaldor! kathy: Thanks, John, that's very kind of you... okay, everyone, last chance to fire away... john: Of course I am happy to elaborate on either of our existing topics (which had an interesting convergence...) samiran: babies as well as older people of course john: If you mean that babies progress more quickly, that is a difficult question, because the route of infection is also different samiran: so the route of infection affects disease evolution? john: Studies in adults suggest not (sexual transmission versus blood contact does not affect progression rates), but the mother to child mechanism is very different, and it is difficult to compare progression in infants with that in adults. john: But it is a good question, that I will look into! anne: What is the typical pathway of infection from mother to child? john: Combination of transplacental, intrapartum and breastfeeding. Avoidance of breastfeeding and caearean delivery reduces transmission rates by over half. But of course the best way to prevent mother to child tranmission is by giving antiretroviral drugs in late pregnancy and to the newborn. Rates as low as 1-2%, compared to 15-25% (others may quibble with the figures but thats the ballpark mary: I am curious about enrolling infants and small children for that matter in Phase I clinical trials since they have no power of consent. Are they always seen as having no hope without treatment? john: There is a well developed framework for paediatric clinical research, and of course parental informed consent is essential. HIV is generally a fatal disease in both children and adults without treatment kenneth: The risk of infecting the sexual partner seems to depend on the sex of the carrier - as relatively more women get infected, what impact has it got at the population level besides having more infected infants? anne: This is sort of a tangent to the current topic: Are there similar rates of infection between HIV and other viruses that have a similar entry into the host? For example, drug users that inject; is the rate of HIV & Hep C similar? kenneth: I guess for IV drug users, the risk of acquiring infection is greater for Hep B/C john: Kenneth: The sex differential is not as great as was originally thought. Its the pattern of sexual networks that is perhaps more important in looking at population impacts. Hepatitis C is about ten times more infectious per blood exposure than HIV (data from health care workers having needle sticks) Hey everyone I guess I have to think about signing off, its been great fun kathy: Everyone, I think we may allow John to get back to his Saturday morning routine at this point... John, thank you ever so much for your generous time; it's been a fantastic, stimulating session. rick: John - thank you so much ... it was great discussion and opportunity for us all to meet online. In case you were wondering, according to the 'users in chat' indicator, you just spent the last hour chatting with colleagues in USA (4), Portugal (1), India (1), Taiwan (1), UK (2) and Australia (4). On behalf of us all, thank you again for your time this morning. We hope you may drop in and view the work occasionally over the next week or so, and of course you are welcome to join any of the remaining 4 'Special Guest' chat sessions this coming week. anne: Thank you!! mary: Thank you for joing us! amy: Thanks! samiran: yeah, thanks (to all of you)! alissa: Thank you to everyone for all of your insightful questions as well as answers rick: Thanks and well done of course to all who came here this mroning/day/evening. I hope you found it a valuable experience. All of your presence made the session a rich community - ;) kathy: everyone else, you are all welcome to continue chatting, as we rarely come together like this amy: I've got to go, but I've thoroughly enjoyed this stimulating "conversation" You guys are great :) mary: Perhaps we could consider scheduling a time for getting together like this even without a famous guest--kathy & Rick are famous enough!