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| TRANSCRIPT OF DR NITIN SAKSENA’S VISIT ON TUESDAY THE 27TH MAY |
| Dr. Kathy Takayama |
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| Head of the Retroviral Genetics Division at the Westmead Millennium Institute (Sydney), Dr. Nitin Saksena visited VSG for a live chat on Tuesday the 27th May from 13:00 - 14:00 (Omnium Time). 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. |
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kathy admin: Mihiri, would you like to repeat your question to start off our discussion with Nitin?
mihiri: Hi Nitin! I'm coming from your paper about AIDS Dimentia Complex .is there anything special to say about the origins of neurotropic HIV strains?
nitin: Mihiri:
I am on line now. Yes, the main message in our virology paper is that the HIV-1 strains differ in their ability to grow on different cell types. Interestingly, the strains from non-dementia patients grow on T cells, monocytes and macrophages, but the strains from patients with AIDS dementia complex grow exclusively on macrophages. Since the cell types in brain largely comprise of cells of macrophage lineage, there is likelihood or a suggestion that neurotropic variants may exist. This is clear from our in vitro studies of viral strains derived from diverse regions of the brain
mihiri: Are there any knwn cases where people infected with the SAME initial strain differing in there susceptibility to ADC?
nallapeta: sir as in one of ur review i read about gene therapy for HIV treatment could u please tell me how could we prevent the replication of HIV and could stud further in laboratory conditions.RT-PCR ?
nitin: Mihiri:
Not to my knowledge. There are cases where people have been infected with similar HIV strains especially in epidemiologically-linked cohorts. None of these linked cohorts have shown any evidence for development of dementia. It will be a nice thing to prove. Good question!!!
nitin: Naplettea:
I can't get your question right, but gene therapy for HIV works by ribozymes which are basically gene scissors. Gene therapy for HIV has failed so I do not know what other approaches are being tried. To stop the replication of HIV, drugs are the best but both protease and RT inhibitors do not stop viral replication but slows down. Targeting multiple regions of HIV may lead to complete replication inhibition. RT-PCR? Well this is technique which can be used for verification of viral RNA being made and also in the detection and diagnosis. Viral RNA detection will be a measure of viral replication and this can be quantified, for example by targeting p24 gene and quantifying the amplified product. I hope my answer is satisfactory.
anne: Dr. Saksena
In several sources I have read that during initial stages of infections there is a higher incidence of M-tropic strains, followed by, what seems to be the more virulent, T-tropic strains. What leads to this change over? Does this change result from selective pressures presented by the host or is this something „pre-programmed‰ in HIV?
nitin: Amy,
The ramifications of synergism are in dual infection. We are the first to demonstrate this and now people think that the regions which have multiple subtypes cocirculating have higher propensity of recombination. Some subtypes of HIV are more promiscuous than others, thus the frequency of recombination between HIV subtypes may vary. The promiscuity etween certain subtypes may define, to some extent, the synergism. Please note that synergism can be additive or may lead to suppression of replicative or functional capacity of virus. Not always, recombination can be beneficial. There are deleterious effects on HIV. But in most cases, synergism and recombination are strategies for increasing viral fitness.
amy: That makes better sense now. Thank you.
kathy admin: Are there any other questions, or discussion topics, everyone?
nitin: Anne:
Although plethora of literature is available, the conversion of M-tropic to T tropic or vice versa still remains enigmatic. In my opinion, the viral strains during infection is of one type. The virus in response to various host seletion pressure tries to diversify. This diversification is a consequence of various cell types, tissue type local area immunological make up. Thus, to hide in a sanctuary site, HIV is under constant evolution and adaptation. This adaptation may provide HIV a long term survival. The emergence of T tropic and M tropic could be mostly governed by surface receptor dynamics on a variety of cell types. The quantity of these receptors on the cell surface may define partially the type of virus (CCR5 M- tropic and CXCR4-T tropic) present or dominating the blood stream at a given time. Please note that although T tropic are syntium inducing, >60% of HIV infected patients die of CCR5 using HIV. Not clear why??? Hope you are satisfied
nallapeta: Dr.Saxena
thanks for ur enlightening answer to my previous question .please do tell us SARS virus and HIV holds any significant similarities during their course of infection.
alissa: What are the consequences of HIV's high mutation rate when you use RNAi to inhibit HIV transcription (Microbiol. Immunol., 2002)? If the siRNA's do not match their target exactly, doesn't RNAi undergo a different mechanism than if they match exactly?
anne: Thank you! That is more clear to me now.
nitin: Nallapeta:
Sorry for spelling error in writing your name. I can't see any similarities between two viruses. One is a coronavirus and the other is a retrovirus. But both are RNA viruses. Coronaviruses are some of the common flu viruses
mary: Do you expect that gene silencing by using dsDNA/plasmids from nef deletions, etc. may be widely used in treatment?
nitin: Alissa:
RNA interference is an excellent technique. HIV variation has nothing to interfere with as this is an approach for post-transcriptional gene silencing. The RNAi are sequence specific in which mRNAs are degraded in a specific manner. If RNAi do not match their target, then binding may not occur. Please note that sequence specificity can discriminate between mismatched target RNA sequences and may represent an avenue for gene therapy.
nitin: Mary: Yes, in some cases, but the whole area of gene silencing is wide open for further research. One thing I can say that G-A hypermutation, which occurs in HIV die to poor fidelity of RT, is a prime cause of gene silencing. But the downside is that such a phenomenon is reversible in some cases. G-A hypermutation lead to defective genomes and this occurs mostly in latent integrated provirus derived from peripheral blood cells.
yue: nitin, how would dsRNA move between cells when RNAi is used in a therapeutic setting?
nitin: Yue: I did not say ds RNA will move between cells. It was about gene silencing which is totally different issue. Hope I have answered correctly.
yue: ah, I had assumed that if this mechanism were to be for therapy then it must have some way of spreading from cell to cell. Guess I'm wrong then
nitin: Yue, sorry to confuse you but gene sillencing I am referring to is through natural defects in gens (mutations, deletions and insertions) because of which the capacity of HIV to replicate is impaired. Other way to silence genes is through the use of ribozymes or antisense scissors. RNAi is another way of doing this, but RNAi may prove to be extremely difficult in clinical setting. The technology is attractive on paper but impossible to do in humans. That is what most researchers think at the moment.
kathy admin: I think we'll wrap up the session now, and thank Dr. Saksena for his valuable insights and generous time.
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