Posted on May 18th, 2009 2 comments
I’m returning to this topic yet again because the French National Commission on HIV/AIDS has now published a statement on treatment as prevention.
This document discusses treatment as prevention at the individual and the population level together.
It places great importance on individual autonomy, which includes the fundamental right individuals have to make decisions on their own behalf. I have come to see the issues in a somewhat different way after reading the French document.
This document can be seen here:
It is worth mentioning again that the term “treatment as prevention” can be applied to two different situations.
At an individual level it refers to prevention of HIV transmission by sexual contact between two individuals. The Swiss statement concentrated on this aspect.
The term is also applied at a population level, where the goal of treatment as prevention is the control of the epidemic, even as suggested by some, a means to end it.
The principle underlying the proposals to use treatment as prevention in both of these situations is the same. It is the reduction in infectivity that results from the effect of antiretroviral therapy.
Unlike the Swiss recommendations that dealt only with transmission between two individuals, the French statement deals with both aspects.
Treatment as prevention is not the same when applied to individuals as opposed to populations. For example, transmission between some individuals may be interrupted by treatment without having an effect on the epidemic.
To have an impact on the epidemic additional factors that do not apply at an individual level have to be considered.
For example, the number of infected people who must be treated in relation to the total number of people who are infected must be taken into account, if treatment is to have an effect on the epidemic.
For treatment as prevention to have a greater effect on the epidemic, a larger proportion of infected people must be treated.
Canadian studies have suggested that the proportion of infected people who must be treated in order to reduce transmission would need to be increased from 50% to 75%. Transmission would be slowed but not reversed with treatment rates below 50%.
Thus the percentage of infected people who are treated is related to the extent of the impact treatment will have on the epidemic.
At an extreme, if the stated objective is to end the epidemic, as has been proposed by some, the proportion of infected people who would need to be treated would be so large that it would have to include those who do not need treatment for their own benefit.
[ Added October 3, 2010: It appears that there are experts who believe that everybody who is HIV infected, no matter at what stage of their disease would benefit from treatment. For them, there would be no ethical problem at al. These experts believe that treatment benefits every HIV infected individual. But the practice of medicine is not a faith-based enterprise, although I imagine individuals holding this belief probably pay lip service to evidence-based medicine. As opposed to a belief that everyone will benefit from treatment there is no evidence of the best quality that for people with greater than 350 CD4 lymphocytes, the benefits of antiviral drugs will outweigh their risks. Hopefully the START trial will provide the evidence needed to help HIV infected individuals and their health care providers make a decision as to when it's best to start treatment, that will be informed with hard evidence rather than belief based interpretations of data. The San Francisco Department of Public Health now recommends that all HIV infected individuals receive treatment. so they are able to avoid having to deal with the ethical problem that arises in recommending treatment to people not known to derive a net benefit from doing so as they too rely on their belief that all benefit. For individuals starting treatment at higher CD4 numbers the harms caused by the drugs may outweigh their benefits. Such individuals may choose to receive treatment in order to make them less infectious, but surely respect for their autonomy means that we must provide them with evidence of the best quality so that their choice is informed, and this also means that where the best evidence is not yet available on when it's best to start treatment we must tell them that this is the case. The concern expressed last May about the threat of coercion may have been justified in the light of the San Francisco Department of Public Health's recommendations. While it is perfectly legitimate and even expected of them, health care providers make recommendations based on their judgement, which in turn depends on the knowledge and experience they have. This is why we turn to experts. But their respect for individual autonomy really requires that where evidence of the best quality does not yet exist to justify their recommendation, and where there is no expert consensus on the issue, that these facts be told to the individual. A failure to do so in making the recommendation, can be seen as being coercive. Consenting to the recommendation will not be fully informed, and in this way the individual's autonomy is not respected.]
I have written about the multitude of problems arising from this situation in previous posts on this topic. Lurking behind such an extreme proposal is the threat of coercion, and the possibility of an infringement of individual rights. Very disappointingly this aspect has been barely acknowledged in English language discussions of treatment as prevention.
However if, as I believe, an additional goal of treating infected people is to add a powerful tool to prevent transmission, we are then not stating an objective that would require the participation of individuals who do not themselves need treatment.
Admittedly, treating only those who need to be treated may not have such a great impact as also treating additional infected people who do not need treatment. Therefore we must also intensify and improve our efforts at targeted prevention education with the promotion of condom use.
But we will avoid the insuperable problems and threats to personal autonomy associated with treating individuals who do not need to be treated for their own benefit.
The goal of treatment as prevention as applied to controlling the epidemic is perhaps better stated in a different way.
It might be preferable to simply state that the goal is to provide treatment to every individual who needs it. This goal must therefore be coupled with enhanced efforts to facilitate regular testing.
If we can achieve this it is likely that not only will the individual benefit, but there will be an impact on the extent of the epidemic.
There is evidence of a reduction in HIV transmission in areas where antiretroviral treatment has been introduced. .
When we emphasize that our efforts are to identify infected individuals and make treatment available to all who need it, we eliminate all the problems connected with treating infected individuals who do not need treatment.
One reason why the French document is so significant is that it stresses the importance of individual autonomy.
It emphasizes the need to respect individual rights and adds a caution to avoid the temptation to employ coercive measures in the name of the public good. Testing is the key to any success of this approach to prevention, but testing must be voluntary and informed. As of course is a decision to receive treatment.
Here is an excerpt from the French statement that shows the concern for individual autonomy and recognizes that there is a potential threat of the employment of coercive measures.
” if screening and massively treating infected persons enables to reduce the epidemic, it could be tempting to consider population compulsory systematic screening and to voice more or less insistent summons for the treatment of persons identified as HIV positive. Should public authorities use all convenient means to implement efficient policies that strengthen screening, they need to be careful not to yield to such fallacious reasoning. The issue of improving screening efficiency surely does not invalidate any of the reasons that have hitherto prevailed for rejecting compulsory screening. Keeping screening hinged on free and informed consent remains a matter of respecting the fundamental right of the person; it is at the same time an obligation even from the public health viewpoint,
Pursuing a probably completely unworkable attempt to end the epidemic by yearly testing and treating everyone infected as has been suggested by some, is wrong. The problems of feasibility, adherence, resistance, and the threats to individual autonomy cannot be overcome.
Instead we should:
Offer treatment to all who need it.
Facilitate testing, identifying and removing barriers that impede it.
Intensify and improve our efforts at targeted prevention education.
Promote condom use and make them available.
There is a final issue.
Who needs to be treated? Certainly everyone with a CD4 count below 200. Apart from this we do not know, so until we obtain some guidance from prospective randomized studies, it is prudent, in general, to not delay treatment to a CD4 count below 350 as is currently recommended.
Posted on May 17th, 2009 1 comment
17th May, 2009
[The relationship between herpes viruses and HIV disease is also discussed in a subsequent post:
The relationship between herpes simplex virus type 2 and HIV is in the news again. This time the press reports are that while acyclovir failed to suppress transmission of HIV it did cause a 17% reduction in HIV disease progression.
This reduction in disease progression was assessed by noting differences between the treated and placebo group in the numbers whose CD4 count dropped below 200, and who died. A reduction in HIV viral load was also observed in those treated with acyclovir.
The concept on which this study was based is absolutely solid.
Herpes simplex virus type 2 is the most frequent cause of genital ulcers, and the presence of genital ulcers is associated with enhanced transmission of HIV.
The failure of acyclovir to suppress HIV transmission is a disappointment, but the study should not be seen as a failure.
There is no doubt that anti herpes drugs can suppress the recurrent herpes ulceration that some individuals experience. This was observed in the study.
Herpes viruses – and not just herpes simplex virus, have an impact on the course of HIV infection. This study provides yet another demonstration that treating herpes virus infections has a beneficial effect on the course of HIV disease.
Valtrex, a drug related to acyclovir was reported to reduce HIV viral loads in infected women in 2007.
“Reduction of HIV-1 RNA Levels with Therapy to Suppress Herpes Simplex Virus” and it appeared in the New England Journal of medicine .
(NEJM 2007 356:790)
It is possible that the association of herpetic genital ulcers with HIV transmission is not as direct as generally assumed. The reasonable suppositions included the possibility that the ulcers provided a portal of entry for HIV in the uninfected partner, that there was an accumulation of CD4 cells in the ulcer that provided a good target for HIV, or even that in the infecting partner HIV was present in greater concentrations in the ulcer.
These assumptions about the reasons for increased HIV transmission may all be mistaken.
We do know with some confidence that transmission of HIV is related to viral load in the infecting partner. It may be that the assumptions outlined above derive from observing an increased frequency and duration of genital ulcers in individuals with higher viral loads who are therefore more infectious not by virtue of the ulcers.
An individual with higher HIV viral loads will more easily transmit the infection, and also experience more frequent recurrences herpetic ulcers. This of course only applies to HIV infected individuals.
As far as individuals who are not HIV infected are concerned, a direct causative association between herpetic ulcers and HIV infection may also be spurious.
Herpes simplex infections are ubiquitous but immunological mechanisms generally control the infection so that it remains latent and not manifested.
Sometimes individuals know what provokes a recurrence. Recurrences can be associated with febrile illnesses. It is completely reasonable to suggest that the effects of some intercurrent infections may cause both herpetic recurrences and increase susceptibility to HIV.
Whatever infection causes the fever may also increase susceptibility to HIV, possibly by an association of the infection with perturbed immunological function. Transient immunological perturbations can accompany many viral and tropical infections and so may not only disturb herpes simplex latency but also increase susceptibility to HIV.
For some reason, interest in the relation of HIV to herpes viruses seems to have been almost completely confined to herpes simplex virus type 2. At least regarding what is reported to the public.
However the herpes virus family includes other members which have long been thought by some – including myself, to play an important role in HIV disease.
Cytomegalovirus (CMV) and the Epstein Barr virus (EBV) are perhaps the two that are most important. These viruses are also sensitive to the anti herpes drugs used in these two trials.
Since infections with CMV and EBV are so widespread how can effects of acyclovir and Valtrex on reducing HIV viral loads be attributed to an effect of these drugs on herpes simplex type2?
I cannot recall that these two other members of the herpes virus family – or even a third, HHV6 were even mentioned in the papers demonstrating effects of acyclovir and Valtrex on HIV viral loads.
It is entirely possible that suppression of two viruses, CMV and EBV, contributed, perhaps to the greatest extent, to the anti HIV effects seen.
One can only hope that sera from these studies were frozen and stored. Such samples could provide information on an effect of these drugs t on EBV reactivation and on active CMV infections.
As an historical comment, acyclovir was tried as a treatment for AIDS in 1987 around the time AZT was introduced.
There were several studies of differing design over for some years from about 1987, some based on the hypothesis that CMV contributed to disease progression.
AZT was tried with or without acyclovir, but the results were contradictory. Interestingly AZT also inhibits EBV replication.
One study, ACTG 204, which compared two doses of acyclovir with Valtrex was stopped because 25% of those taking Valtrex died compared to 20% taking acyclovir.
Some observational studies (including the MACS study) found that there was some survival benefit among those taking acyclovir. Another retrospective observational study found no benefit.
Nothing much can be made of these contradictory early results.
But now, with newer techniques for measuring HIV activity by viral load assays, we have very clear evidence that treating herpes virus infections has a beneficial effect on HIV infection.
With the advent of the newer potent antiviral drugs, interest in anti- herpes drugs did wane, until there was a renewed interest in the past few years in connection with herpes simplex virus 2 and genital ulcer disease, Unfortunately most of the emphasis is on herpes simplex virus, when suppression of CMV and EBV may be as – or I believe, of even greater importance.
Actually there had been interest in CMV and EBV in relation to AIDS from the time the disease was first reported in 1981.
I have been involved in AIDS research and treating patients with this disease from the time it started and so can provide some historical perspective on the interest in herpes viruses, that dates to the late 1970s, even before AIDS was described and long before HIV was discovered. At this early time epidemiological studies on the prevalence of infection by CMV among sexually active gay men were undertaken in the US.
As another historical interlude, interest in herpes viruses also provided the basis for safer sex, as it is understood today. As remarkable as this may seem, the first published and disseminated proposal to use condoms to prevent the transmission of AIDS had nothing to with HIV. Condom use was proposed a few years before this virus was discovered, and had everything to do with herpes viruses, specifically CMV.
From about 1978 I had the opportunity to observe and treat a very large number of men who were to be the first to succumb to this new disease.
I knew that over 90 % of gay men attending a clinic for sexually transmitted diseases around that time had antibodies to CMV compared to 54% of heterosexual men. By 1983 over 40% of a cohort of gay men in New York City carried CMV in their semen. Amongst my patients, studies on EBV carried out by David Purtilo at the University of Nebraska showed an extraordinary high prevalence of reactivated EBV infections. (Epstein Barr Virus and chronic lymphadenopathy in make homosexuals with Acquired Immunodeficiency Syndrome. H Lipscomb et al. AIDS Research 1983 1: 59)
At that time – 1981-1982, many of the patients I was taking care of experienced reactivated EBV infections as determined by serological methods, and were excreting CMV in semen. Of course they were also infected with HIV , but this could not be known at that time.
But from what was known about CMV and EBV it was reasonable to postulate that these viruses were somehow implicated in the disease. It was thus possible to propose a way to at least prevent the sexual transmission of CMV.
This formed the basis for the first published recommendations for condom use.
With two of my patients, Michael Callen and Richard Berkowitz a booklet was written called “How to have sex in an epidemic: One approach”.
The appropriate title was coined by Richard.
The twenty fifth anniversary of the publication of this booklet, that was essentially produced and widely distributed by four individuals, and funded by a single person, went almost completely unnoticed in 2007. Although it is in fact a landmark event in the history of the epidemic.
Richard is only now receiving some acknowledgement for this life saving proposal because a documentary film called Sex Positive has brought attention to his achievement.
An account of our collaboration in producing the safer sex guidelines can be seen by following this link.
Michael Callen is remembered by many for his activism. There is even a clinic in New York City named for him and Audre Lorde .
I actually worked there as a physician for a short period, and with very few exceptions, the health care providers and others working there had no idea of who he was, let alone his contribution to safer sex.
I just visited the Callen Lorde website, and indeed there is a photograph of Michael and of Audre Lorde with a few words about each, but no mention of Michaels contribution to safer sex.
Thus herpes viruses, at least CMV had a role in the development of safer sex recommendations.
As it turns out herpes viruses – CMV and EBV included, have a great deal to do with AIDS. This is quite apart from their multiple clinical manifestations as opportunistic pathogens. Both of these viruses almost definitely contribute to pathogenesis.
Evidence that some herpes viruses can play a critical role in HIV disease progression has accumulated for many years.
In fact some evidence for this was already apparent when AIDS was first described.
This considerable body of evidence did not disappear with the discovery of HIV, but was relatively neglected.
As work on HIV proceeded we gained some understanding of the ways in which herpes viruses can interact with HIV to accelerate disease progression, increase HIV infectivity and thus enhance its transmission.
I should now describe some of the interactions that exist between herpes viruses, particularly CMV and EBV, and HIV.
Many, perhaps most of these interactions also involve herpes simplex viruses types 1 and 2.
The role of CMV in immune system activation, a major force in driving HIV infection.
The systemic effects of CMV and EBV infections are most probably of great importance in this respect.
Systemic effects resulting in immune system activation and activation of HIV replication may also accompany reactivated herpes simplex virus infecteions.
Among the systemic effects of active herpes virus infections are the secretion of pro inflammatory cytokines. These circulate and attach to specific receptors on the cell surface. A consequence of this is that certain sequences on DNA will be activated resulting in the transcription of HIV DNA and ultimately the production of new HIV particles. So, this is but one way in which an active herpes virus infections can promote the replication of HIV. The general mechanisms are described in a previous post..
An important and interesting paper that also deals with EBV and CMV in relation to HIV replication was published by V Appay and colleagues. It can be seen by clicking the following link.
I am reproducing some excerpts from Dr Appay’s paper here as the descriptions are very clear and there are references. The references can be seen in the complete text seen by following the above link.
“HIV-1 also causes immune activation and inflammation through indirect means. Antigenic stimulation during HIV-1 infection may be induced by other viruses, such as CMV and EBV”
“In addition, inflammatory conditions occurring during HIV infection (eg release of proinflammatory cytokines) may also participate in
the reactivation of latent forms of CMV and EBV. Recent studies have shown significant activation of EBV- and CMV-specific CD8+ T cells during HIV-1 acute infection [40,41] . Hence, sustained
antigen mediated immune activation occurs in HIV-1-infected
patients, which is due to HIV-1, but also to other viruses (and may be restricted to CMV and EBV)”.
“CMV has been associated with strong and persistent expansions of T cell subsets that show characteristics of late differentiation and replicative exhaustion [94-96]. The anti-CMV response appears
to monopolize a significant fraction of the whole T cell repertoire , so that it might compromise the response to other antigens by shrinking the remaining T cell repertoire and reducing T cell diversity. CMV infection is actually extremely common in HIV-1- infected individuals and its recurrent reactivation may put further stress on their immune resources. Interestingly, CMV-seropositive subjects generally experience more rapid HIV disease progression than CMV seronegative subjects “.
Herpes virus (including herpes simplex) infected cells express Fc receptors on their surface. These receptors can bind certain sequences on antibody molecules. If these antibodies are attached to HIV, a portal for entry of HIV is provided on herpes infected cells that do not possess CD4 molecules on their surface. This process has in fact been demonstrated.
Transactivation of HIV by herpes viruses.
In cells infected with both viruses herpes virus gene products can activate HIV and promote its replication. The transactivation is reciprocal as HIV can promote herpes virus replication.
In the early 1980s when we had no effective measures against this disease I treated my patients with high dose acyclovir.
There then was evidence, albeit theoretical and indirect for a role for these viruses in this new disease.
In the absence of clear evidence from clinical studies, and given the gravity of the disease, it seemed completely appropriate to be guided by these theoretical considerations, particularly involving a drug that is so free of toxicity.
But interestingly, at that time, none of these theoretical considerations placed much importance on HSV 2.
The practice of medicine in those years, dealing with such a mysterious and deadly disorder of unknown causation , demanded responses that could only be based on one’s best judgment.
Fortunately I also had had some experience in the transplant field and was also able to provide bactrim to my patients years before recommendations for its use were issued.
But it was not until potent antiviral drugs became available that we were able to make significant and life saving, rather than life extending interventions.
What I have written of this experience with bactrim in the early years can be seen by following this LINK
In the light of later evidence, I believe it is possible I was able to provide some small benefit in prescribing high dose acyclovir in those very early years.
[i] Acyclovir, when phosphate is added to it, acts like the nucleoside analogues active against HIV, drugs like AZT, D4T, 3TC etc. But this drug has a truly remarkable quality. The cellular enzyme that adds phosphate to make drugs of this type active, does not work on acyclovir as it does on AZT, 3TC and other anti HIV nucleoside analogues. But an enzyme, thymidine kinase that is encoded by herpes viruses, and therefore only appears in herpes virus infected cells has the ability to add the phosphate group and turn acyclovir into an active drug. This is the reason why acyclovir is such a safe drug. It only disrupts DNA synthesis in herpes virus infected cells, where of course this effect is desirable; it has no effect on uninfected cells.
However, if the same cell happens to be infected with HIV and a herpes virus, the herpes thymidine kinase will phosphorylate acyclovir, which now can work to terminate HIV DNA synthesis just as 3TC , AZT and similar drugs do when phosphorylated by the cellular enzyme.
This effect , only observed in doubly infected cells in the laboratory is unlikely to be of much significance in the body.
Posted on May 10th, 2009 No comments
This is about something I wrote in 1964, which was recently reproduced and is now available on line.
It can be seen by clicking on this link:
Seeing this 45 year old document prompted me to write this post.
It is about interferon and has nothing to do with AIDS, at least not in any immediately obvious fashion.
It is an interesting story, about at least one of the ways in which science progresses. It is a story of how an apparently insignificant change in an experiment can sometimes lead to very significant advances. In this instance, about how cytokines exert their effects.
Cytokines are protein or peptide molecules released by cells which then attach to the surfaces of other cells. As a consequence, the behaviour of the cells to which they attach is altered. In this respect cytokines are similar to hormones.
Generally, each cytokine will only attach to a specific receptor on the surface of the cell.
When a cytokine attaches to its matching receptor, a cascade of events is set in motion resulting in the activation of specific sequences in nuclear DNA.
Messenger RNA molecules are then transcribed from specific DNA sequences and these direct the synthesis of specific proteins that ultimately are the molecules that cause the particular effects produced by the cytokine.
Therefore, as the picture below demonstrates, cytokines are not themselves the molecules that directly mediate the effects they cause. Through a complex series of signalling events in the cell, set in motion by the binding of the cytokine to its receptor, specific proteins are made by the cell. These proteins are the actual mediators of the cytokine’s effects. 
In the illustration, the right angled arrow in the nucleus represents the messenger RNAs which will direct the synthesis of these proteins.
HIV DNA is integrated into host DNA. Should certain cytokines, IL-6 or TNF alpha for example, attach to their receptors on the cell membrane, a series of events follow, ultimately resulting in sequences in nuclear DNA being activated which in turn causes HIV DNA to make RNA which directs the synthesis of HIV proteins and ultimately of new HIV particles.
Since many of those cytokines that can activate HIV in this way are produced during the course of many different infections, this then is but one of the several ways in which HIV replication can be enhanced by many different concurrent infections. TB and malaria are among them, as are the bacterial diarrheal infections associated with a lack of sanitation and clean water. Controlling these many HIV enhancing infections, is with the exception of TB, a neglected target in the fight against the epidemic.
Interestingly, discoveries about the ways in which cytokines exert their actions have largely been made since AIDS was first recognized in 1981.
Thus HIV research has progressed in tandem with research on molecular cell biology. There have been reciprocal benefits. HIV research has both contributed to our understanding of molecular cell biology, as well as itself being advanced by discoveries in this field.
Interferon was the very first cytokine to be discovered. It was discovered by Alick Isaacs and Jean Lindenmann . Actually it was not really discovered as a specific molecule; the term interferon was coined by Alick Isaacs in 1957, to describe an activity – an antiviral activity released by virus infected cells. It was perhaps a bit premature to assume that this activity resided in a single molecule. But that was what we all thought at the time; it was nonetheless a concept that facilitated research as probably did the coining of the word “interferon” to describe this antiviral substance.
We now know that there are many types of interferon, and we therefore should properly speak of the interferons. Also, as is the case with cytokines generally, the interferons have multiple effects, but the antiviral effect is how it was first recognized and also measured.
Alick Isaacs was my mentor in the laboratory study of viruses; I shared a lab with him and worked on the mechanism of the antiviral action of interferon.
In 1963, we had no idea about how interferon exerted its antiviral effect. We at least knew that it did not directly inactivate viruses. Molecular biology – at least as far as eukaryotic cells were concerned, had hardly developed.
The 1964 article that can be seen by following the link at the beginning of this post resulted from the work of Joyce Taylor.1964 interferon article.
Joyce Taylor is a biochemist. She also worked in Alick’s lab in 1963. It was rather unusual, in those days for a biochemist to be working in a lab concerned with animal viruses. Animal virology was just beginning to employ biochemical methods.
Joyce was attempting to show that interferon blocked the synthesis of viral RNA. This of course required the use of biochemical techniques to identify and measure viral RNA.
She was able to demonstrate that viral RNA was not made in cells treated with interferon. This was accomplished by using a compound that blocked DNA directed cell RNA synthesis, actinomycin D. It was necessary to use actinimycin D because there is so much background cellular DNA directed RNA synthesis that unless this can be stopped it would be impossible to observer viral RNA synthesis. She used an RNA virus (SFV) that was unaffected by actinomycin D.
Joyce very clearly showed that the synthesis of SFV RNA was blocked in cells treated with interferon. as with the availability of actinomycin D, she was able to detect and measure viral RNA.
We are now coming to the happy, but at the time seemingly insignificant change in the sequence of steps in an experiment, that had such far reaching consequences.
This is how Joyce did her experiments. Cells were exposed to interferon for some hours, and then the SFV virus added with actinomycin D, to allow the measurement of viral RNA synthesis by removing the background of cellular RNA synthesis. As mentioned, in this way, Joyce was able to show very clearly that pre-treatment of the cells with interferon blocked the synthesis of SFV RNA.
One day, because Joyce had to leave early and she did not want her technician to handle actinomycin D, she added this drug with the interferon, at the beginning of the period of interferon treatment . Nobody at that time would have thought that this would make the slightest difference. It is this change in the time when the actinomycin was added that was critical, but it was not at all expected to have any effect.
But it did have an extraordinary effect. When cells were treated with interferon in the presence of actinomycin D it had no antiviral effect. At first it was thought that an inactive preparation of interferon was used, but the same result was obtained when the experiment was repeated.
The significance of the change in the order in which actinomycin was added was that now, while the cells were exposed to interferon, DNA directed RNA synthesis was also blocked.
The implications of this were quite extraordinary. At that time, 1963 and 1964, the foundations of our understanding of basic molecular cell biology were being worked out mostly in bacterial systems. The structure of DNA had been worked out, messenger RNA discovered (although there is some dispute as to who discovered it) and there was some understanding of derepression – that is the ability of certain molecules to cause the synthesis of specific proteins by bacteria.
The result of the changed order of Joyce’s experiment suggested that something similar might be happening in animal cells- that interferon was inducing the synthesis of a specific messenger RNA which in turn directed the synthesis of a protein responsible for its antiviral effect. This is what prompted me to write the short article that can be seen by clicking the link at the beginning of this post.
What was described in 1964 was in fact the first demonstration that cytokines exert their effect by attaching to a receptor on the cell surface, and as a result of this, specific regions on cellular DNA are activated,and RNA synthesized. Work showing that this RNA is responsible for the synthesis of proteins followed immediately.
Robert Friedman, was visiting the laboratory from the National Cancer Institute, and we worked together to show that not only RNA synthesis, but also protein synthesis was required for interferon action – and as was to be found, for the action of all cytokines.
Joyce Taylor remembers this story somewhat differently, but I trust that my version is correct. I have repeated it so frequently since the events in question, as an illustration of how science sometimes progresses.
Joyce changed the order of adding reagents. As a result we knew that interferon action needed cell the participation of cell DNA and the synthesis of RNA. Bob Friedman and I then showed that interferon action also required cell protein synthesis. Ian Kerr who was also in the lab around that time, and others then showed a part of what changes interferon induced in cells.
Interferon was the tool by which a signalling pathway was demonstrated that could account for the effects exerted on nuclear DNA by a molecule interacting with its receptor at the cell surface. Ian Kerr was a key contributor to this work.
This post was not directly connected with HIV/AIDS. But cytokines are most certainly connected with HIV/AIDS. This will be the subject of future posts.
 The genetic code is defined by the sequence of the four bases that make up genomic DNA. A particular sequence of three nucleotides can be regarded as a code component which ultimately defines a particular amino acid; amino acids are the building blocks of proteins. The DNA code is conveyed from the nucleus to the protein synthesizing apparatus in the cell cytoplasm in the form of messenger RNA. This RNA molecule is made from a DNA template and exactly reflects the nucleotide sequence of the section of DNA from which it is transcribed.
Posted on May 1st, 2009 No comments
I have written several posts dealing with “Treatment as Prevention” referring to proposals that the epidemic could be controlled by testing and treating all infected people. However, as this phrase is also used in a different, although related context, I am adding this last postscript.
Thus, “treatment as prevention” has a context that concerns populations and considers a strategy to control and even end the epidemic. The same phrase also has a context that deals with prevention of infection at an individual level, and focuses on transmission risks between two people.
The latter context was brought to attention in 2008 by the Swiss Federal Commission on HIV/AIDS. Their publication essentially states that, under certain conditions, with effective antiviral treatment achieving an undetectable viral load, the risk of sexual transmission without condom use is not greater than that with the use of condoms.
Among the conditions stipulated is that there is no sexually transmitted infection, and that the viral load has been undetectable for at least six months.
Now a German voluntary organization, Deutsche AIDS-Hilfe, has added support – with some modifications to the Swiss statement.
There was a huge controversy when the Swiss recommendations were first made public in 2008. Their conclusions were rejected by groups in the US, even by those who promoted the application of the same principle – the reduction in infectivity conferred by treatment – as a means of controlling the epidemic.
I was – and am – absolutely supportive of the Swiss recommendations as applied to individuals. Here is an excerpt from a letter I wrote when the Swiss document was published:
“The report is absolutely reasonable. There are caveats and cautions in it, and since I can see no reasonable objection to them, we have to look elsewhere to try and understand why the report has provoked such a furious response. I know it is a bit pedantic and pretentious but I’m going to add a quotation that is over 100 years old that recognizes that scientists can be as irrational as anyone else (especially about sex), here it is:
In Man Adapting, Rene Dubos notes that:
“The presuppositions on which medicine operates are thus conditioned by the general philosophy of the social group as a whole” and adds the words of Oliver Wendell Holmes in 1860:
“The truth is that medicine, professedly founded on observation, is as sensitive to outside influences, political, religious, philosophical, imaginative, as is the barometer to the changes in atmospheric density”10
I would bet that some who have commented have not even read the cautious Swiss text, and have allowed their prejudices and squeamishness about sex in general to surface at the very mention of sex without condoms.
The Swiss authors do deserve some recognition for their courage. There are circumstances in which it is not irresponsible to have sex without condoms. And even for those for whom these circumstances do not apply, the knowledge of the possibility of sex without condoms will be an encouragement, in at least two ways.
Firstly, to continue using condoms when this is necessary, and then as a support with treatment adherence and monitoring.
I say these things as someone who had something to do with the original introduction of condom use for AIDS prevention in 1983, – briefly described here:
and until now thought – as probably most did, that condom use would be forever.
Knowing that this is not necessarily so is a tremendous encouragement and I believe this thought alone will help our prevention efforts”.
I have continued to encourage the use of condoms, but I do welcome the Swiss document for pointing out, with appropriate documentation and caution, that there are circumstances when it is not irresponsible to dispense with them.
This also means that there are circumstances when conception is possible. There are also implications in situations where there are laws that criminalize sexual contact with HIV infected people under certain circumstances.
A large part of the irrational responses to the proposal are I believe based on a disparaging attitude towards sex.
For many, the use of condoms is a barrier to intimacy. The knowledge that if certain circumstances can be met, an infected person is not endangering their sexual partner by dispensing with condoms is in fact a life affirming celebration of sex, one of life’s joys.
Admittedly, dispensing with condoms will not be possible for most individuals. It is probably most relevant to serodiscordant couples in a stable relationship – that is where only one of the partners is HIV infected.
But knowing that this might be achieved could be a great support to most HIV infected people who must continue to use condoms It will also be a greater incentive to remain adherent to one’s treatment regimen.
Of course the diminished infectivity of effectively treated individuals is the basis for the proposals to use treatment of all infected people as a means of controlling the epidemic.
This is a very different situation, most importantly because it will involve treating people who do not need to be treated for their own personal benefit. These healthier people will derive no benefit from the medications and only be exposed to their side effects. I have written about this in previous posts on treatment as prevention.
Except for the relatively uncommon situations outlined in the Swiss document, and more cautiously and explicitly, in the German document, the consistent use of condoms remains one of the most important measures we have to prevent infection.