CD3 CD4 and all the more modern names... 3 September 2004
Previous Rapid Response Next Rapid Response Top
Nicholas Bennett,
Infectious Disease Postdoc/Clinician
Department of Pediatrics, University Hospital, Syracuse NY

Send response to journal:
Re: CD3 CD4 and all the more modern names...

I never questioned that the CD4 receptor expression wouldn't alter, but I reiterate the fact that it is pivotal in the immune response. Both the acquired syndrome of AIDS, the rare condition of ICL, and inborne errors of immunity in humans and other animals have repeatedly underscored this.

What has happened in the immunological field has been an explosion of detail, far surpassing anything from even 5 years ago and drastically refining our understanding (or complicating, depend on how you look at things) of the immune responses. The commentary quoted is from more than two full decades ago: the fact that my undergradate lectures in immunology were outdated three months after the lecturer wrote them speaks volumes about the rate of change in the field: the Perth Group would do well to re -acquaint themselves with the current understanding, as best as can be done. Janeway and Travers is a particularly well written volume.

A case in point is the Perth Group's marvelously simplistic view of hypergammaglobinaemia. T Helper cells do all manner of things, basically to induce specific immunity from non-specific. What they fail to mention is that Th cells come in two sorts, Th1 and Th2 (in fact three, if we consider the naive Th0 cells). Th1 induces CD8 and macrophage type responses, Th2 induces antibody responses. The differentiation between Th1 and Th2 lead to the name "Suppressor T cells" seen in some journals, since depending on what function you look at, CD4 T cells will promote or suppress it. Far from CD4 (OTK4) being irrelevant, CD4 is only the tip of the iceberg! The "helper" is not so much to promote the immune responses as to prevent inappropriate activation by providing a second check of antigen presentation before giving a stimulatory signal. The important role isn't the stimulatory signal, it's the antigen check: once the B or CD8 cell is activated it no longer requires confirmatory CD4 T cell "help", and autoimmune diseases are examples of where this checkpoint has gone awry.

What is massively clear in AIDS is that along with the decline in CD4 T cells as a whole there is a skewing of Th1 to Th2 responses such that antibodies are incorrectly promoted compared to cellular immunity. The same effect can be seen in lieshmaniasis and schistosomiasis, albeit on a smaller scale. The cytokine profile that causes this is probably why the thymic replacement of T cells is decreased in HIV infection, but maybe the Perth Group don't believe this either. It's a fact, indisputable, and by far the best explanation is HIV infection (not least because uninfected controls are, well, normal, and treatment with HAART reverses the problem). Nothing else from nitrates to the man in the moon is currently offered as a better explanation of this effect that is so clearly related to immune deficiency.

CD4+ T cell decline in AIDS is not supposed to be purely cell death, except in the eyes of those trying to refute it. CD4 is downregulated by HIV infection through the actions of specific viral genes (vpu, nef), cell fusion through syncitium-inducing strains will also reduce functional CD4 "count" (and any argument that these fused cells are normal will be met with rolled eyes and derision). Since CD4 is crucial to the actions of Th cells in binding to MHC class 2 molecules, antigen recognition cannot possibly be expected to progress normally.

In fact, AIDS is one of the great success stories of the CD-surface antigen field. For once a SPECIFIC subset of T cells does indeed seem to be affected distinctly from any other! Only specific genetic disorders such as Bruton's, Job's and Hyper IgM syndrome have shed similar light on the cascades involved in immunity (but of course the Perth Group favour cell-wide "oxidative" type effects over things like enzyme cascades and cytokine profiles).

IRD is a transient phenomenon, not entirely unique to AIDS, as the Perth Group will well know having read all the available literature. They will also know from the same literature that not all AIDS-defining conditions have an associated IRD and in fact HAART is associated with a significant decline in AIDS-defining conditions in those treated versus untreated. They ignore this because it doesn't agree with their world view. In fact IRD is an effect of restored immune function, since those diseases which tend to flare up are those with an inflammatory component (e.g. CMV retinitis). I will quote from the 2004 paper that the Perth Group cite:

"Suppression of HIV replication by highly active antiretroviral therapy (HAART) often restores protective pathogen-specific immune responses, but in some patients the restored immune response is immunopathological"

"[HAART] has resulted in a sharp decline in the prevalence of opportunistic infections in HIV patients."

"Secondly, a CD4 T-cell count below 50 X 10^6 cells/l is a major risk factor for IRD"

One has to ask just how the person got a CD4 count of less than 50 per microliter prior to HAART, the normal range being at the lowest ten times greater!

Contrary to what the Perth Group suggest, the return of specific anti -pathogen responses can be documented to explain the IRD, as is detailed in the very same article they cite.

As far as I am aware people aren't dying from IRD in quite the same way they died from AIDS in the pre-treatment era. To imply or in fact state otherwise (the patient dies from "immune restoration disease", not AIDS) is not just misleading but downright untrue. What is a sad fact is that those infected with HIV are now living long enough to suffer from significant chronic side effects of the medications, and that unlike other conditions, AIDS-lymphoma risk is not affected by HAART. These reiterate that in this age of infection control we really have a tenous grasp of the reins, and the only way to prevent deaths from HIV is to prevent transmission. To that end, promoting it as a harmless passenger virus and undermining the importance of the HIV tests and antiviral drugs is extraordinarily reckless.

The Perth Group have done no original research, have clearly little if any experience in the fields of molecular biology and virology and have a dubious grasp of basic medical tenets such as epidemiology. One has to ask the question why the Perth Group think themselves qualfied to continually question the HIV/AIDS paradigm despite clearly having their flaws and errors pointed out to them.

I would understand a questioning viewpoint were it not based on a lack of understanding or knowledge, and if it actually fitted with the facts of the situation. I ask why the Perth Group refuse to acknowledge both the facts that have been repeatedly given to them, and their own errors. Quite simply they are mistaken in their understanding of medical science. Can the Perth Group refute the brief explanation I offered a few weeks ago of the mechanism by which HIV causes AIDS, by fitting their own proposals into the observed facts?

I note that the corresponding author of French et al is based at the Royal Perth Hospital: perhaps they could pop in for coffee and a chat about basic AIDS science.

Competing interests: None declared