Infectious Disease Postdoc/Clinician
Department of Pediatrics, University Hospital, Syracuse NY
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In reply to James Whitehead,
I don't think it's usually accepted that viral load and CD4 counts have a reciprocal relationship. Clearly, the work of Mellors et al showed that viral load, independantly of CD4 count, predicted the rate of future CD4 loss (so the same viral load was seen throughout a range of CD4 counts for any individual patient). It does seem though that lowering viral load through natural immune responses or through antivirals results in higher circulating CD4 T cells. This is through a number of mechanisms, including cell death, sequestration in the lymph nodes and apoptosis.
Additionally, I have read reports where so-called "virological failure" in treated individuals was seen without CD4 T cell losses. In some of these people the virus was isolated and sequenced and found to be resistent to the nucleoside analogues in their regimen, but still sensitive to the protease inhibitors. This then makes perfect sense, since PI's cannot stop an integrated provirus from making virions (viral load), but will inhibit the maturation of the virus, so most likely the viral load really is entirely non-infectious virus. I think such studies might do well to be extended, rather than being performed almost for curiousity's sake.
CD4 counts are also variable on a day to day basis: hence the clinical guidelines that recommend the use of serial tests rather than one -off results. Additionally the trends noted in studies like those of Mellors are just that - trends. If 90% of a certain cohort progress within 5 years, then naturally 10% did not!
Apoptosis in my mind has a great deal to do with AIDS, and I apologise if I haven't given this due prominence in the past. In fact apoptosis appears to be a factor of immune-stimulation due to HIV infection (apoptosis is a natural regulatory part of any immune response, to prevent massive overgrowth of unneeded cells). The cell deaths noted in this way are not preferentially involving HIV-infected cells, meaning that HIV is actually involved in the deaths of CD4 T cells indiscriminately (so-called bystander apoptosis). The HIV proteins Tat and Env have been implicated in this [1, 2].
Regardless, it might be expected that T cell replacements should be sufficient to cope with this. However Hellerstein et al  found that thymic replacement rates are decreased in HIV infection, and reversible with antiretroviral therapy. One could reasonably argue that either prevention of HIV-induced apoptosis or release of the thymic inhibition might prevent AIDS entirely. HIV really would become a passenger virus, much like EBV in most people.
IL-2 is perhaps one of the most central cytokines. It's dual effects on CD4 T cells and HIV are explained by the fact that IL-2 stimulates the NF-kappa B transcription factor cascade. NF-kB activates T cells, AND it activates HIV (HIV contains the same promotor region as many immune- mediated genes, a perfect adaptation to infecting T cells). This is partly why HIV is so effective at preventing responses to new antigens: HIV infects a resting T cell, resting T cell recognises an antigen, T cell activates, HIV activates, T cell dies. Not a very good response to an infection, one must agree.
Chun et al (Fauci's group) took the concept a little further and tried high dose IL-2 to flush the HIV out, while suppressing it with antivirals . This appeared to reduce HIV to entirely undetectable levels, even by lymph node culture. However, when antiviral therapy was stopped the virus rebounded . High dose IL-2 is also apparently rather nasty to take (imagine the flu non-stop). Low-dose IL-2 is far better tolerated, but I would be leery about trying it without antivirals - it could make the situation worse.
As regards CD4 count changes under low-dose IL-2 therapy, one metaanalysis of 218 patients receiving HAART found an impressive dose- response curve, with a maximum average rise in CD4 T cells of 605/ul (!) after three cycles of 7.5mIU IL-2. Lower doses were also associated with more top-up doses of IL-2 . Additionally, there are many short summaries of research (including IL-2 only, without antivirals) at
http://www.aidsmap.com/en/docs/A6EBE51D-F332-4634-AB52- 62D1FA62DC98.asp (remove space from URL)
The general message appears to be that it can work, but IL-2 plus HAART is better. The eradication strategy tried by Fauci is unlikely to work, but better maintanence might well be possible. IL-2 is, I think, currently just a research biochemical. It's cost as a drug might be somewhat different...
On a rather cynical note, Anthony Fauci (Director of the NIAID at the NIH) owns the patent on IL-2. I know that there are several who would (probably unfairly!) question the motives of recommending it for regular use in HIV infection, at least in the US where the recent highly publicised changes in NIH funding disclosures may affect public confidence. I personally would ignore that and simply concentrate on the sticky question of whether the immune-related benefits can be balanced against the pro-viral effects! At the moment it does seem rather favourable as an adjunct therapy, and even as a solo intervention.
It is not too surprising that various infections can cause transient rises in viral load - immune stimulation after all acts via the NF-kB promotor which would upregulate HIV as well. Malaria is the first example that springs to mind, but the increase was transient and the clinical significance isn't known . I have not heard of candida affecting viral load.
As regards to the last point, I don't think that apoptosis can _cause_ hypergammaglobulinaemia, but I can imagine that B cell over- activation will result in raised B cell apoptosis as well as hypergammagobulinaemia.
I'm extremely pleased that Mr Whitehead is feeling well in himself, and of course the virologist in me is pleased with his lab progress! I wish him all the best for his health and look forward to his next contribution.
Nick Bennett email@example.com
1. Campbell et al J Biol Chem. 2004 Nov 2;279(46):48197-204. "The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis."
2. Ahr et al Retrovirology. 2004 Jun 23;1(1):12. "Apoptosis of uninfected cells induced by HIV envelope glycoproteins."
3. Hellerstein et al Nat Med. 1999 Jan;5(1):83-9. "Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans."
4. Chun Nat Med. 1999 Jun;5(6):651-5."Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy."
5. Davey et al Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15109-14. "HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression."
6. Kublin et al Lancet. 2005 Jan 15;365(9455):233-40. "Effect of Plasmodium falciparum malaria on concentration of HIV-1-RNA in the blood of adults in rural Malawi: a prospective cohort study."
7. Arduino et al Clin Infect Dis. 2004 Jul 1;39(1):115-22. Epub 2004 Jun 14. "CD4 cell response to 3 doses of subcutaneous interleukin 2: meta- analysis of 3 Vanguard studies."
Competing interests: None declared