Infectious Disease Postdoc/Clinician
Department of Pediatrics, University Hospital, Syracuse NY
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Since my description of the mechanism of HIV-induced immunesuppression of a month ago was written "off the cuff", and the Perth Group have recently requested references, here they are.
Firstly however, it might be worth clarifying some more of the Perth Group's misconceptions.
HIV infection can be demonstrated not just by viral load (which isn't approved for primary diagnosis anyway) or combination ELISA/Western Blot criteria, but also through lymph node cultures, peripheral blood cultures, p24 antigen detection, DNA proviral detection etc. All of these have uses as investigational or clinical diagnostic criteria in certain circumstances. As I showed here previously, HIV culture correlates practically 100% with the presence or absence of HIV positive serology. [1 -3] These make a reasonable Gold Standard and surpass that of many other diagnostic criteria in infectious disease. The Perth Group have argued that without isolation by their criteria (criteria of people who do not work in the field of retrovirology) the protein and nucleotide sequences attributed to HIV cannot be said to be so. HIV has been isolated and characterised at the molecular level by criteria surpassing those of many other micro-organisms - sufficient to produce the protein, serological and nucleotide-based detection methods to the satisfaction of general science. The Perth Group have repeatedly demonstrated their ignorance of basic scientific method and fact by requesting clarification of numerous principles and facts here on the Rapid Responses, and so their opinions regarding the validity of the current HIV-detection methods are, in my eyes, largely worthless.
Secondly, it is clear that CD4 cells vary over time, but there is a profound and continuing decline seen during HIV infection that is highly unusual. The fact that CD4 T cell levels vary is precisely why single CD4 counts are not taken in isolation when making a diagnosis of presumptive HIV infection or progression to AIDS (I'm assuming that since the Perth Group are not in clinical practise with HIV patients they were unaware of this fact). What is important is that HIV can induce a decline in CD4 counts, not that all low CD4 counts are due to HIV! [4, 5] By this criteria, the Perth Group would argue that since not all anaemics have low iron, iron deficiency cannot cause anaemia. What about post-influenzal bacterial pneumonia? Does this mean that we should stop flu vaccination in the elderly because flu isn't the primary cause of death? The Perth Group point out that in the MACS study, after an AIDS-defining CD4 count of <200/ul, 10% percent of patients were "alive and well" after 6 years. Errr...that implies that 90% were not!!!! The fact that the likelihood of being well dropped with time further supports the chronic and progressive nature of AIDS, as rejected by the Perth Group. To do so in the face of contradictory evidence, to QUOTE this very evidence, is entertaining for myself but no doubt hugely misleading to the layman - it is no surprise that Perth Group publications have been rejected by the peer review process if they display the same level of logic and analysis.
Thirdly, the same caveat about low CD4 counts applies to the appearance of opportunistic infections (OIs). Transient low counts may not represent a true loss of CD4 T cells or immune function, but the fact that a low CD4 count correlates with declining immunity and increased risk of OIs cannot be argued against with any degree of honesty. [e.g 6, 7] It's not so much that all individuals with low CD4 counts should get AIDS OI's, or that all people with AIDS-OI's will have a low CD4 count. It is that individuals with a low CD4 count will have an increased RISK of getting an OI - this is indisputible. To establish a false argument based on dogmatic logic and interpretation is not a good approach to unbiased science. They seem extraordinarily hung up on KS as a measure of profound immune suppression, when the understanding among AIDS researchers is that it can appear at higher levels of immune function than other OI's. They then quote the supporting literature in apparent indignation that the wool was pulled over their eyes: when in fact it's merely that they misunderstood KS in the first place. It is perhaps the fact that KS can appear earlier than other OIs that makes it several tens of thousands of times more common in HIV+ patients than the normal population (as I have shown here previously). It is obvious that someone in a plastic bubble will be unlikely to get an OI - it is a simple extrapolation to state that someone in the developed world is less likely to get TB than someone in the developing world, or that a homosexual HIV+ person is more likely to have KS (through sexually acquired HHV8 infection) than a HIV+ haemophiliac. Exposures will dictate which OIs occur to a large degree, and where there is no exposure to a particular pathogen, no OI will occur! To argue that decreased CD4 cell number does not influence OI's and then present a series of HIV-related pulmonary infections of which 116 of 134 cases (86.5%) had CD4 counts lower than 200 (only 20% of the average level in uninfected controls) is hilarious. To use a group of ITU patients as a comparison with "only" 17% having a CD4 count below 200 is laughable - the mere act of being on an ITU, and presumably intubated and/or comatose, puts patients at risk of pneumonia in the absence of anything else. This displays a shocking lack of appreciation of the limits of modern interventional medicine.
Fourthly, sexual infections may well be bi-directionally transmitted, but there is no reason to suppose that to be exclusively true. At the very least it is not hard to entertain the idea that perhaps transmission in one direction would be far more efficient than the other. Most obviously, infection due to a viral innoculum supplied by semen would be far more likely to occur in the receptive rather than the insertive partner! STDs where this is not the case (e.g. herpes, crabs) would be expected to have a far more equal distribution between the partners. Additionally, insertive intercourse is not completely without risk, merely at a low level of risk.  The fact that in the MACS study continuing receptive anal intercourse was an independant predictor of progression within HIV+ men, suggests that dual-infection may be a reason for faster progression, as noted in several anecdotal reports and supported by some work from Kenya in prostitutes . It's entertaining to read the Perth Group quote a paper that says:"sexually transmitted co-factors, pre- seroconversion and/or postseroconversion…augment (or determine) the rate of progression to AIDS" and conclude that "co-factors that augment (or determine)" progression to AIDS are non-infectious". The "sexually transmitted" bit somewhat implies an infectious cause, but then coming to opposite conclusions to the original authors of an article is what the Perth Group do best. No doubt their dogmatic approach to epidemiology (among other sciences) is hindering their cognitive ability, since their assumptions about sexually transmitted infections are wrong, as stated above. I'm actually surprised they quote this study, since it also shows that aside from anything else, AIDS only occurs in those who are seropositive to HIV!
Fifthly, the transient loss of CD4 cells seen during primary infection is proof-positive that HIV induces CD4 cell loss! The fact that the cases of PCP reported all had counts lower than 100 (62-91/ ul - literally decimated compared to the normal range) also shows the link between CD4 cell count and immune function! The fact that the Perth Group interpret these results otherwise is crazy. The transient dip seen post infection is well documented (see ref 4 for graphs) and as such the return to normal, or near normal, would be expected. This in fact supports one of my points below about immune responses to HIV controlling primary infection ! They state that the CD4 counts were normal prior to PCP, but since this was also prior to HIV infection (by at least 1 to 2 months) it is a ridiculous argument to say that "[Preceding CD4 decline]...is not the case even for...PCP". Once again their own references (their own abstracts no less!) refute their statements. They have formed an argument that can be summarised as: (transient, tiny, brief) dips in CD4 count occur in uninfected people, and these are not associated with OIs: the (profound, prolonged, progressive) low CD4 counts associated with HIV infection are associated with OIs, but cannot be anything to do with low CD4 count due to the situations in uninfected controls. Mind-boggling.
Sixthly, as I pointed out in my reply to the Perth Group's original post on "OTK3...", one of the very papers they were quoting from also stated that HAART reduced the incidence of OIs, a fact supported by many longitudinal cohort studies. OI's may continue to appear, but do the Perth Group seriously expect every instance to be prevented? The fact that the Perth Group fail to accept this point of information suggests a dogmatic adherence to their beliefs that overrides any amount of logic or fact. To repeat a previously refuted statement without even a nod to the rebuttal is extremely cheeky, but par for the course here it seems.
Seventhly, if HIV antibodies are so useless, and co-factors so important, why do cohort members in a prospective, untreated population only develop AIDS or declines in CD4 T cells if they (and only after) they seroconvert...? [10-13] Why do only 5% of HIV+ people exhibit true long term non-progression whereas the vast majority show a steady decline in CD4 count?  No amount of armchair pseudoscience, handwaving or misrepresentation is going to detract from that.
If I didn't know better I would say that the Perth Group are actually being impersonated by someone out to discredit them...such is the level their posts have dropped to. Having removed the chaff it appears there wasn't any wheat there after all.
But to cut to the chase, here is a repost of my "mechanism" with accompanying references. Enjoy.
HIV infection - > immediate CD4 cell loss through:
Trafficking to Lymph nodes  (activated T cells traffic)
Cell death [15, 16] (HIV is cytotoxic to T cells, in vitro at least - in vivo data less convincing)
Immune responses then become established :
Cell death due to HIV decreases, immune activation decreases (T cell levels return to more normal levels ).
Chronic "latent" asymptomatic phase:
Ongoing immune activation keeps cells over activated and therefore replicating and trafficked towards lymph nodes. 
HIV preferentially infects and replicates in activated T cells [19- 21]. The biological situation is therefore supportive of continued HIV replication, assisted by the fact that it is an integrated provirus in many cells and therefore resistant to immune and drug attack [22-24]. Later activation of the proviral reservoir through antigen recognition (HIV or new infection) leads to HIV activation and cell death [21, 26]. Therefore HIV SELECTS for those cells responding to itself or new infections (a very effective immune-deficiency causing process).
Cell signalling is altered as cell cycle arrest is mediated by HIV , and progression through the cell cycle is required for successful cytokine production .
Lack of correct cytokine environment reduces T cell replacement from the thymus (hypothetical at the moment, observational evidence only, based on [18, 25, 27] and others with more clinical application: eg [28, 29]).
CD8 killer T cells preferentially destroy HIV-infected CD4 T cells, but this seems to correlate with improved outcomes due to overall control of the replication . The actual anti-HIV activity may be impaired due to effects of HIV itself through CD4 T cell dysfunction .
All the above leads to: selective loss of activated (useful) T cells , cytokine skewing through chronic activation [34, 35], premature immune system aging  (seen in other viral infections), gradual decline in immune repertoire  and eventual thymic exhaustion [28, 29].
As the available T cell repertoire is reduced to the point where HIV can no longer be controlled, the infection becomes overwhelming. It is at this stage that AIDS usually occurs. 
I could go on, and on, and on - but this is rather more than the tip of the iceberg. I hope it (and the accompanying references, and the references within them) made for interesting reading.
1. Jackson et al J Clinical Mole Bio 1988 pp1418-1418 "Rapid and sensitive viral culture method for human immunodeficiency virus type 1."
2. Jackson et al J Clinical Mole Bio 1990 pp 16-19 "Human immunodeficiency virus type 1 detected in all seropositive symptomatic and asymptomatic individuals."
3. Ho et al NEJM 1989 321:pp 1621-1625 "Quantitation of human immunodeficiency virus type 1 in the blood of infected persons."
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8. Vittinghoff et al. Am J Epidemiol 1999 Aug 1;150(3):306-11 "Per- contact risk of human immunodeficiency virus transmission between male sexual partners."
9. Sarah Rowland Jones. Personal Communication based on Kaul et al. J Immunol. 2000 Feb 1;164(3):1602-11. "HIV-1-specific mucosal CD8+ lymphocyte responses in the cervix of HIV-1-resistant prostitutes in Nairobi." and earlier work.
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23. Chun et al. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8869-73. "Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection."
24. Chun et al. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):10958- 61. "Latent reservoirs of HIV: obstacles to the eradication of virus."
25. Rogel et al. J. Virol., Feb 1995, 882-888, Vol 69, No. 2 "The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection."
26. Tobiume et al. J Gen Virol. 1998 Jun;79 ( Pt 6):1363-71. "Dependence on host cell cycle for activation of human immunodeficiency virus type 1 gene expression from latency."
27. Bird et al. Immunity. 1998 Aug;9(2):229-37. "Helper T cell differentiation is controlled by the cell cycle."
28. Ruiz-Mateos et al. Clin Exp Immunol. 2004 Jun;136(3):501-6. "Thymic volume is associated independently with the magnitude of short- and long-term repopulation of CD4+ T cells in HIV-infected adults after highly active antiretroviral therapy (HAART)."
29. de la Rosa et al. Antivir Ther. 2002 Sep;7(3):159-63. "Baseline thymic volume is a predictor for CD4 T cell repopulation in adult HIV- infected patients under highly active antiretroviral therapy."
30. Ogg et al. J Virol. 1999 Nov;73(11):9153-60. "Longitudinal phenotypic analysis of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes: correlation with disease progression."
31. Appay et al. J Exp Med. 2000 Jul 3;192(1):63-75. "HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function."
32. Weekes et al Immunology. 1999 Nov;98(3):443-9. "Large clonal expansions of human virus-specific memory cytotoxic T lymphocytes within the CD57+ CD28- CD8+ T-cell population."
33. Pahwa et al. AIDS Res Hum Retroviruses. 2003 Jun;19(6):487-95. "CD4+ and CD8+ T cell receptor repertoire perturbations with normal levels of T cell receptor excision circles in HIV-infected, therapy-naive adolescents."
34. Spellberg and Edwards Clin Infect Dis. 2001 Jan;32(1):76-102. Epub 2000 Dec 15. "Type 1/Type 2 immunity in infectious diseases."
35. Nunnari et al. Ann Intern Med. 2003 Jul 1;139(1):26-30. "Slower progression of HIV-1 infection in persons with GB virus C co-infection correlates with an intact T-helper 1 cytokine profile."
Competing interests: None declared