(2)Herzenberg et al, (1997) PNAS, V94, 1967

In Part One, the first part of the deductive chain: HIV causes CD4 depletion in-turn causing OI is weakened, i.e. casts doubts on HAART works, therefore HIV causes AIDS.

Reference (2) responds to “My focus, and that of many others, has been on pushing for progress in immune-based therapy that would reduce or eliminate reliance on potentially toxic drugs…”.

It opens the discussion to the wider world of oxidosis (too many pro-oxidants/dysoxygenation (deranged cellular oxygen dysfunction), i.e. loss of reducing power (electron donators) and T-cell production as covered in Part One.

EXCERPTS:

“Glutathione (GSH), a cysteine-containing tripeptide, is essential for the viability and function of virtually all cells. In vitro studies showing that low GSH levels both promote HIV expression and impair T cell function suggested a link between GSH depletion and HIV disease progression. Clinical studies presented here directly demonstrate that low GSH levels predict poor survival in otherwise indistinguishable HIV-infected subjects. Specifically, we show that GSH deficiency in CD4 T cells from such subjects is associated with markedly decreased survival 2-3 years after baseline data collection (Kaplan-Meier and logistic regression analyses, P < 0.0001 for both analyses). This finding, supported by evidence demonstrating that oral administration of the GSH prodrug N-acetylcysteine replenishes GSH in these subjects and suggesting that N-acetylcysteine administration can improve their survival, establishes GSH deficiency as a key determinant of survival in HIV disease. Further, it argues strongly that the unnecessary or excessive use of acetaminophen, alcohol, or other drugs known to deplete GSH should be avoided by HIV-infected individuals.”

“Glutathione (GSH), like nitric oxide (NO), is a small, ubiquitous molecule that plays key regulatory roles in metabolic and cell-cycle-related functions…(It)is found in millimolar concentrations in all animal cells, also provides the principal intracellular defense against oxidative stress and participates in detoxification of many molecules. GSH depletion, caused for example by acetaminophen overdose, results in hepatic and renal failure and ultimately in death.”

“Findings presented here link GSH deficiency to impaired survival of HIV-infected subjects and suggest a potential intervention to relieve this impairment…In addition, we have presented preliminary evidence suggesting that oral administration of NAC (N-acetylcysteine), which supplies the cysteine required to replenish GSH, may be associated with improved survival of subjects with very low GSH levels.”

“Multiple mechanisms may contribute to systemic GSH deficiency in HIV disease, including excessive production of inflammatory cytokines and excessive use of GSH-depleting drugs. In addition, the HIV infection may itself play a key role through the production and release of HIV-TAT (trans-acting transcriptional activator), since TAT blocks transcription of manganese superoxide dismutase, an enzyme that helps prevent OXIDATIVE STRESS, and markedly decreases the activity of glucose-6-phosphate dehydrogenase, a key enzyme in pathways that maintain GSH in its reduced state.” (Emphasis Added)

Here, it is worth noting that the “role” of “HIV infection”, i.e. cellular transcription of TAT, has nothing to do with “HIV replication”, which directs our attention to the “multiple mechanisms” causing reduced glutathione depletion. Additionally, the “reduced state” is the energy store required for the essential antioxidation process that maintains the redox balance.

“The preliminary evidence of improved survival associated with oral NAC administration that we report here is consistent both with GSH deficiency being an important determinant of survival in AIDS and with GSH restoration potentially being beneficial. If these findings are confirmed in prospective long-term trials, they will provide the foundation for the use of NAC as an inexpensive, nontoxic adjunct therapy for HIV/AIDS, potentially valuable even in remote locations where only minimal medical supervision is available.”

I am eagerly awaiting for TAC advocacy of prospective long-term trials and an NAC roll-out in Africa.

“At a more immediate level, the demonstration here that prognosis worsens as GSH levels decrease suggests that certain precautions be taken to minimize GSH deficiency in HIV-infected individuals. In general, it may be prudent for these individuals to avoid excessive exposure to UV irradiation and UNNECESSARY USE OF DRUGS that can deplete GSHe.g., alcohol and prescription or over-the-counter formulations containing acetaminophen.” (Emphasis Added)

This paper suggests an energy deficiency, accelerated aging model of AIDS which can account for the processes described in Part One, especially in AIDS risk groups.

A rough sketch, (sighting shots): damage to lymph nodes, liver and mitochondria plus methemoglobulinemia in the blood result in loss of cellular energy, decreasing T-cell production plus loss of “innate immunity” (inducible defenses possesed by cells). Results: activation of post-death program – normally harmless eukaryotes eat tissues, clog respiratory tract, etc.

Reference (1) responds to “( I)t is critical that more efforts are made to unravel the mysteries of T cell homeostasis in humans so that we can fully grasp how and why the persistent immune activation that typically accompanies HIV infection leads to severely compromised memory T cell function and, ultimately, opportunistic infections. ”

Of interest to all of us, of course, are the author’s conclusions re Ho and Wei. I have taken the liberty of inserting numbers, for clarity, in the penultimate paragraph which reveals a scoreboard: denialists 2, aidschurch 1.

EXCERPTS:

“The dynamic basis for T-cell depletion in late-stage HIV-1 disease remains controversial. Using a new, non-radioactive, endogenous labeling technique1, we report direct measurements of circulating T-cell kinetics in normal and in HIV-1-infected humans.”

“These direct measurements indicate that CD4+ T-cell lymphopenia is due to both a shortened survival time and a failure to increase the production of circulating CD4+ T cells. Our results focus attention on T-cell production systems in the pathogenesis of HIV-1 disease and the response to antiretroviral therapy.”

“A defining feature of late-stage HIV-1 disease is CD4+ T lymphopenia, but the primary cause of falling T-cell levels remains unclear. Some studies using indirect techniques…have indicated that T-cell proliferation is increased after HIV-1 or SIV infection, whereas other studies…have suggested that CD4+ T-cell turnover is not increased. Each of these indirect methods has substantial and well-known limitations.”

“The measurement of blood CD4 accumulation rates after antiretroviral therapy assumes that suppression of viral replication reduces destruction of CD4+ T cells to zero and does not affect production rates…Indeed, there is experimental support for the conclusion that T lymphopenia is due to either accelerated CD4+ T-cell destruction or decreased CD4+ T-cell production or both. Because the methods used have generally relied on static measurements, the dynamic balance of this input–output equation has resisted characterization.”

“Because the circulating T-cell pool was sampled in this study, but T-cell division occurs predominantly in tissues, a definitive biological interpretation of the kinetic results cannot be made at present. Some models, however, can be excluded. The increase in fractional replacement rate and absolute production rate of blood T cells in the HAART group could be explained by (i)prevention of HIV-mediated killing of dividing T cells in tissues, allowing entry into the circulating pool; (ii)reduced adherence of dividing T cells to lymphoid tissues, allowing redistribution of these dividing cells into the circulating pool; or (iii)disinhibition of T-cell proliferation in tissues, allowing greater release of dividing cells into the circulating pool. All of these would result in increased appearance of dividing T cells in the bloodstream; distinguishing between them will require measurement of lymphoid tissue T-cell kinetics and comparison to blood T-cell kinetics.

“The results are not consistent with other possibilities including prolonged survival of circulating T cells due to cessation of HIV-mediated killing (because the half-life of circulating T cells was shorter, not longer in the HAART Group); redistribution of all cells, non-dividing and dividing alike, from tissue to the circulating pool, due to reduced adherence in tissues (because the fraction of newly divided cells, not just the absolute number, increased in the circulation); and simple escape of T cells from HIV-mediated killing in or adherence to tissues, with subsequent normal survival in blood (because the half-life of the T cells in blood was shorter on HAART). Moreover, the idea that kinetics of circulating T cells after HAART reflect kinetics before HAART (refs. 5–7) is also incompatible with our results.”

“Although we cannot identify the reason for the failure to increase CD4+ T-cell production (for example, impaired proliferation compared with in situ killing), our results are inconsistent with a highly accelerated destruction of circulating CD4+T cells that overcomes a higher than normal total production rate (‘open drain/open tap’ model, refs. 5,6) or with isolated failure of tissue CD4 production systems (with normal survival of circulating T cells). Thus, identifying the scenarios that are compatible or incompatible with our kinetic results substantially narrows the focus of future investigations.”

(1)HELLERSTEIN, HANLEY et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. NATURE MEDICINE, VOLUME 5, NUMBER 1, JANUARY 1999. 83-89. http://www.kinemed.comwp-content/uploads/nar/Directly_Measured_Kinetics.pdf

5. Ho, D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123–126 (1995).
6. Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117–20 (1995).
7. Wain-Hobson, S. Virological mayhem. Nature 373, 102 (1995).

End of Part One

Actually some readers are genuinely interested in the science as well as the clinical histories and dramas as hiv plays out its role in human society.

More importantly, debate ought take second place to these kind of actual and real scary reports.

CDC Wants Routine AIDS Virus Testing