AIDS CURE  
TREATMENT BY PROGRAMMED LYMPHOCYTE ACTIVATION

Inductive Therapy to "Flush Out"
Latent Viruses, Plus Conventional
Therapygrouse to Strike "On-the-Wing"! 
 
                 
          

Pangens, Rinderpest, and Virus Latency (1868)

Grouse Shooting and Antibiotic Resistance

Programmed Activation of T-Lymphocytes (1991)

  Quotations from Chun et al. (1998)
  Quotations from Ho (1998)
  Attack Reservoirs (Steve Bunk 1998)

COMMENTARY (The Scientist, Jan 2000)

Definition of "Antibiotic"

The Truth Dawns

Bioinformatic analysis of potential target sites (1995)

Codon Choice in Retroviruses

Death While Seeking the Origin of AIDS

More of the Same in South Africa

The Drug Companies Win the "Image Game"

HIV Recombination and Speciation (2013)

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Pangens, Ringerpest, and Virus Latency

In developing his hypothesis of "pangenesis", Darwin (1868) was encouraged by reports (Romano, 1997, 2002) of the great proliferative powers of microorganisms, as related in the 1866 Third Report of the Commissioners on the Cattle Plague, Rinderpest, which is now known to be caused by a Morbillivirus (Click Here):

Charles Darwin Nor does the extreme minuteness of the gemmules [small "germs"], which can hardly differ much in nature from the lowest and simpliest organisms, render it improbable that they should grow and multiply. A great authority, Dr. Beale, says:

"that minute yeast cells are capable of throwing off buds or gemmules, much less than the 1/100000 of an inch in diameter;" and these he thinks are "capable of subdivision practically ad infinitum".

A particle of small-pox matter, so simple as to be borne by the wind, must multiply itself many thousandfold in a person thus inoculated; and so [also is the case] with the contagious matter of scarlet fever. It has recently been ascertained that a minute portion of the mucous discharge from an animal affected with rinderpest, if placed in the blood of a healthy ox, increases so fast that in a short space of time

'the whole mass of blood, weighing many pounds, is infected, and every small particle of that blood contains enough poison to give, within less than forty-eight hours, the disease to another animal.'"

 

    The hypothesis of pangenesis required modification by Hugo de Vries (1889) to make it approximate to modern concepts (e.g. the "Weismann barrier" that prevents transmission of genes from soma to the germ-line). Darwin's point was reiterated in 1922 by H. J. Muller when commenting on observations by Canadian Felix d'Herelle on agents (viruses) which infect bacteria (now known as bacteriophages):

"That two distinct kinds of substances - the d'Herelle substances and the genes - should both possess this most remarkable property of heritable variation or 'mutability', each working by a totally different mechanism, is quite conceivable, considering the complexity of the protoplasm; yet it would seem a curious coincidence indeed. It would open up the possibility of two totally different kinds of life, working by different mechanisms.

       On the other hand, if these d'Herelle bodies were really genes, fundamentally like our chromosomal genes, they would give us an utterly new angle from which to attack the gene problem. They are filterable, to some extent isolatable, can be handled in test-tubes, and their properties, as shown by their effects on bacteria, can then be studied after treatment.

       It would be very rash to call these bodies genes, and yet at present we must confess that there is no distinction known between genes and them. Hence we cannot categorically deny that perhaps we may be able to grind genes in a mortar and cook them in a beaker after all. Must we geneticists become bacteriologists, physiological chemists, and physicists, simultaneously with being zoologists and botanists? Let us hope so."

Darwin's idea that "gemmules" could transfer from one cell to another, where they could become part of the genetic material of the new cell, finds a modern analogy in the phenomenon of viral latency, where viral nucleic acid seamlessly integrates and hides in the genome of its host. In the case of HIV, the virus is not known to enter the germ line. 

    Nevertheless, our genomes are littered with retroviral remnants, indicating that, in the past, HIV-like viruses, similar to Darwin's proposed "gemmules," have transferred somatically-acquired information to the germ cells, and hence to the offspring. Gregory Bateson (1979) considered that "gemmules" in the form of RNA molecules, might transfer information from a blacksmith's biceps to his germ-line (hence facilitating the Lamarckian inheritance of acquired characters), and questioned the absolute nature of the Weismann barrier:

"But that assumption does not look so safe today as it did twenty years ago. If RNA can carry imprints of portions of DNA to other parts of the cell and possibly to other parts of the body, then it is imaginable that imprints of chemical changes in the biceps could be carried to the germ-plasm."

    Indeed, we now know that RNA can spread information systemically throughout plant tissues (Waterhouse et al. 2001), but there is no evidence that the spread can include germ-line tissues (albeit the distinction between germ-line and soma in plants in less distinct than in animals). In microorganisms the "memory" of prior infection is transferred to descendants in the CRISPR system so this, in the words of Koonin and Wolf (2009), would indeed constitute "a bona fide Lamarckian mechanism."

Darwin, C. (1868) The Variation of Animals and Plants under Domestication. Chapter 27. Murray, London.

Koonin, E. V. & Wolf Y. I. (2009) Is evolution Darwinian or/and Lamarckian? Biology Direct 4:42

Liu, Y. (2006) Advances in Genetics 56, 101-129. Historical and modern genetics of plant graft hybridization.

Muller, H. J. (1921) American Naturalist 56, 32-50.

Bateson, G. (1979) Mind and Nature. Dutton, N. Y. p. 166.

Romano, T. M. (1997) The cattle plague of 1865 and the reception of "the germ theory" in mid-Victorian Britain. J. Hist. Med. Allied Sci. 52, 51-80.

Romano, T. M. (2002) Making Medicine Scientific. John Burdon Sanderson and the Culture of Victorian Science. John Hopkins University Press.

Third Report of The Commissioners appointed to inquire into The Origin and Nature, etc. of The Cattle Plague. (1866) House of Parliament, London (Click Here)

Vries, H. de (1889) Intracellular Pangenesis. Fischer, Jena.

Waterhouse, P.M., Wang, M-B., & Lough, T. (2001) Gene silencing as an adaptive defence against viruses. Nature 411, 834-841.

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Grouse Shooting and Antibiotic Resistance

A proposed treatment of AIDS, taking into account the phenomenon of viral latency, only began to receive serious attention several years after its formal presentation in 1991. Its underlying principle:

The fundamental tenet of antibiotic usage is that, wherever possible, one hits the pathogen with a dose of drug sufficient to kill all organisms in a short period, thus not allowing antibiotic resistant strains to emerge.  

HIV has the latency option which allows it to "sit out" until the antiviral antibiotic gunfire has subsided. Biomedical researchers have long known this, yet they have continued to hunt for more and more antiviral antibiotics that they knew could only be administered under conditions (i.e. long-term therapy) such that resistance in the pathogen would be actively fostered.

Thus some of the most effective antiviral agents against HIV have been rendered useless.

Had research funds been available to those researchers who painfully spelled out, time and time again, in grant application after grant application, the overwhelming importance of investigating virus latency, we might have avoided the antibiotic resistance problem and by now had an effective, cheap, short term, cure for AIDS.

   In principle, the approach is quite simple, as a grouse shooting metaphor can show. In the grouse shooting season the woods and copses echo not only gun-fire, but the thwack of the beaters. To rid land of grouse requires a two-fold approach:

  • (i) Beaters to get the birds to fly up.

  • (ii) Guns and good shooters.

The beaters alone will just cause the grouse to spread to other sites.

The shooters alone will just be able to shoot the occasional grouse which is so unfortunate as to expose itself.

traflit2.gif (224 bytes)The combination is lethal!traflit2.gif (224 bytes)

In the AIDS context, the guns are drugs such as AZT, and a complex of drugs including inhibitors of a viral protease ("combination therapy" or "HAART"). These drugs hit AIDS viruses "on the wing", but are useless against latent virus which hides, usually in DNA form,  integrated into the DNA of its host cell. We need drugs to simulate the beaters.

    In 1991 it was suggested that cytokines such as TNF-alpha might fill this role. It was not until 1998 that major laboratories in the field began to recognize this, although the most influential still believed that the emergence of resistant strains was "inevitable". But by 2003 work from Dean Hamer's laboratory had shown:

"Following reactivation viral expression was dramatically increased, rendering the infected cells susceptible to an anti-HIV immunotoxin. Treatment with the immunotoxin in conjunction with agents that activate virus expression without inducing cell division (IL-7 or the non-tumor-promoting phorbol ester prostratin) depleted the bulk of the latent reservoir and left uninfected cells able to respond to subsequent costimulation. We demonstrate that activation of latent virus is required for targeting by antiviral agents and provide a basis for future therapeutic strategies to eradicate the latent reservoir."


The strategy even acquired its own acronym "IAT" (immune activation therapy; Kulkosky & Pomerantz 2002). Similar progress was achieved by Jerome Zack and his colleagues. Even the New York Times (Sept. 23rd, 2003) began to sit up:

"In the U.C.L.A. study, released last week by the journal Immunity, Dr. Zack described choosing his drugs - prostratin and interleukin-7, to "tickle the cell, just turn the virus on without turning on the cell."

While perhaps unduly cautious about not turning on the cell (which would be destroyed by its own activated virus) in the paper, Brooks et al. noted:

"Our studies demonstrate in primary cells the functional dormancy of HIV in the latent state and consequently, the necessity for viral reactivation for recognition by antiviral agents."

They also noted that in latent HIV there is a low level of virus RNA production that is aborted. They speculate that:

"Latency is not necessarily maintained by active inhibition of the LTR, but instead ... there is a lack of specific cellular proteins in quiescent T cells that are necessary for productive viral expression. Exactly which factors these are is currently unclear, but in their absence the virus is dormant. ...These cellular transcription factors must be induced early following stimulation and prior to a substantial increase in cellular RNA production."

Candidates for such transcription factors would include G0S30/EGR1 and other putative "G0/G1 switch genes" Click Here. Some of the pathways involved in T cell activation involve "nuclear factor kappa B" (NFkB; see below), which can be activated by agents reacting with a particular receptor at the cell surface known as "Toll-like receptor 5" (TLR) - present on T cells (Williams et al. 2004; Caron et al. 2005). In 2008 Burdelya and coworkers showed that a bacterial polypeptide (derived from Salmonella flagellin and code named CBLB502) could activate TLR5, but the possibility of its use in AIDS therapy was not even mentioned. In 2009 Richman and coworkers renewed the appeal for IAT, pointing out the long-term cumulative toxicities of HAART and foreseeing an era "in which HAART is no longer a lifetime necessity."

  • Berger, E. A., Moss, B. & Pastan, I. (1998) Reconsidering target toxins to eliminate HIV infection: You gotta have HAART. Proc. Natl. Acad. Sci. USA 95, 11511-11513. 

  • Bocklandt, S., Blumberg, P. M. & Hamer, D. H. (2003) Activation of latent HIV-1 expression by the potent anti-tumor promotor 12-deoxyphorbol 13-phenacetate. Antiviral Research 59, 89-98.
  • Brooks, D. G., Hamer, D. H., Arlen, P. A., Gao, L., Bristol, G., Kitchen, C. M. R., Berger, E. A. & Zack, J. A. (2003) Molecular characterization, reactivation and depletion of latent HIV. Immunity 19, 413-423.
  • Burdelya, L. G. et al. (2008) An agonist of Toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320, 226-230.
  • Caron, G. et al. (2005) Direct stimulation of human T cells via TLR5 and TLR7/8: flagelling and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells. J. Immunol. 175, 1551-1557.
  • Chun et al., (1998). Induction of HIV-1 replication in latently infected CD4 T cells using a combination of cytokines. J. Exp. Med. 188, 83-91.
  • Cohen, O. J. & Fauci, A. S. (1998) HIV/AIDS in 1998 - Gaining the upper hand? J. Amer. Med. Assoc. 280, 87-88.  
  • Cohen, O. J. & Fauci, A. S.(1999) Transmission of drug-resistant strains of HIV-1: unfortunate, but inevitable. Lancet 354, 697-698.
  • Forsdyke, D. R. (1991). Programmed activation of T-lymphocytes. A theoretical basis for short term treatment of AIDS with Azidothymidine. Medical Hypothesis 34, 24-27.
  • Ho, D. D. (1998). Towards HIV eradication or remission. Science 280, 1866-1967.
  • Kulkosky, J. & Pomerantz, R. J. (2002) Approaching eradication of highly infectious antiretroviral therapy - persistent HIV-1 reservoirs with immune activation therapy. Clinical Infectious Diseases 35, 1520-26.
  • Maeda, M. et al. (2006) Tristetraproline [G0S24] inhibits HIV-1 production by binding to genomic RNA. Microbes and Infection 8, 2647-2656.
  • Richman, D. D., Margolis, D. M., Delaney, M., Greene, W. C., Hazuda, D. & Pomerantz, R. J. (2009) The challenge of finding a cure for HIV infection. Science 323, 1304-7.
  • Williams, S. A., Chen, L-F., Kwon, H., Fenard, D., Bisgrove, D., Verdin, E. & Greene, W. C. (2004) Prostratin antagonizes HIV latency by activating NF-kB. J. Biol. Chem. 279, 42008-17.[This paper cites Forsdyke 1991.]

 

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HIV-1: virus particles assembled prior to budding from the cell

Programmed Activation of T-Lymphocytes. A Theoretical Basis for Short Term Treatment of AIDS with Azidothymidine

D. R. Forsdyke. Medical Hypothesis (1991) 34, 24-27. (With copyright permission from Academic Press)

Abstract

Introduction

Renewal of the T-lymphocyte population does not require feed-back to the stem-cell level

HIV DNA is destroyed when the host cell is destroyed

Mechanism of action of AZT


Need for programmed synchronous activation of all host T cells


HIV infection of non-lymphoid tissues

Abstract - When its T-lymphocyte host cell is activated, the latent (DNA) form of human immunodeficiency virus (HIV) is activated to produce RNA copies which are liberated as virus particles from the cell. In this process the cell is destroyed together with the latent virus. If administered at this time, 3'-azidothymidine (AZT) would specifically prevent the liberated RNA copies replicating and establishing latency in new host cells. The RNA copies would then be degraded by viral or host ribonucleases. Thus, one DNA copy of HIV and its RNA progeny would be eliminated from the body.

 
       However, many DNA copies of HIV would remain in other cells ("latency"). The main problem of therapy with AZT is that activation of host cells to become permissive for production of virus is random in time. Activation depends on chance encounters of an infected person with the particular foreign antigens to which individual T-cells bearing latent HIV can specifically respond. It is primarily for this reason that AZT must be administered continuously. If all T-cells could be polyclonally stimulated at one time, all HIV-bearing T-cells would be destroyed and concomitant administration of AZT for a short term would prevent the replication of all liberated viruses.

 
       Unlike most renewable end cells in the body, the maturation of T-cells involves processes of positive and negative selection. To preserve the 'educated' T-cell population, T-cell renewal occurs at the end cell level, rather than at the stem cell level. It is possible that normal physiological signals concerned with this homeostatic regulation of T-lymphocyte population size could be harnessed to produce synchronous activation of all T-lymphocytes. Tumor necrosis factor-alpha (TNF) has some of the properties expected of a postulated polyclonal activator needed for this programmed activation of T-lymphocytes.


Introduction

Prolonged treatment with 3'-azidothymidine (AZT) extends the life of patients with AIDS who are infected with the human immunodeficiency virus (1). Recent evidence suggests that asymptomatic HIV-seropositive individuals can also benefit from prolonged AZT treatment (2). The continuing exponential increase in the number of seropositive individuals and the need for prolonged treatment with this expensive drug threatens to seriously burden healthcare systems worldwide.

      To be sure of curing AIDS, all forms of HIV within the body, both free and latent, need to be eradicated. Although there are many recent reviews on AIDS treatment strategies (2 - 6), to our knowledge none of these considers the possibilities that there might be conditions under which AZT could be employed:

  • (i)   For short periods.

  • (ii) To eliminate HIV entirely from the T-lymphocyte population.

We here consider various aspects of lymphocyte biology, the HIV life-cycle, and the mechanism of action of AZT, which lead us to a more optimistic assessment of the role of AZT and related drugs in the treatment of AIDS.

Renewal of the T-lymphocyte population does not require feed-back to the stem-cell level

 
Lymphocyte

The 'education' of T-lymphocytes involves both positive and negative selection (7, 8). Positive selection generates sets of T-lymphocytes with the potential to respond to various 'self' determinants (e.g. MHC, CDI, TI and Qa-1 antigens; 9-11). Negative selection eliminates cells responding to self with high specificity. The final immunological repertoire consists of numerous small clones of cells. Members of a particular clone are each capable of recognizing a particular set of 'nearself' antigenic determinants with varying degrees of specificity.

      The range of specific responsiveness exhibited by an individual reflects the outcome of these selection processes (and further positive selections by foreign antigens), over many years. To renew the educated T-lymphocyte population after depletion (perhaps due to haemorrhage), could be a protracted process if renewal required reeducation. Individual T-cells (end cells), rather than stem cells, should be responsive to homeostatic control mechanisms affecting the size of the total T-lymphocyte population (7). Thus peripheral immunologically-competent clones of T-cells should be responsive not only to the cues provided by foreign antigenic determinants (through the determinant-specific T-cell antigen receptor) but also to cues provided by the growth factors concerned with T-lymphocyte population size homeostasis (through appropriate receptors). This self-renewing property of the peripheral T-lymphocyte population is now established experimentally (12-14).

HIV DNA is destroyed when the host cell is destroyed

Like other retroviruses, HIV integrates into the DNA of its host-cell and can remain there in quiescent form for prolonged periods (15, 16). Activation of latent viruses generally requires concomitant activation of their host cells, which then become permissive for virus production (17). In the case of HIV-infected 'resting' T-lymphocytes this activation appears to require reaction with antigen or lectin (18). Subsequent intracellular signals result in rapid changes in at least one protein encoded by a host gene (NFkB; 19). This protein may then transmit activation signals to other host genes which play a role in the switch from the resting (G0) phase to the activated (G1) phase of the cell cycle and/or in progression through the G1 phase (20, 21). The protein may also transactivate HIV genes (22, 23). The activated HIV genome (DNA) is then transcribed to generate RNA copies of itself which are eventually packaged and released. The host cell with its associated HIV DNA is destroyed in this process.

     Thus cell activation is therapeutic to the extent that the latent DNA form of the virus is destroyed. The virus is triggered to destroy itself. The problem, of course, is that newly liberated viruses in RNA form infect new cells and can then establish latency in these cells. Effective therapy of AIDS requires a drug, or drugs, which can achieve two, preferably concomitant, results:

  • The first of these is activation of all host cells carrying latent virus so that such cells will be destroyed by the virus.

  • The second is the prevention of liberated viruses infecting, replicating in, and establishing latency in, previously uninfected cells

Mechanism of action of AZT

The ideal therapeutic agent is a 'magic bullet' which exploits some difference between the metabolisms of a pathogen and its host. The replication of HIV is strictly dependent on the viral enzyme reverse transcriptase, which is a DNA polymerase generating DNA from the viral RNA template. This enzyme is widely distributed in both eukaryotes and prokaryotes (24), but has not been shown to play a critical role in eukaryotes. The enzyme differs from the major host DNA polymerase activity in not being in a multienzyme complex (25, 26), and not being capable of proof-reading DNA. The nucleotides which are linked together linearly to make DNA are not scrutinized for abnormalities (27, 28). The resulting high error rate results in a diversity of forms which may be advantageous for the virus (29).

       The most widely accepted view of the selectivity of the action of the nucleotide analogue AZT is that it is added by the viral reverse transcriptase to the elongating copy of viral DNA, but is rejected by the proof-reading activity of host DNA polymerase. Thus replication of HIV-RNA is selectively interrupted (3, 4, 30). Ribonuclease associated with the reverse transcriptase, or a host ribonuclease, would probably then destroy the RNA so that it could not act as a template for more copies of itself.

Need for programmed synchronous activation of all host T cells

The switch of a G0 T-lymphocyte containing HIV DNA in its genome to the G1 state permissive for viral replication can occur under two circumstances:

  • The cell can be activated by an antigenic determinant corresponding to the cell's specific antigen-receptor (monoclonal response). The timing of this event would be entirely dependent on random chance encounter of the infected person with that particular antigen.

  • Alternatively, the cell can be activated as part of a polyclonal homeostatic response to a lectin-like factor (lymphokine, growth factor) which signals a need to restore the size of the T-lymphocyte population (or a subpopulation). The timing of this event could be orchestrated by, for example, administration of the appropriate factor.

  Currently, treatment with AZT must be prolonged because the triggering of latent HIV (DNA) to destroy itself is mainly dependent on G0/G1 switches generated by random antigenic signals. At one point in time only one cell (or a small group of cells), becomes permissive for HIV replication. The cell, with its integrated HIV DNA, is then destroyed. AZT prevents the liberated viruses replicating and establishing latency in fresh host cells. However, if all host T-lymphocyte were activated synchronously by an appropriate concentration of an appropriate growth factor, all the integrated HIV DNA molecules would be destroyed with their host cells. Furthermore, all liberated RNA viruses could be prevented from replicating in previously uninfected cells by a short and intensive concomitant course of AZT. For this purpose, the effectiveness of AZT might be increased by combining AZT with drugs (e.g. 5-fluorodeoxyuridine; 25, 31), which deplete intracellular pools of natural AZT competitors and reduce feedback inhibition of the enzyme which is rate-limiting for incorporation of AZT (32).

     While much remains to be learned about the normal signals affecting cell population size homeostasis, there are indications that this 'one shot' approach to AZT therapy is feasible. Matsuyama et al (33) have suggested that a suitable polyclonal 'growth factor' might be tumor necrosis factor-alpha (TNF-alpha). This can activate host cell NFkB-like factors which, in turn, can activate latent HIV (34, 35). Treatment with TNF-alpha alone would be expected to accelerate the progression of AIDS (36). Concomitant treatment with AZT might turn this progression to the advantage of the host.

HIV infection of non-lymphoid tissues

The above discussion is concerned with eliminating the AIDS virus from the T-lymphocyte population and thus preventing or correcting acquired immune deficiency. The virus can also persist in various other tissues, thus constituting a reservoir from which reinfection of T-lymphocytes might occur (16). Cotherapy with AZT and an appropriate end-cell specific cytokine or growth factor, to convert the cells to a state permissive for viral growth, might eliminate this reservoir (37, 38).

Acknowledgements. I thank Dr. P Ford for helpful comments on the manuscript. These studies were supported by grants from the American Foundation for AIDS Research (AMFAR) and Queen's University.

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8. Schwartz RH. Acquisition of immunologic self-tolerance. Cell 57, 1073, 1989.

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10. Porcelli S. Brennar M B, Greenstein J L, Balk S P, Terhorst C. Bleicher PA. Recognition of cluster of differentiation antigens by human CD4, CD8, cytolytic T-lymphocytes. Nature 341, 447, 1989.

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13. Rocha B, Dautigny N, Pereira P. Peripheral T-lymphocytes: expansion potential and homeostatic regulation of pool sizes and CD4/CD8 ratios in vivo. Eur J Immunol. 19, 905, 1989.

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17. Bloom BR, Senik A, Stoner G, Ju M, Nowakowski M, Kano S, Jiniinez L. Studies on the interactions between viruses and lymphocytes. Cold Spring Harb Conf Quant Biol. 41, 73, 1976.

18. McDougal JS, Mawle A, Cort SP, Nicholson JK, Cross GD, Scheppler-Campbell JA, Hicks D, Sligh J. Cellular tropism of the human retrovirus HTLVI/LAV. Role of T-cell activation and expression of the T4 antigen. J Immunol 135 135, 3151, 1985.

19. Nabel G. Baltimore D. An inducible transcription factor activates expression of HIV in T-cells. Nature 326, 711, 1987.

20. Forsdyke DR. cDNA cloning of mRNAs which increase rapidly in human lymphocytes cultured with concanavalin-A and cycloheximide. Biochem Biophys Res Com 129, 619, 1985.

21. Greene WC, Bohnlein E, Ballard W. Immunol Today 10, 272, 1989.

22. Rosenberg ZF, Fauci AS. AIDS Res Hum Retrovir 5, 1, 1989.

23. Cullen B, Green WC. Regulatory pathways governing HIV-1 replication. Cell 58, 423, 1989.

24. Lim D, Maas WK. Reverse transcriptase in bacteria. Molec. Microbiol 3, 1141, 1989.

25. Forsdyke DR, Scott FW. Evidence for non-convergence of de novo and salvage pathways of purine deoxyribonucleotide synthesis, p. 177, in Cell Compartmentation and Metabolic Channeling. Ed. (L Nover, F Lynen, K Moher) Elsevier Pub Co, Amsterdam, 1980.

26. Mathews CK, Moen LK, Wang Y, Sargent RG. Intracellular organization of DNA precursor biosynthetic enzymes. TIBS 139, 394, 1988.

27. Preston BD, Poiesz BF, Loeb LL. Fidelity of HIV-1 reverse transcriptase. Science 242, 1168, 1988.

28. Loeb LA. Endogenous Carcinogenesis: Molecular Oncology into the Twenty-first Century. Cancer Res. 49, 5489, 1989.

29. Temin HM. Retrovirus variation and evolution. Genome 31, 17, 1989.

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31. Sjostrom DA, Forsdyke DR. Isotope-dilution analysis of rate-limiting steps and pools affecting the incorporation of thymidine and deoxycytidine into cultured thymus cells. Biochem J 138, 253, 1974.

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33. Matsuyama T. Hamamoto Y, Soma G, Mizuno D, Yamamoto N, Kobayashi N. Cytocidal effect of tumor necrosis factor on cell s chronically infected with HIV: enhancement of HIV replication. J Virol 63, 2504, 1989.

34. Lowenthal JW, Ballard DW, Bohnlein E, Greene WC. Tumor necrosis factor alpha induces proteins that bind specifically to kappa- B-like enhancer elements and regulate interleukin-2 receptor alpha chain expression in primary human T-lymphocytes. Proc Natl Acad Sci. USA 86, 2331, 1989.

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Some quotations from Tae-Wook Chun et al. (1998)

 
  • "The presence of this latent reservoir of HIV is of considerable concern since these cells remain as a potential source of reactivation of viral replication."


  • "Since it is likely that ... infected cells die upon activation of virus and that HAART prevents spread of virus to adjacent cells, the observation that this combination of cytokines [IL6, TNF-alpha, IL2] can markedly induce viral replication in this reservoir may have important implications for the activation-mediated diminution of the latent reservoir of HIV in patients receiving HAART."


  • "Since cytokines alone can reactive HIV-1 replication in latently infected, resting, CD4+ cells, and since these cells probably die upon reactivation, it is conceivable that a strategy of administration of cytokines together with HAART might result in a diminution of this reservoir of latently infected cells".


  • "Given the relatively long half-life of these latently infected, resting CD4+ T cells, and the fact that they are constantly within an environment capable of providing the stimuli for reactivation, it is not unreasonable to explore strategies aimed at deliberately diminishing the size of this pool of cells. In this regard, since cytokine-mediated induction of HIV-1 replication in these cells with subsequent release of virus probably results in death of the cell, and since the presence of HAART in vitro prevents spread of released virus, it is conceivable that in vivo administration of cytokines together with HAART may have such an effect."


Some quotations from David Ho (1998)

 
  • "Infectious HIV-1 persists latently in resting, memory CD4 lymphocytes in a post-integrated form despite 1 to 2 years of combination therapy [i.e. AZT or similar compounds + protease inhibitors]. This latent reservoir of HIV-1, denoted "L" , ... represents the major documented hurdle to virus eradication, although other ... viral sanctuaries may exist."


  • "5 to 7 years of continuous, completely inhibitory therapy will be necessary to eliminate L. Treatment interruptions that permit HIV-1 replication to resume will rapidly restore the size of L. For larger pool sizes ... more than 10 years of continuous treatment will be required. A treatment duration this protracted is unacceptable because of the complexity, toxicity and cost of the current drug regimes... ."
     

  • "Infectious proviruses are undoubtedly harbored within a diverse population of resting CD4 lymphocytes with memory for a large array of exogenous antigens. Thus, administration of a limited set of antigens is unlikely to activate a sufficient number of these cells to replicate and thereby facilitate their rapid death. On the other hand, the use of a large panel of antigens would be impractical.

            What about the administration of cytokines? Interleukin-2 (IL-2) alone is not expected to activate resting [G0] lymphocytes because such cells do not express the appropriate high affinity receptor. However, mixtures of certain cytokines, such as IL-2, IL-6 and tumor necrosis factor, have been shown to activate resting T cells in vitro. "

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Steve Bunk's article from The Scientist 7 Dec 1998 
New Weapon Attacks Latent HIV Reservoirs. (Click Here)

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The Scientist 14, no.2 page 6, 24th January 2000 (Click Here):

COMMENTARY (with copyright permission from the publisher Alexander Grimwade)

HIV: A Grouse-shooting Analogy

By Donald R. Forsdyke

The Hot Papers article1 of Dec. 6 on the failure of various combinations of antibiotics to eradicate latent HIV gives the false impression that AIDS researchers were not aware of this possibility. ("Scientists are still grappling with the questions raised by this sobering discovery.")

    Doctors learn at medical school the fundamental rule that antibiotics should be given for short periods in adequate doses to destroy all pathogens and prevent the emergence of resistant strains. As soon as it was appreciated that AIDS was caused by a retrovirus, it was predictable that antibiotics alone would be unlikely to work. Retroviruses usually have a latency option and are highly prone to mutate.

     Thus, future therapy would have to be rather like grouse-shooting; one would need guns to shoot the birds and beaters to flush them out. To rid an area of grouse neither alone suffices. The combination is lethal.2

     Accordingly, the research agenda for AIDS had to develop along two lines:

  • (1) research on viral growth and replication to find antibiotics such as AZT, which would hit the virus "on the wing," and

  • (2) research on latency to find drugs such as TNF-alpha, which would flush out viral reservoirs.

A short and inexpensive period of treatment should then suffice (expense being a particularly important factor in Third World countries).

     Unfortunately, our research systems do not operate this way.3,4 Antibiotics were emphasized rather than latency-disrupting drugs. When AZT did not come up to expectations and resistant strains emerged, the call came for bigger and better guns, rather than for beaters. If regular guns won't work, add the howitzers! If that combination does not work, add the mortars! And to forestall criticism, call it "highly active anti- retroviral therapy"  (HAART)!

     The quite predictable consequence is that we have a variety of initially highly effective antibiotics to which HIV is now resistant. Thankfully, HAART can increase the life span of patients, but these same patients, by virtue of the resistant strains they harbor, remain as potentially dangerous sources of infection. When latency-disrupting drugs eventually emerge (and let us hope the work on IL-2 is not just hype), it may be too late. HIV may be totally resistant.5,6

     Part of the problem is a refusal to use the word "antibiotic" in the context of HIV treatment. Instead, patients are subject to antiretroviral therapy with "agents" or "drugs." Furthermore, it is argued that "therapy for HIV-1 disease can be viewed in a way that is similar to treatment for cancer," instead of similar to treatment of other pathogen-caused diseases.7

References

1. S. Bunk with comments by D.D. Richman and R.F. Siliciano, Hot Papers, The Scientist, 13[24]:22, Dec. 6, 1999.

2. D.R. Forsdyke, "Programmed activation of T lymphocytes: a theoretical basis for short term treatment of AIDS with Azidothymidine," Medical Hypotheses, 34: 247, 1991.

3. D.R. Forsdyke, "A systems analyst asks about AIDS research funding," Lancet, 2:13824, 1989.

4. D.R. Forsdyke, "Bicameral grant review: how a systems analyst with AIDS would reform research funding," Accountability in Research, 2:23741, 1993.

5. D.R. Forsdyke, post.queensu.ca/~forsdyke/aids.htm

6. D.R. Forsdyke, Tomorrow's Cures Today? Newark, Harwood Academic, 2000. (Click Here)

7. R.J. Pomerantz, "Residual HIV-1 disease in the era of highly active antiretroviral therapy." New England Journal of Medicine, 340:16724, 1999.

Comment on the above Commentary: 2000-02-02 email

"Regarding your article in The Scientist:

I think that the 'reason for refusal to use the word "antibiotic" in the context of HIV treatment' is that many virologists think that term is incorrect. Many microbiologists, and most virologists I know, consider an "antibiotic" to refer strictly to an antibacterial agent (never mind that its etymological meaning can be broader). For agents against viruses, "antiviral" is the standard term (and against fungi, antimycotic, etc.).  

[Prefers to remain anonymous]
Professor
[                      ]
Department of Genetics
University of [   ]"

USA

A similar point was made in
The Scientist March 20th (Click Here), which was briefly replied to in the April issue: (Click Here)

Reply to Comment

Definition of "Antibiotic"

Thank you for your comment concerning "the standard term". Webster's Dictionary defines "antibiotic", when used as an adjective, as something "tending to prevent, inhibit, or destroy life." As you imply, a strict etymological interpretation would regard lions as antibiotic with respect to humans, and Popeye as antibiotic with respect to spinach. Clearly the word has to be understood in context. 

    In the present discussion this context relates to chemicals which are antibiotic with respect to microorganisms which can invade the body of a host organism, such as man. Antibiotics are not "antiseptics" or "disinfectants" which can sterilize at the surface or outside of a host, but are usually not tolerated within host tissues. 

     Thus, in the present context I would define the noun "antibiotic" as a chemical [of natural or synthetic origin] which, [usually at low concentrations], inhibits microorganisms of some type within a host organism, while not unacceptably interfering with the life of that organism.

[This does not exclude the possibility that the chemical will also inhibit the microorganisms outside the host (e.g. on a Petri dish) but, by virtue  of being tolerated within the body of the host, the chemical is an antibiotic not an antiseptic. Most modern antibiotics work at low concentrations, and are toxic to the host at high concentrations. It is possible that in future we might find a chemical which works only at  high concentrations and these concentrations are not toxic to the host. So concentration should not be in the definition.]

    Since, historically, many of the early antibiotics worked only against bacteria ("antibacterial antibiotics"), it is easily to fall into the trap of thinking that antivirals ("antiviral antibiotics") are different. If we think of them as in a separate, non-antibiotic, category, then the lessons we have learned about antibiotic usage (i.e. mode of use to prevent resistant strains emerging) can easily get disregarded (the point of my Commentary).

    Unfortunately, the Webster's Dictionary (1976) definition has archaic aspects when defining the noun as "a substance produced by a microorganism and able in dilute solution to inhibit or kill another microorganism". It gets it right when referring to the target of an antibiotic as "another microorganism" (virus, bacterium, fungus, protozoan, etc.), but is wrong in postulating that antibiotics are necessarily "produced by a microorganism".

     Yes, historically, many antibiotics were isolated from microorganisms (e.g. penicillin produced by a fungal mould), but also many were synthesized by the chemist (the arsenicals for the bacterium causing syphilis, and the sulphonamides, which were effective against a variety of bacteria). The list of synthetic antibiotics now includes AZT (antiviral antibiotic) and modified forms of penicillin (antibacterial antibiotics). Antibiotic forms initially derived by purification from microorganisms are now being chemically synthesized and further modified.

       This history can be reversed. Among the antibiotics now available only through chemical synthesis, in future we may find some which are synthesized by some organism, perhaps an organism yet to be discovered. Including the source of antibiotics, and/or the type of microorganisms they attack, in the definition, is archaic. Our nomenclature must move with the times in order not to confuse ourselves, our students, and our patients.

Donald Forsdyke

Another gospel: American Heritage Dictionary 1996.

"NOUN:
A substance, such as penicillin or streptomycin, produced by or derived from certain fungi, bacteria, and other organisms, that can destroy or inhibit the growth of other microorganisms. Antibiotics are widely used in the prevention and treatment of infectious diseases.

ADJECTIVE
:

1. Of or relating to antibiotics. 2. Of or relating to antibiosis. 3. Destroying life or preventing the inception or continuance of life".

For more on this matter, see:

Bentley, R.& Bennett, J. W. (2003) What is an antibiotic? revisitedAdvances in Applied Microbiology 52, 303-331.

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The Truth Continues to Dawn [commentary circa 2000]

"However, the most worrisome reservoir consists of latently infected resting memory CD4+ T cells carrying integrated HIV-1 DNA. Definitive demonstration of the presence of this form of latency required development of methods for isolating extremely pure populations of resting CD4+ T cells and for demonstrating that a small fraction of these cells contain integrated HIV-1 DNA that is competent for replication if the cells undergo antigen-driven activation. 

    Most of the latent virus in resting CD4+ T cells is found in cells of the memory phenotype. The half-life of this latent reservoir is extremely long (44 months). At this rate, eradication of this reservoir would require over 60 years of treatment. Thus, latently infected resting CD4+ T cells provide a mechanism for life-long persistence of replication-competent forms of HIV-1, rendering unrealistic hopes of virus eradication with current antiretroviral regimens. 

    The extraordinary stability of the reservoir may reflect gradual reseeding by a very low level of ongoing viral replication and/or mechanisms that contribute to the intrinsic stability of the memory T cell compartment. Given the substantial long-term toxicities of current combination therapy regimens, novel approaches traflite.gif (995 bytes) to eradicating this latent reservoir are urgently needed."

   

T. Pierson, J. McArthur & R. F. Siliciano. (2000) Annual Reviews of Immunology 18, 665-708.

 
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And Dawn...

In October 2000 it was eventually admitted that:

"In cases with apparent complete HIV suppression by HAART, viral rebound after cessation of therapy could have originated from the activation of virus from the latent reservoir." (Zhang et al. 2000).

In a major concession to the viewpoint advanced on this web-page it was stated:

"Several research goals assume paramount importance.

  • First, it is critical to determine whether additional viral reservoirs exist.


  • Second, it is important to understand the nature and source of the ongoing virus production that is seen in most patients on HAART.


  • Finally, novel approaches are needed to eliminate latently infected cells which clearly represent a very serious barrier to HIV-1 eradication."

That such research goals "assume" importance only by the year 2000 is of note. The readers of these pages may infer that individuals such as the authors cited above were among those rejecting grant applications from researchers who, a decade or more before, had considered it quite obvious that these goals were of paramount importance.

    Their goals did not get support, not because of scientific logic, but because of the mind-set of the well-intentioned people who held the political high ground, but all-too-often could not see beyond their noses. 

    There is nothing new in this, as the example of diphtheria immunization in the early decades of the 20th century has shown (Forsdyke, 2000). Amazingly, in 2003 Dr. Siliciano declared that: "It is difficult to envision any targeting mechanism that will allow specific elimination of this reservoir."(Click Here). Of course, he is not required to "envision." He just has to read the scientific literature (see above)!

     The implications of this go far beyond the management of natural diseases. Currently, the greatest threat to humankind seems to be overt or terrorist warfare conducted not with nuclear weapons, but with biological weapons. A nation which uses the peer-review process, as it currently (2001) operates, to select those who give it advice on biomedical matters, may not fare well in confrontation with a nation which has adapted the peer-review process to identify those (e.g. Irvine Page, Szent-Gyorgyi, Erwin Chargaff) who can see beyond their noses. 

Forsdyke, D. R. (2000) Tomorrow's Cures Today? How to Reform the Health Research System. Harwood Academic, Newark.

Siliciano, J. D. & Siliciano, R. F. (2000) Latency and viral persistence in HIV-1 infection. J. Clin. Invest. 106, 823-824.

Zhang, L., Chung, C., Hu, B-S., He, T., Guo, Y., Kim, A. J., Skulsky, E., Jin, X., Hurley, A., Ramratnam, B., Markowitz, M. & Ho, D. D. (2000) J. Clin. Invest. 106, 839-845.

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Bioinformatic Analysis of Retroviruses (Click Here). Deals with the origin of retroviral species (with implications for speciation in general), and notes a region of high conservation just upstream of GAG, which is vital for dimerization and packaging and is thus a potential target sites for therapeutic agents (e.g. antisense oligonucleotides).

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Codon Choice in Retroviruses (Click Here) There are 20 amino acids and 61 codons, and one amino acid can have more than one codon. All genes in a particular genome tend to use the same set of codons. In his "genome hypothesis" Grantham concluded that differences in choice of codons by different species reveal the presence of fundamental genomic forces. We ignore these at our peril.

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Death While Seeking the Origin of AIDS (Click Here) William D. Hamilton, the biologist whose work was popularized in Dawkins' The Selfish Gene, went to the jungle to find out for himself.

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More of the Same in South Africa (Click Here) By putting all their "eggs" into the immunization "basket" the Medical Research Council of South Africa became part of the problem not the solution to the problem.

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The Drug Companies Win the "Image Game" and Promote the Spread of AIDS (Click Here)

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Return to: AIDS Index (Click Here)

Back to: Home Page (Click here)

Back to: Peer Review Page (Click here)

Back to: Theoretical Immunology Page (Click here)

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Other Sites:

All the Virology on the WWW (Click Here)

Acquisition of HIV from Monkey Kidney Cells used for Polio Vaccine ? (Click Here)

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This page was established by Donald Forsdyke circa 1998 and was  last edited: 01 Sep 2014


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