TREATMENT BY PROGRAMMED LYMPHOCYTE ACTIVATION
Inductive Therapy to "Flush Out"
Latent Viruses, Plus Conventional
Therapy to Strike "On-the-Wing"!
Pangens and Virus Latency (1868)
Grouse Shooting and Antibiotic Resistance
Programmed Activation of T-Lymphocytes (1991)
Quotations from Chun et
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
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"
Pangens 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 know to be caused by a Morbillivirus:
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 hypothesis of pangenesis required modification by Hugo de Vries (1889) to make it approximate to modern concepts of the gene. 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. Similarly, "gemmules" in the form of RNA molecules can spread systemically throughout plant tissues, but they are not known to enter the host genome (Waterhouse et al. 2001).
Darwin, C. (1868) The Variation of Animals and Plants under Domestication. Chapter 27. Murray, London.
Muller, H. J. (1921) American Naturalist 56, 32-50.
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.
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:
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.
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:
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:
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:
They also noted that in latent HIV there is a low level of virus RNA production that is aborted. They speculate that:
Candidates for such transcription factors would include G0S30/EGR1 and other putative "G0/G1 switch genes" Click Here.
D. R. Forsdyke. Medical Hypothesis (1991) 34, 24-27. (With copyright permission from Academic Press)
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.
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:
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
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:
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:
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.
1. Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volherding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT, Jackson GG, Durack DT, Phil D, King D. Aids Collaborative Working Group. The efficiency of AZT in the treatment of patients with AIDS and AIDS-related complex. New Eng J Med 317, 185, 1987.
2. Yarchoan R, Mitsuya H, Myers CE, Broder S. Clinical pharmacology of 3'-azido-2', 3'-dideoxythyniidine and related dideoxynucleosides. New Eng J Med 321, 726, 1989.
3. Yarchoan R, Broder S. Development of antiretroviral therapy for AIDS and related disorders. New Eng J Med 316, 557, 1987.
4. Mitsuya H. Broder S. Strategies for antiviral therapy in AIDS. Nature 325, 773, 1987.
5. Peterlin BM, Luciw PA. Replication of the human immunodeficiency virus: strategies for inhibition. Biotechnol 6, 794, 1988.
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7. Forsdyke DR. Further implications of a theory of immunity. J Theor. Biol 52, 187, 1975.
8. Schwartz RH. Acquisition of immunologic self-tolerance. Cell 57, 1073, 1989.
9. Bluestone JA, Cron RQ, Cotterman M, Houlden BA, Matis LA. Structure and specificity of T cell receptor gamma-delta on MHC antigen-specific CD3+, CD4-, CD8- T lymphocytes. J Exp Med 168, 1899, 1988.
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.
11. Vidovic D. Rogfic M, McKune K, Guerder S, Mackay C, Dembic Z. Qa-1 restricted recognition of foreign antigens by a gamma-delta T-cell hybridoma. Nature 340, 646, 1989.
12. Wallis V J. Leuchards E, Chauduri H, Davies JS. Studies in hyperlymphoid mice. Immunology 38, 163, 1979.
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.
14. Miller RA, Sturman 0. T-cell repopulation from functionally restricted splenic progenitors. J. Immunol 133, 2925, 1984.
15. Fauci AS. The human immunodeficiency virus: infectivity and mechanism of pathogenesis. Science 259, 617, 1988.
16. Levy JA. Mysteries of HIV: challenges for therapy and prevention. Nature 333, 519, 1988.
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, 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.
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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.
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Some quotations from Tae-Wook Chun et al. (1998)
Some quotations from David Ho (1998)
Steve Bunk's article from The Scientist 1998
New Weapon Attacks Latent HIV Reservoirs. (Click Here)
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:
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
1. S. Bunk with comments by D.D. Richman and R.F. Siliciano, Hot Papers, The Scientist, 13:22, 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:
"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]
Definition of "Antibiotic"
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.]
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
Another gospel: American Heritage Dictionary 1996.
For more on this matter, see:
Bentley, R.& Bennett, J. W. (2003) What is an antibiotic? revisited. Advances in Applied Microbiology 52, 303-331.
The Truth Continues to Dawn
"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 to eradicating this latent reservoir are urgently needed."
T. Pierson, J. McArthur & R. F. Siliciano. (2000) Annual Reviews of Immunology 18, 665-708.
|In October 2000 it was eventually admitted
"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.
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.
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 antisense oligonucleotides and specific immunotherapy.
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.
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.
More of the Same in South Africa (Click Here) The Medical Research Council of South Africa becomes part of the problem not the solution to the problem.
The Drug Companies Win the "Image Game" and Promote the Spread of AIDS (Click Here)
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Date last edited: 06 Nov 2003
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