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Oxford researcher John Frater explains the strategy of targeting viral reservoirs to beat HIV.
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May 14, 2015
Functional Cures in HIV Patients Receiving
High Level Whole Body Hyperthermia (Heatheal)
“A Twenty-five Year Effort”
Milton Yatvin (1,2,5), Alexei Suvernev (3,4,5), George Ivanov (3,4) Sergey Cheresiz (3,4)
Oregon Health & Sciences University Portland, Oregon, USA (1), Reed College Portland, Oregon, USA (2), Novosibirsk State Medical University, Novosibirsk, Russian Federation (3), Siberian Hyperthermia Institute, Novosibirsk, Russian Federation (4), WBH TEC LLC, Washington, DC, USA (5).
The current goal of HIV researchers and therapists is to obtain either complete or functional cures. The latter refers to the establishment of long-term remissions in the absence of therapy. Attaining that goal has been, and continues to be, blocked by the inability of current “HIV activating” drugs to activate and eliminate all the body’s reservoirs of latently infected cells. We believe that a therapy already exists witch is capable of activating HIV production in latently HIV infected cells. Moreover, as a result of its global distribution throughout the body, it has the potential of doing so in all their reservoirs. In addition to activating the production of virus, that therapy also enhances immune function. Such treatments are already capable of producing long-term remissions and, perhaps, future cures. That therapy is Extreme level-whole body hyperthermia (Heatheal).
In1988 in an article published in Medical Hypothesis, We proposed that high level-whole body hyperthermia be used to treat HIV patients (1). Unfortunately, due consideration of that hypothesis was undermined in 1990 by the NIH’s response to the work of physicians in Atlanta, Georgia who used whole body hyperthermia to treat two patients who were in the late stages of AIDS. As a result they lacked the immunological capacity to respond to the beneficial effects of hyperthermia and died shortly after treatment.
Responding those treatments, the National Institute of Allergy and Infectious Diseases (NIAID) established a panel to “evaluate” the potential value of Whole Body Hyperthermia in treating patients with HIV. After deliberation, the panel released the following statement: “there appears to be no clinical, immunological or virological support for the use of hyperthermia in the treatment of HIV disease or Kaposis Sarcoma. Neither does there appear to be any support for further human experimentation in this area at this time.” In addition the panel also referred to the Medical Hypothesis article, said, “Yatvin’s theoretical arguments do not address the fact that following acute HIV infection, the virus is incorporated into human DNA and thus is not accessible to denaturation.” Then, on January 5, 1990 the New York Times quoted Dr. Anthony Fauci, who then was and still remains the Director of NIAID, on the use of Whole Body Hyperthermia: “There is very little rationale for the procedure, since some laboratory experiments have shown that heat actually increased the activity of the virus rather than killing it” (2,3).
As a result of the failed treatments in Atlanta, the panel’s negative conclusion, and Dr. Fauci’s skepticism, there was essentially no support in the USA for further exploration of the possibilities of using WBH for treating HIV infected patients. Nevertheless, we persisted despite those views and in a subsequent article in Selective Cancer Therapeutics in 1991 (4), which was reprinted in AIDS Patient Care with an addendum in 1992 (5), we said,“ One such approach (to fighting HIV) could involve activating immunologically silent cells either by heat (HL-WBH) or various cytokines”.
Later, in 1993 in AIDS Patient Care (6) we reported that “Heat induction of viral and Hsp proteins would overcome the ability of these quiescent cells to escape immune surveillance. Such treatment is more likely be effective early in HIV infection because virus-specific responses of CTLs are lost in patients with advanced HIV infections”. And, in a report in Oncology (7), we said, “We believe that the current approach of trying to spare CD4+ and other HIV infected cells in individuals during the asymptomatic stage of HIV disease is counter-productive. The strategy of trying to kill diseased cells during the early stages of disease is preferable, in that it presents the possibility of eliminating an HIV latent cell infection. We believe that patients with relatively intact immune systems will be able to eliminate such unmasked cells.” (7). In making those statements we were trying to increase awareness in the field that one of the actions of high-level whole body hyperthermia (Heatheal) is its ability to activate virus production in latently infected cells and enhance patient immune function. Unfortunately, this approach to recognizing and dealing with the latent cell pool was not pursued until some years later (8-12).
Despite roadblocks colleagues and I have continued to pursue both basic and clinical research related to HL-WBH treatment for HIV infections. In 2009 we participated in a clinical trial at the Siberian Hyperthermia Institute, Novosibirsk, the Russian Federation. It involved 30 HIV patients, 15 female and 15 male, who were naïve with respect to antiretroviral therapy ART prior to and throughout the trial. All had CD4+ cell counts of 400 or above at the start of the trial, indicating that they were relatively immune competent. To start, patients received three HL-WBH treatments at weekly intervals and a fourth treatment eight weeks after the third. No additional treatments were administered for the next twenty-eight weeks. At that time all patients had viral load reductions that averaged 1.8 logs (13). The remissions lasted a minimum of 200 days, which is more than 20X the remissions reported by Davey et al. after cessation of HAART (14).
Stimulation of immune function as well as reactivating latent HIV-1infected cells is essential for successful eradication of virus, and exposure to Heatheal does both. It also could accomplish the following: a) up-regulation of all components of the latent HIV infected cell reservoir as a result of its “Global” distribution of heat throughout the entire body, b) induces a prolonged non-canonical up-regulation of the latent HIV infected cell pool; and c) enhances immune function, thereby enabling up-regulated cells to be recognized and eliminated by both re-invigorated and new cytotoxic T-cells. Specifically, Heatheal induces heat shock proteins, regulators of immune response that activate both innate and adaptive immunity (15- 19).
Finally a report by Dowd et al. (20) supports a role for HL-WBH in modifying antibody access to relatively inaccessible viral epitopes. They showed that AbE53 neutralized mature West Nile virus in a time-and-temperature dependent manner. Because the kinetics of neutralization increased with elevated temperature, they speculate that certain classes of antibodies may function better in the context of a febrile response. Their findings are consistent with a model in which dynamic epitope motion provides an opportunity for antibodies to engage virions at otherwise inaccessible epitopes.
When HIV infected patients with relatively intact immune systems are exposed to a Heatheal treatment regimen, the evidence offered above indicates that they are more likely to be able to purge the critically important, long lived, pool(s) of latently infected cells than those treated by HAART. Because of its global action, HL-WBH has the potential to exert an effect on any and all of the latent cell reservoirs. It does so as a result of its capacity to enhance immune function and up-regulate and prolong HIV production.
1.Yatvin, M.B. Medical Hypothesis 27,163-165 (1988)
2. Geelen, J.L.M.C. J. gen. Virol. 69, 2913-2917 (1988),
3. Stanley, S.K. et al. J of Immunology 4, 1120-1126 (1990)
4. Yatvin, M.B. Selective Cancer Therapeutics 7, 23-28 (1991)
5. Yatvin, M.B. AIDS Patient Care 6, 232-236 (1992)
6. Yatvin, M.B. et al. AIDS Patient Care 7, 5-9 (1993)
7, Yatvin, M.B. et al. Oncology 50, 380-389 (1993)
8. Chun T.W. et al. Nat Med 1, 1284-1290 (1995)
9. Chun T.W. et al. Proc Natl Acad Sci 94, 13193–13197 (1997)
10. Wong J.K. et al. Science 278, 1291–1295 (1997)
11. Finzi D. et al. Science 278, 1295–1300 (1997)
12. Finzi D. et al. Nat Med 5, 512–517 (1999)
13. Suvernev et al, 11th Inter. Cong. of Hyperthermic Oncol. Aug. 8, 2012, Kyoto Japan
14. Davey R.T. et al. PNAS 96, 15109–15114 (1999)
15. Pockley, A.G. Review The Lancet Published online April 29, 2003
16. Basu, S. et al. Internat Immunology 12, 1549-1546 (2000)
17. Anderson K.M. And Srivastava P.K. Immunol Lett 74, 35-39 (2000).
18. Basu and Srivastava Cell Stress Chapter 5, 443-451 (2000)
19. Srivastava P.K. et al. Nat Review Immunol 2, 185-194 (2002)
20. Dowd K.A. et al. PLoS pathogens 7, 1-14 (2011)
May 15, 2015
Yatvin and colleagues cite their 1988 paper in Medical Hypothesis that proposed hyperthermic treatment. Shortly thereafter, having had little success in getting my AmFAR grant renewed, I proposed what some now call the "kick and kill" approach to HIV cure in Medical Hypothesis (1991) 34, 24-27 (see http://post.queensu.ca/~forsdyke/aids.htm). We are grateful to David Horrobin (1939-2003) for his editorship of Medical Hypothesis in those difficult years.