A New Direction in AIDS TherapyBy Andrew Keech, PhD
The appearance of AIDS in the early 1980s shook the medical and scientific communities to their core. Prior to this it appeared that modern medicine had infectious disease on the run. Age-old killers like polio and smallpox had been all but eliminated. There was a general feeling that all diseases would be conquered in time, that viruses and other pathogens had met their match at last.
Then this new killer appeared out of nowhere. It killed young, healthy people rapidly and horribly. No treatment gave more than temporary relief. Just when humanity had seemed on the verge of complete victory over infectious disease, this new threat, worse than any previously known, loomed over us. Our ignorance of the retrovirus that finally was linked to the disease and our futile attempts to control it made it seem as if nature was laughing at our hubris.
In the quarter century since AIDS first appeared, a great deal has been learned about viruses in general and retroviruses in particular. Many new treatments have emerged for both HIV infection itself and the opportunistic diseases which take advantage of the compromised immune systems of AIDS sufferers. Yet still the cure for the disease eludes us, as does an effective vaccine. According to the Joint United Nations Programme on AIDS and the World Health Organization (WHO), some 25 million people have died of AIDS in those 25 years (that's a million a year), and an estimated 38.6 million are infected with the virus, making it one of the most lethal epidemics in history. In 2005, AIDS claimed 2.4-3.3 million lives, including over 570,000 children[1].
While sub-Saharan
Efforts continue to find both a cure for AIDS and an effective vaccine to prevent further AIDS infections. Yet the very nature of retroviruses make them an exceedingly difficult target.
HIV is a single-stranded, positive-sense, enveloped RNA virus. When the virus infects a cell, its RNA is encoded into a double-stranded DNA molecule by a virally encoded reverse transcriptase molecule present in the viral particle. The viral DNA is then integrated into the cellular DNA by a virally encoded integrase enzyme. Often the virus will become latent at this stage, making any antiviral treatment impossible until it once again becomes active. This latency period can last for years. When the virus becomes active, it replicates and produces large numbers of viral particles that are then released to infect other cells.
What is particularly lethal about HIV is that it primarily infects the very cells in the immune system that would normally keep it in check – CD4+ T cells, macrophages and dendritic cells. Infection of CD4+ cells kills in three different ways: direct viral killing of the cells; increased rates of apoptosis (programmed cell death) in infected cells; and targeting of CD4+ cells by CD8 cytotoxic lymphocytes that recognize infected cells and destroy them. This loss of CD4+ cells is cumulative, and eventually the numbers of CD4+ cells decline below critical levels to where cell-mediated immune function is lost. This leaves the body open to opportunistic infections like Pneumocystis pneumonia and Kaposi's sarcoma, which are what actually kill victims. By robbing the body of its own defenses against it, HIV ultimately kills its host, though at times over a period of years. The virus also mutates rapidly making it difficult to produce an effective vaccine.
The main strategy that the scientific community has used in its attempts to attack HIV reflect the trends used against other pathogens, namely a pharmaceutical strategy to directly attack the virus. As such the antiviral drugs that have been developed to combat HIV have many of the same limitations as previous pharmaceutical drugs developed to combat viral infections. First, they target the infected cells directly, usually by disrupting their ability to replicate the virus. Unfortunately, many uninfected cells in the area of the infected cells are collaterally affected and killed. These drugs are also not effective in all patients. Secondly, all of the antivirals developed to fight HIV have serious side effects, including nausea, diarrhea, vomiting, anemia, and others. Lastly, these drugs are very expensive and thus not available to those who have no insurance coverage or other means of paying for them. This is a major problem in
Currently the FDA has approved 29 pharmaceutical drugs for use in the treatment of HIV infection[5]. Nearly all inhibit viral replication and include reverse transcriptase inhibitors and protease inhibitors. One, Fuzeon, blocks viral fusion to target cells. HIV has responded by developing resistant strains that are not affected by the drugs, even combinations of them. The future outlook for AIDS treatment from a pharmaceutical perspective remains bleak.
This situation has forced scientists to look elsewhere for effective solutions. ART focuses primarily on attacking infected cells directly. A more effective method would be to stimulate the body’s own defenses to attack the virus as well as infected cells. This would make it much more difficult for the HIV to avoid attack through mutation as the immune system has the ability to adapt to the new strains rapidly. One such area of investigation is based on an old remedy, colostrum, the first milk produced by a mammal following the birth of a newborn, which was widely investigated as an antibiotic before modern antibiotics were developed. Specifically one of the components of colostrum, called alternatively PRP (proline-rich polypeptide), transfer factor, dialyzable leukocyte extract (DLE), infopeptides, or colostrinin, has shown great promise. This unique polypeptide (actually a peptide fraction of whole colostrum) has been shown to have immunomodulatory abilities as well as antiviral activity[6].
The principal immunomodulatory action of PRP is to stimulate the maturation of immature thymocytes into either helper or suppressor (also called regulatory) T cells[7],[8], depending on the need of the body at the time. Helper T cells present antigens (such as a viral protein) to B lymphocytes, which then produce antibodies to that antigen[9]. Helper T cells also help produce memory T cells which retain the “memory” of an antigen in order to expedite the production of antibodies in the event the antigen is reencountered in the future[10]. Suppressor T cells, on the other hand, deactivate other lymphocytes after an infection has been cleared to avoid damage to healthy tissues[11]. PRP also promotes the growth and differentiation of B cells in response to an infection[12] and the differentiation and maturation of macrophages and monocytes[13]. The activity of Natural Killer (NK) cells, cytotoxic cells of the innate immune system, was increased up to 5 times by PRP[14],[15],[16].
PRP modulates the cytokine system as well. It stimulates the production of a wide range of cytokines, including the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), which initiates the inflammatory cascade of cytokine production, and interferon-gamma (INF-γ), and the anti-inflammatory cytokines interleukins-6 and -10 (IL-6 and IL-10)[17].
PRP functions as a molecular signaling device which works through receptors on target cell surfaces[18] to initiate or suppress the production of specific proteins. It is not species specific; PRP from bovine colostrum works as effectively in humans as PRP from human colostrum[19]. As it is a natural product, there are no known side effects or drug interactions, and it can be taken safely by all ages.
Preliminary experimental and clinical studies have shown that PRP holds great promise in combating AIDS. In an experimental in vitro system, PRP blocked HIV infection of cells[20]. PRP in combination with zidovudine (ZDV), an anti-retroviral drug, is known to be effective in patients suffering from AIDS-Related Complex (ARC), increasing levels of white blood cells, CD8 lymphocytes and IL-2[21]. A preliminary study on 25 men with AIDS resulted in clinical improvement or a stabilized clinical condition in 20 of the 25. 12 of 14 anergic (unresponsive to antigenic stimulation) patients demonstrated restored delayed type hypersensitivity to recall antigens within 60 days[22].
Recent research has found that while HIV targets both helper CD4+ and suppressor (or regulatory) CD4+ T cells, they are not suppressed at the same rate. In fact, regulatory T cells decline at a slower rate than helper T cells. As regulatory T cells actively down-regulate the immune response, the disparity between regulatory T cells and helper T cells tends to accelerate the course of the disease and is a strong clinical predictor of CD4+ depletion and death[23]. The immunomodulatory effect of PRP could potentially help restore the balance of helper and regulatory T cells.
With this alternative treatment approach in mind, clinical trials were developed to test a new oral spray product containing colostrum-derived PRP as well as other growth and immune factors, including trypsin inhibitors, glycoconjugates, orotic acid, lysozyme, and others. Phase I trials were conducted at the Infectious Disease Clinic in
|
|
Initial |
30 Day |
60 Day |
90 Day |
|
Total Patient Reports |
35 |
31 |
20 |
17 |
|
Score |
6.1 |
1.8 |
1.2 |
1.3 |
|
Percent Reduction |
|
69 |
80 |
79 |
|
Expected Phase III % Reduction |
|
50-70 |
60-80 |
75-85 |
Table1. Clinical Symptoms Score.
|
Initial |
30 Day |
60 Day |
90 Day |
|
|
Total Patient Reports |
30 |
27 |
13 |
13 |
|
Score |
4.0 |
2.5 |
2.1 |
1.6 |
|
Percent Reduction |
|
38 |
49 |
60 |
|
Expected Phase III % Reduction |
|
30-50 |
40-60 |
50-70 |
Table 2. Physical Findings Score.
|
|
Initial Total |
30 Day Total |
60 Day Total |
|
|
92,448 |
9,755 |
445 |
|
|
28,049 |
625 |
n/a |
|
|
33,093 |
239 |
n/a |
|
|
439 |
n/a |
175 |
|
|
59,821 |
n/a |
320 |
|
|
40,381 |
180 |
n/a |
|
Expected Phase III % Reduction |
|
<1,000 |
<500 (<250 at 90 days) |
Table 3. Viral Load. Viral load counts are available only from six patients from the Phase II Trial.
|
|
Initial Total |
30 Day Total |
60 Day Total |
|
|
74 |
153 |
121 |
|
|
274 |
282 |
n/a |
|
|
245 |
301 |
n/a |
|
|
60 |
47 |
n/a |
|
|
101 |
n/a |
117 |
|
|
211 |
n/a |
291 |
|
|
249 |
271 |
n/a |
|
Expected Phase III % Reduction |
|
>250 |
>250 (>500 at 90 days) |
Table 4. CD4+ Count. Only available for seven patients from the Phase II Trial.
The status of specific clinical conditions in the patients was also monitored during the two studies. Results are shown in Tables 5-12.
|
|
30 Days |
60 Days |
90 Days |
||||||
|
|
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
|
Patients Reporting |
16 |
14 |
11 |
6 |
6 |
6 |
5 |
5 |
5 |
|
Percent of Total |
|
87.5 |
68.8 |
|
100 |
100 |
|
100 |
100 |
|
Expected Phase III %Reduction |
|
70-90 |
50-75 |
|
>80 |
>75 |
|
>80 |
>75 |
Table 5. Diarrhea.
|
|
30 Days |
60 Days |
90 Days |
||||||
|
|
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
|
Patients Reporting |
25 |
22 |
11 |
12 |
10 |
10 |
10 |
9 |
9 |
|
Percent of Total |
|
88 |
80 |
|
83 |
83 |
|
90 |
90 |
|
Expected Phase III %Reduction |
|
70-90 |
50-75 |
|
>80 |
>75 |
|
>80 |
>75 |
Table 6. Nausea
|
|
30 Days |
60 Days |
90 Days |
||||||
|
|
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
|
Patients Reporting |
4 |
4 |
3 |
2 |
2 |
2 |
1 |
1 |
1 |
|
Percent of Total |
|
100 |
75 |
|
100 |
100 |
|
100 |
100 |
|
Expected Phase III %Reduction |
|
70-90 |
50-75 |
|
>80 |
>75 |
|
>80 |
>75 |
Table 7. Vomiting.
|
|
30 Days |
60 Days |
90 Days |
||||||
|
|
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
|
Patients Reporting |
8 |
6 |
6 |
5 |
4 |
4 |
5 |
4 |
4 |
|
Percent of Total |
|
75 |
75 |
|
80 |
80 |
|
80 |
80 |
|
Expected Phase III %Reduction |
|
70-90 |
50-75 |
|
>80 |
>75 |
|
>80 |
>75 |
Table 8. Fever.
|
30 Days |
60 Days |
90 Days |
||||||
|
|
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
|
Patients Reporting |
16 |
14 |
11 |
6 |
6 |
6 |
5 |
5 |
5 |
|
Percent of Total |
|
87.5 |
68.8 |
|
100 |
100 |
|
100 |
100 |
|
Expected Phase III %Reduction |
|
70-90 |
50-75 |
|
>80 |
>75 |
|
>80 |
>75 |
Table 9. Cough.
|
|
30 Days |
60 Days |
90 Days |
||||||
|
|
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
|
Patients Reporting |
3 |
3 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
|
Percent of Total |
|
100 |
67 |
|
100 |
100 |
|
100 |
100 |
|
Expected Phase III %Reduction |
|
70-90 |
50-75 |
|
>80 |
>75 |
|
>80 |
>75 |
Table 10. Tuberculosis.
|
30 Days |
60 Days |
90 Days |
|||||||
|
|
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
|
Patients Reporting |
29 |
23 |
18 |
17 |
14 |
14 |
16 |
12 |
12 |
|
Percent of Total |
|
79 |
62 |
|
82 |
82 |
|
75 |
75 |
|
Expected Phase III %Reduction |
|
70-90 |
50-75 |
|
>80 |
>75 |
|
>80 |
>75 |
Table 11. Fatigue/Malaise.
|
|
30 Days |
60 Days |
90 Days |
||||||
|
|
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
Total |
Reduction |
Elimination |
|
Patients Reporting |
8 |
6 |
5 |
4 |
4 |
4 |
4 |
4 |
4 |
|
Percent of Total |
|
75 |
62 |
|
100 |
100 |
|
100 |
100 |
|
Expected Phase III %Reduction |
|
70-90 |
50-75 |
|
>80 |
>75 |
|
>80 |
>75 |
Table 12. Paresthesia.
A comment on the CD4+ results. CD4+ counts are a valid marker of the progression of the HIV infection. However, CD4+ levels are only one measure of wellness. With PRP treatment, CD4+ levels are likely to normalize more slowly than other measures of wellness. Viral load levels may actually increase in the peripheral blood after initiation of treatment as the virus is prevented from entering T cells, particularly in the lymph nodes. This increase in blood levels of HIV causes a temporary drop in CD4+ levels in the peripheral blood. CD4+ levels do increase over time with continued treatment. Normal CD4+ counts for adults range from 500-1500 cells/mm3.
In the Nigerian study, PRP oral spray products were shown to boost T-cell (CD4+) levels to normal or near-normal levels (median 502, none less than 300) in AIDS patients whose T-cell levels prior to treatment were well below normal (median 275) (see Tables 13 and 14). Along with the increase in T-cells came a remission of AIDS symptoms within two days of start of treatment, including nausea, vomiting and diarrhea. Weight gains of up to 5% were recorded (Table 15). Patients taking the PRP spray fared much better in terms of quality of life than did patients on anti-retroviral drugs.
|
|
Before |
After |
||
|
|
No. |
% |
No. |
% |
|
150-200 |
17 |
29% |
0 |
0% |
|
201-250 |
10 |
17% |
0 |
0% |
|
251-300 |
21 |
36% |
0 |
0% |
|
301-400 |
4 |
7% |
8 |
14% |
|
401-500 |
4 |
7% |
19 |
33% |
|
501-600 |
2 |
3% |
12 |
21% |
|
601-1000 |
0 |
0% |
19 |
33% |
|
Totals |
58 |
|
58 |
|
Table 13. CD4+ counts in 58 experimental
subjects before and after application of oral
PRP spray.
Table 14. CD4+ lymphocyte levels in HIV compromised individuals before and after treatment with PRP oral spray. This bar graph clearly illustrates the marked increase in CD4+ lymphocyte counts in patients with long-term AIDS and severely depleted CD4+ counts after administration of oral PRP spray. Results from Trial 1 held in
Table 15. Cd4+ lymphocyte levels in HIV compromised individuals before and after treatment with PRP oral spray. These results are from Trial 2 held in
Table 16. A graphical representation of changes in CD4+ lymphocyte levels in patients participating in Trial 2. While levels for some increased over 100% in some cases, what is particularly significant is that levels increased for all participants in the study.
|
PRP |
ART |
||
|
Loss/Gain |
No. |
Loss/Gain |
No. |
|
-10 |
1 |
-11 |
1 |
|
-7 |
1 |
-10 |
1 |
|
-4 |
1 |
-8 |
2 |
|
-3 |
1 |
-7 |
1 |
|
0 |
2 |
-6 |
2 |
|
+2 |
1 |
-4 |
4 |
|
+3 |
2 |
-3 |
3 |
|
+4 |
1 |
-2 |
4 |
|
+5 |
1 |
-1 |
1 |
|
+7 |
1 |
0 |
7 |
|
+8 |
1 |
+2 |
3 |
|
+11 |
1 |
+3 |
2 |
|
+12 |
2 |
+4 |
3 |
|
+15 |
1 |
+8 |
1 |
|
|
|
+10 |
1 |
|
|
|
+12 |
1 |
|
|
|
+22 |
1 |
|
|
|
+26 |
1 |
|
Average +3.4 |
|
Average +0.3 |
|
Table 17. Weight loss/gain for patients on oral PRP or anti-retrovirus therapy.
The results of the African trials confirm the earlier results that an oral PRP spray treatment can be an important alternative or adjunct therapy for AIDS patients. Further studies will be needed to study the long-term effects of the therapy and whether treatment over a longer period can eliminate the virus from the body. Phase III trials are currently underway under the auspices of WHO, and results should soon be available.
[1] Figures cited in Wikipedia article on AIDS, http://en.wikipedia.org/wiki/AIDS
[2] The Henry J. Kaiser Family Foundation: HIV/AIDS Policy Fact Sheet (November 2005).
[3] United Nations Department of Economic and Social Affairs/Population Division report: The Impact of AIDS (2004). http://www.un.org/esa/population/publications/AIDSimpact/AIDSWebAnnounce.htm
[4] BBC News, 24 October 2000, AIDS Drug Factfile http://news.bbc.co.uk/1/hi/health/background_briefings/aids/988245.stm
[5] U.S. Food and Drug Administration, “Drugs used in the treatment of HIV infection” (August 2006). http://www.fda.gov/oashi/aids/virals.html
[6] Zimecki, M, Artym, J. [Therapeutic properties of proteins and peptides from colostrum and milk] Postȩpy Higieny i Medycyny Doświadczalnej 59:309-323 (2005). Colostrum and milk are rich in peptides and proteins which play an active role in innate immunity. PRP has a variety of immunotropic functions, including the promotion of T cell maturation and inhibition of autoimmune disorders.
[7] Janusz, M, Staroscik, K, Zimecki, M, Wieczorek, Z, Lisowski, J. A proline-rich polypeptide (PRP) with immunoregulatory properties isolated from ovine colostrum. Murine thymocytes have on their surface a receptor specific for PRP. Archivum immunologiae et therapiae experimentalis (Warszava) 34(4):427-436 (1986). PRP has immunoregulatory properties. It induces the maturation of thymocytes into mature helper or suppressor T cells.
[8] Wieczorek, Z, Zimecki, M, Spiegel, K, Lisowski, J, Janusz, M. Differentiation of T cells into helper cells from immature precursors: identification of a target cell for a proline-rich polypeptide (PRP). Archivum immunologiae et therapiae experimentalis (Warszava) 37(3-4):313-322 (1989). The precursors of helper T cells belong to a minor thymocyte subset bearing the Thy-1 +/-, H-2+, L3T4-, lyt 2-, CD3- phenotype. PRP induced the production of antigens consistent with mature helper T cells
[9] Bishop, GA, Haxhinasto, SA, Stunz, LL, Hostager, BS. Antigen-specific B-lymphocyte activation. Critical Reviews in Immunology 23(3):159-197 (2003). B cells have the exclusive ability to produce and secrete immunoglobulins of various types. They also function in antigen presentation and the production of a number of cytokines and chemokines.
[10] Shi, M, Hao, S, Chan, T, Xiang, J. CD4+ T cells stimulate memory CD8+ T cell expansion via acquired pMHC I complexes and costimulatory molecules, and IL-2 secretion. Journal of Leukocyte Biology (2006). CD8+ memory T cell expansion following a second encounter with a pathogen is a hallmark of adaptive immunity. Antigen-specific CD4+ cells, activated by dendritic cells, stimulate the this expansion of CD8+ cells.
[11] Zimecki, M, Staroscik, K, Janusz, M, Lisowski, J, Wieczorek, Z. The inhibitory activity of a proline-rich polypeptide (PRP) on the immune response to polyvinylpyrrolidone (PVP). Archivum immunologiae et therapiae experimentalis (Warszava) 31(6):895-903 (1983). PRP administered to a test animal before immunization with PVP inhibits the immune response to this antigen. PRP did this by increasing the activity of suppressor T cells and by increasing the generation of new suppressor T cells.
[12] Julius, MH, Janusz, M, Lisowski, J. A colostral protein that induces the growth and differentiation of resting B lymphocytes. Journal of Immunology 140(5):1366-371 (1988). PRP induced resting B cells and supported their progression through the cell cycle to form mature B cells. It had the same action on splenocytes.
[13] Kubis, A, Marcinkowska, E, Janusz, M, Lisowski, J. Studies on the mechanism of action of a proline-rich polypeptide complex (PRP): effect on the stage of cell differentiation. Peptides 26(11):2188-2192 (2005). PRP affects the differentiation and maturation of cells of the monocyte/ macrophage lineage and may regulate in this way the inflammatory processes in which these cells participate.
[14] Research study carried out by Advanced Protein Systems,
[15] Effects of Oral Dietary Supplementation with Ai/E¹º® Upon Natural Killer (NK) Cell Activity in a Healthy Human Population. Quantum Research, Inc.,
[16] An Examination of Immune Response Modulation in Humans by Ai/E¹º® Utilizing A Double Blind Study. Immune Consultants, Inc.,
[17] Zablocka, A, Janusz, M, Rybka, K, Wirkus-Romanowska, I, Kupryszewski, G, Lisowski, J. Cytokine-inducing activity of a proline-rich polypeptide complex (PRP) from ovine colostrum and its active nonapeptide fragment analogs. European Cytokine Network 12(3):462-467 (2001). PRP induces the production of INF-γ, TNF-α, IL-6 and IL-10 in human whole blood cultures.
[18] Boldogh, I, Liebenthal, D, Hughes, TK, Juelich, TL, Georgiades, JA, Kruzel, ML, Stanton, GJ. Modulation of 4HNE-mediated signaling by proline-rich peptides from ovine colostrum. Journal of Molecular Neuroscience 20(2):125-134 (2003). PRP, also known as colostrinin, induces mitogenic stimulation as well as a variety of cytokines in peripheral leukocytes. It also possess antioxidant activity in pheochromocytoma (P12) cells, a cancer cell line used for in vitro studies. PRP was shown to reduce the amount of 4HNE-protein adducts, reduce intracellular levels of reactive oxygen species, inhibit 4HNE-mediated glutathione depletion, and inhibit 4HNE-induced activation of the molecular signal cascade which results in the production of c-Jun N-terminal kinase (JNK) in P12 cells. This shows that PRP acts as both an antioxidant and a molecular signaling device.
[19] Khan, A. Non-specificity of transfer factor. Annals of Allergy 38(5):320-322 (1977).
[20] Fernandez-Ortega, C, Dubed, M, Ruibal, O, Vilarrubia, OL, Menendez de San Pedro, JC, Navea, L, Ojeda, M, Arana, MJ. Inhibition of in vitro HIV infection by dialysable leucocyte extracts. Biotherapy 9(1-3):33-40 (1996). A PRP extract from leukocytes inhibits HIV infection in MT-4 cell cultures.
[21] Raise, E, Guerra, L, Viza, D, Pizza, G, De Vinci, C, Schiattone, ML, Rocaccio, L, Cicognani, M, Gritti, F. Preliminary results in HIV-1-infected patients treated with transfer factor (TF) and zidovudine (ZDV). Biotherapy 9(1-3):49-54 (1996). HIV-1 specific transfer factor (an alternative name for PRP) plus zidovudine (ZDV) was tested for efficacy in patients with AIDS-related complex (ARC). Patients receiving both transfer factor and ZDV experienced an increase in white blood cells, CD8+ lymphocytes and IL-2 levels over those receiving ZDV alone.
[22] Pizza, G, Chiodo, F, Colangeli, V, Gritti, F, Raise, E, Fudenberg, HH, De Vinci, C, Viza, D. Preliminary observations using HIV-specific transfer factor in AIDS. Biotherapy 9(1-3):4-47 (1996). 25 HIV infected patients at various stages (CDC stages II-IV) were treated with HIV-specific transfer factor (PRP) for periods of 60-1870 days. All patients were receiving antiviral treatment as well. Clinical improvement or a stabilized clinical condition was observed in 20 of the 25, and 12 of 14 anergic patients showed restored delayed hypersensitivity reactions to recall antigens within 60 days. Treatment was well-tolerated and appears beneficial to AIDS patients.
[23] Eggena, MP, Barugahare, B, Jones, N, Okello, M, Mutalya, S, Kityo, C, Mugyenyi, P, Cao, H. Depletion of regulatory T cells in HIV infection is associated with immune activation. Journal of Immunology 174(7):4407-4414 (2005). Immune activation during chronic HIV infection is a strong clinical predictor of death and may mediate helper CD4+ T cell depletion. Regulatory T cells actively down-regulate immune responses. In a study using 81 Ugandan volunteers, it was found that depletion of regulatory T cells occurs at different rates than other CD4+ T cells, resulting in an increased regulator to helper ratio in many patients with advanced disease. This skewing may contribute to T cell effector dysfunction.
Anderson, Ian, "Powdered Milk Cure for Fatal Diarrhoea" New Scientist. January:6 1994.
Berkhout, B, et al. Characterization of the anti-HIV effects of native lactoferrin and other milk proteins and protein-derived peptides. Antiviral Research 55(2):341-355 (2002). Bovine lactoferrin as well as peptides derived from lactoferrin blocks the entry process of HIV into cells.
Bogstedt, A.K.; et al. "Passive Immunity Against Diarrhea," Acta Paediatr 8:125-128, 1996.
Bishop, GA, Haxhinasto, SA, Stunz, LL, Hostager, BS. Antigen-specific B-lymphocyte activation. Critical Reviews in Immunology 23(3):159-197 (2003). B cells have the exclusive ability to produce and secrete immunoglobulins of various types. They also function in antigen presentation and the production of a number of cytokines and chemokines.
Boldogh, I, Liebenthal, D, Hughes, TK, Juelich, TL, Georgiades, JA, Kruzel, ML, Stanton, GJ. Modulation of 4HNE-mediated signaling by proline-rich peptides from ovine colostrum. Journal of Molecular Neuroscience 20(2):125-134 (2003). PRP, also known as colostrinin, induces mitogenic stimulation as well as a variety of cytokines in peripheral leukocytes. It also possess antioxidant activity in pheochromocytoma (P12) cells, a cancer cell line used for in vitro studies. PRP was shown to reduce the amount of 4HNE-protein adducts, reduce intracellular levels of reactive oxygen species, inhibit 4HNE-mediated glutathione depletion, and inhibit 4HNE-induced activation of the molecular signal cascade which results in the production of c-Jun N-terminal kinase (JNK) in P12 cells. This shows that PRP acts as both an antioxidant and a molecular signaling device.
Claes-Henrik, F., Chinenye, S., Elfstrand L., Hagman, C., Ihse,
Effects of Oral Dietary Supplementation with Ai/E¹º® Upon Natural Killer (NK) Cell Activity in a Healthy Human Population. Quantum Research, Inc., Scottsdale, Arizona (2001). Dialyzable Leukocyte Extract (DLE) was administered to 12 healthy male and female subjects aged 24-63. Natural Killer (NK) cell activity was prior to initiation of the study and after completion of the study. NK cell activity averaged 30 lytic units (LU) prior to the study and 101 LU following the study for an average increase of 207%. An Examination of Immune Response Modulation in Humans by Ai/E¹º® Utilizing A Double Blind Study. Immune Consultants, Inc.,
Eggena, MP, Barugahare, B, Jones, N, Okello, M, Mutalya, S, Kityo, C, Mugyenyi, P, Cao, H. Depletion of regulatory T cells in HIV infection is associated with immune activation. Journal of Immunology 174(7):4407-4414 (2005). Immune activation during chronic HIV infection is a strong clinical predictor of death and may mediate helper CD4+ T cell depletion. Regulatory T cells actively down-regulate immune responses. In a study using 81 Ugandan volunteers, it was found that depletion of regulatory T cells occurs at different rates than other CD4+ T cells, resulting in an increased regulator to helper ratio in many patients with advanced disease. This skewing may contribute to T cell effector dysfunction.
Floren, CH, Chinenye, S, Elfstrand, L, Hagman, C, Ihse, I. ColoPlus, a new product based on bovine colostrum, alleviates HIV-associated diarrhea. Scandinavian Journal of Gastroenterology 41(6):682-686 (2006). HIV-associated diarrhea is common in AIDS patients in developing countries particularly. It is a major contributory factor in the decrease in the helper CD4+ T-cell population. ColoPlus is a product derived from bovine colostrum which is rich in immunoglobulins, growth factors, antibacterial peptides and nutrients. It is specially designed for slow passage through the gastrointestinal tract and high nutritional value. The study was undertaken to see if oral doses of ColoPlus could influence HIV-associated diarrhea. The study was done in
Fernandez-Ortega, C, Dubed, M, Ruibal, O, Vilarrubia, OL, Menendez de San Pedro, JC, Navea, L, Ojeda, M, Arana, MJ. Inhibition of in vitro HIV infection by dialysable leucocyte extracts. Biotherapy 9(1-3):33-40 (1996). A PRP extract from leukocytes inhibits HIV infection in MT-4 cell cultures.
Greenberg PD, Cello JP. J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Dec 1;13(4):348-54. Related Articles, Links, Treatment of severe diarrhea caused by Cryptosporidium parvum with oral bovine immunoglobulin concentrate in patients with AIDS. Division of Gastroenterology, Hepatology, and Clinical Nutrition,
Heaton, P. Bovine colostrum immunoglobulin concentrate for cryptosporidiosis in AIDS. Archives of Disease in Childhood 70(4):356-357 (1994).
Heinerman, John. Dr. Heinerman¹s Encyclopedia of Anti-Aging Remedies.
Harmsen, M. C.; Swart, P. J.; Bethune, M.; Pauwels, R.; De Clercq, E.; et al. "Antiviral Effects of Plasma and Milk Proteins: Lactoferrin Shows Potent Activity against Both Human Immunodeficiency Virus and Human Cytomegalovirus Replication In Vitro," Journal of Infectious Diseases. 172:380-8, 1995.
Janusz, M, Staroscik, K, Zimecki, M, Wieczorek, Z, Lisowski, J. A proline-rich polypeptide (PRP) with immunoregulatory properties isolated from ovine colostrum. Murine thymocytes have on their surface a receptor specific for PRP. Archivum immunologiae et therapiae experimentalis (Warszava) 34(4):427-436 (1986). PRP has immunoregulatory properties. It induces the maturation of thymocytes into mature helper or suppressor T cells.
Julius, MH, Janusz, M, Lisowski, J. A colostral protein that induces the growth and differentiation of resting B lymphocytes. Journal of Immunology 140(5):1366-371 (1988). PRP induced resting B cells and supported their progression through the cell cycle to form mature B cells. It had the same action on splenocytes.
Khan, A. Non-specificity of transfer factor. Annals of Allergy 38(5):320-322 (1977).
Kubis, A, Marcinkowska, E, Janusz, M, Lisowski, J. Studies on the mechanism of action of a proline-rich polypeptide complex (PRP): effect on the stage of cell differentiation. Peptides 26(11):2188-2192 (2005). PRP affects the differentiation and maturation of cells of the monocyte/ macrophage lineage and may regulate in this way the inflammatory processes in which these cells participate.
Nord; DiJohn; Tripori; Tacket. "Treatment with Bovine Hyperimmune Colostrum of Cryptosporidial Diarrhea in AIDS Patients" AIDS. 4(6):581-584, 1990.
Nowa; McMichael. "How HIV Defeats the Immune system" Scientific American. Aug:58-65, 1995.
Pizza, G, Chiodo, F, Colangeli, V, Gritti, F, Raise, E, Fudenberg, HH, De Vinci, C, Viza, D. Preliminary observations using HIV-specific transfer factor in AIDS. Biotherapy 9(1-3):4-47 (1996). 25 HIV infected patients at various stages (CDC stages II-IV) were treated with HIV-specific transfer factor (PRP) for periods of 60-1870 days. All patients were receiving antiviral treatment as well. Clinical improvement or a stabilized clinical condition was observed in 20 of the 25, and 12 of 14 anergic patients showed restored delayed hypersensitivity reactions to recall antigens within 60 days. Treatment was well-tolerated and appears beneficial to AIDS patients.
Palmer,E.L. et al. Antiviral Activity of Colostrum and Serum Immunoglobulins A and G. J. Med. Virol. 5:123-129. 1980.
Plettenberg, A, et al. A preparation from bovine colostrum in the treatment of HIV-positive patients with chronic diarrhea. Clinical Investigator 71(1):42-45 (1993). Another study which examined the use of immunoglobulins from bovine colostrum in the treatment of chronic diarrhea in AIDS patients. 40% of the study group experienced complete remission of symptoms and 24% partial remission.
Raise, E, Guerra, L, Viza, D, Pizza, G, De Vinci, C, Schiattone, ML, Rocaccio, L, Cicognani, M, Gritti, F. Preliminary results in HIV-1-infected patients treated with transfer factor (TF) and zidovudine (ZDV). Biotherapy 9(1-3):49-54 (1996).
Richie, J.; "Update on the Management of Intestinal Cryptosporidiosis in AIDS" Ann.Pharmacother 28:767-778, 1994.
Rump, J. A.; Aarndt, R.; Arnold, A.; Bendick, C.; Dichtelmuller, H.; Franke, M.; Helm, E. B.; Jager, H.; Kampmann, B.; Kolb, P.; et al. "Treatment of Diarrhoea in Human Immunodeficiency Virus-Infected Patients with Immunoglobulins from Bovine Colostrum" Clin Investig. 70(7):588-594,(1992).
Stephan, W.; et al. "Antibodies from Colostrum in Oral Immunotherapy" J. Clinical Biochem. 28:19-23, 1990.
Shield, J, Melville, C, Novelli, V, Anderson, G, Scheimberg, I, Gibb, D, Milla, P. Bovine colostrum immunoglobulin concentrate for cryptosporidiosis in AIDS. Archives of Disease in Childhood 69(4):451-453 (1993).
Shield J, Melville C, Novelli V,
Shi, M, Hao, S, Chan, T, Xiang, J. CD4+ T cells stimulate memory CD8+ T cell expansion via acquired pMHC I complexes and costimulatory molecules, and IL-2 secretion. Journal of Leukocyte Biology (2006). CD8+ memory T cell expansion following a second encounter with a pathogen is a hallmark of adaptive immunity. Antigen-specific CD4+ cells, activated by dendritic cells, stimulate the this expansion of CD8+ cells.
Unger, B. L. P.; et al. "Cessation of Cryptosporidium-Associated Diarrhea in AIDS Patients After Treatment with Hyperimmune Bovine Colostrum" Gastroenterology. 98:486-489, 1990.
Wieczorek, Z, Zimecki, M, Spiegel, K, Lisowski, J, Janusz, M. Differentiation of T cells into helper cells from immature precursors: identification of a target cell for a proline-rich polypeptide (PRP). Archivum immunologiae et therapiae experimentalis (Warszava) 37(3-4):313-322 (1989). The precursors of helper T cells belong to a minor thymocyte subset bearing the Thy-1 +/-, H-2+, L3T4-, lyt 2-, CD3- phenotype. PRP induced the production of antigens consistent with mature helper T cells
Zablocka, A, Janusz, M, Rybka, K, Wirkus-Romanowska, I, Kupryszewski, G, Lisowski, J. Cytokine-inducing activity of a proline-rich polypeptide complex (PRP) from ovine colostrum and its active nonapeptide fragment analogs. European Cytokine Network 12(3):462-467 (2001). PRP induces the production of INF-g, TNF-a, IL-6 and IL-10 in human whole blood cultures.
Zimecki, M, Staroscik, K, Janusz, M, Lisowski, J, Wieczorek, Z. The inhibitory activity of a proline-rich polypeptide (PRP) on the immune response to polyvinylpyrrolidone (PVP). Archivum immunologiae et therapiae experimentalis (Warszava) 31(6):895-903 (1983). PRP administered to a test animal before immunization with PVP inhibits the immune response to this antigen. PRP did this by increasing the activity of suppressor T cells and by increasing the generation of new suppressor T cells.
Zimecki, M, Artym, J. [Therapeutic properties of proteins and peptides from colostrum and milk] Post?py Higieny i Medycyny Doswiadczalnej 59:309-323 (2005). Colostrum and milk are rich in peptides and proteins which play an active role in innate immunity. PRP has a variety of immunotropic functions, including the promotion of T cell maturation and inhibition of autoimmune disorders.
"Reducing viral levels in the body and stimulating natural immune capabilities holds the most promise in helping our immune systems contain the HIV virus," according to Dr. Nowa and Dr. McMichael in Scientific American.
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