A NEW DIRECTION IN AIDS THERAPY   

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 Africa has been hardest hit, AIDS is a major problem globally.  Over one million are reported to be infected in China and six million in India.  More than a half million have died from AIDS in the US, and over a million are infected (2).  In Botswana, approximately one in three people in the entire country are infected, and life expectancy has declined from 65 pre-AIDS to only 40 today(3).

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 Africa where nearly all AIDS victims have no means to pay for expensive antiretroviral therapies (ART).   Combination therapy, which is currently the treatment of choice, costs about $950 a month.  Drug companies have lowered their prices in some African countries to about $500 a month, but this is still far beyond most people’s ability to pay.  The average monthly salary among middle class wage earners in Uganda, for example, is only about $400 a month(4).

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 Dayton, Ohio, from February to April, 1996.  Phase II trials were conducted at the University of Nairobi, Nairobi, Kenya, from March to August 2000.  A total of 39 patients took part in the two studies.  Results of the Nigerian study are summarized in Tables 1-4.

Table1.  Clinical Symptoms Score. 

Table 2.  Physical Findings Score.

Table 3.  Viral Load.  Viral load counts are available only from

six patients from the Phase II Trial.

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.

Table 5.  Diarrhea.

Table 6.  Nausea

Table 7. Vomiting.

Table 8.  Fever.

Table 9. Cough.