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What is the real extent of the AIDS epidemic? Why does AIDS attract so
much controversy? Do conventional anti HIV drugs do more harm than good? Are
there safe and effective treatments that can be made widely available at
This special mini-series is part of an in-depth report, Unravelling
AIDS, to be published by ISIS later this year.
If you are interested in reserving a copy of the full report at a
special prepublication price of £7.50, please e-mail [email protected]
The most effective way to control the HIV/AIDS pandemic would be the development
of a safe and effective HIV vaccine. Unfortunately, despite enormous scientific
and financial resources being deployed worldwide over the past 15 years, no
vaccine candidate is on the immediate horizon [1,2] (but see "Pink panacea,
an AIDS vaccine?" this series). There are strong indications, besides,
that the AIDS vaccines currently tested in humans are not only ineffective but
also harmful [3-5]. In addition, current medical therapy of HIV disease is extremely
toxic, with multiple side effects and drug interactions (see "AIDS &
HIV?" this series). It is also very expensive, and carries risks of developing
drug-resistant HIV strains.
It is clearly desirable to pursue other less toxic, inexpensive,
non-drug approaches in order to slow the spread of HIV infection and to decrease
the burden of HIV infection and treatment.
The answer may come from certain antibodies that appear to be
directly involved in controlling HIV disease progression [6,7]. These antibodies
have specific affinity, or cross reactivity, to the HIV-1 envelope protein (gp120
surface antigen, residues 280-302, designated peptide NTM); but may be naturally
occurring auto-antibodies (antibodies generated against the individual's
own antigens) against a small protein molecule that acts to dilate the blood
vessels in the intestine, the vasoactive intestinal peptide (VIP) [8,9].
It so happens that aerobic exercise training stimulates the formation
of these anti-VIP/NTM antibodies  in both normal and HIV-positive individuals,
and perhaps both could benefit from such exercise .
Increased levels of anti-VIP/NTM antibodies induced by exercise
may have two beneficial effects. First, in HIV-negative individuals, the anti-VIP/NTM
antibodies could bind HIV particles in circulation and prevent them from reaching
their target cell, thereby, reducing the risk of infection with HIV and decrease
the transmission of the disease. Second, in HIV-positive individuals, increased
levels of anti-VIP/NTM could slow HIV disease progression and reconstitute the
damaged immune system.
Aerobic exercise may be an important, inexpensive, non-toxic,
widely available front line defence and therapy against HIV/AIDS. By acting
as an immune stimulant (for both HIV positive and HIV negative individuals),
it creates a type of "natural vaccine" that, if widely adopted, could contribute
to a worldwide slow-down of the AIDS pandemic.
HIV and AIDS disease
The first step in HIV infection involves the gp 120 on the outer envelope of
the virus binding to receptors on the cell surface of the host, allowing the
HIV virus to enter the cell. The central portion of the gp120 molecule has an
immunoglobulin-like structure, which facilitates participation in the immune
network. Therefore, immediately after infection, HIV tries to produce a fit
to the host idiotype (individual type) by producing thousands of variants
of gp120. This process of adaptation usually takes years, and during this time,
the host immune system is more or less able to control the HIV disease.
In some HIV-infected persons, this period is short, and in others it can be
quite long, giving rise to the designations "slow" and "fast"
disease progression. After this latent period, a separate fraction of viruses
will be established whose gp120 carries the host idiotype [11-13]. This population
of HIV becomes accepted by the host immune system as 'self' and
therefore protected from the host's immune attack. Even worse, these gp120
molecules will be included in regulation of the immune network, destabilizing
its vital components and accelerating progression of disease . In this way,
HIV may escape from the latent period and progressively destroy the immune system
of the infected person.
The gp120 protein represents the key component of all AIDS vaccine candidates
that are currently in clinical trials. These vaccines may have an important
flaw in that they produce antibodies that neutralize only the HIV variants,
which carry vaccine-like gp120. As the variants of gp120 are produced by the
HIV infection, the vaccine antibodies may have the effect of disarming the immune
system's antiviral response and thus, increasing the likelihood of rapid
disease progression [1,4,5]. This phenomenon has been seen in gp120 vaccine
volunteers who later became infected with HIV [15,16], and would certainly reduce
the utility of an HIV vaccine in AIDS prevention.
Useful auto-antibodies in HIV disease
If an Achilles' heel exists in HIV, it might be in the central portion
of gp120 (residues 280-302, RSANFTDNACTIIVQLNESVEIN, designated as peptide NTM
). (The letters stand for different amino acids: R=Arginine, S=Serine, A=Alanine,
N=Asparagine, F=Phenylalanin, T=Threonine, D=Aspartic acid, C=Cystine, I=Isoleucine
V=Valine, Q=Glutamine, L=Leucine, E=Glutamic acid) This portion of the molecule
is highly conserved in all known HIV variants and appears to be crucial for
viral infectivity. In fact, researchers have demonstrated that minimal changes
in this sensitive peptide region will completely abolish HIV infectivity. Unfortunately,
this part of gp120 is not immunogenic in humans  because the immune system
treats this part of gp120 as 'self', possibly due to peptide 's
similarity to several human proteins . However, an antibody, found in both
HIV positive and HIV negative individuals, seems to have reactivity to this
region of the gp120 molecule.
A computer-assisted search of the Swiss-Prot database reveals vasoactive intestinal
peptide (VIP) as the best match to NTM among currently analyzed human proteins
[8,9]. The antibodies reacting to NTM may therefore be auto-antibodies against
VIP is a small naturally occurring peptide, which plays several important roles
in the human body as a vasodilatator (dilates blood vessels), neurotransmitter,
and modulator of the immune system.
VIP stimulates natural killer (NK) cells in the immune system (among the first
line of defence against infection) and also the production of cytokine, a hormone
that influences the activity of other cells in the immune system. VIP therefore
has a very important role in modulating the immune system.
The HIV protein gp120 is sufficiently similar to VIP to serve as a molecular
mimic and interfere with its function. The main consequence of this mimicry
is to undermine the NK cells, making them dysfunctional, which is common in
HIV-infected subjects. As Peruzzi and co-workers demonstrated, gp120 inhibits
the ability of NK cells to kill infected cells, and this inhibition affects
also the production of the pro-inflammatory cytokine IFN-gamma , which enlists
the help of other cells in the immune system to fight the infection.
Thus, increase in circulating VIP can counteract the effects of the HIV gp120,
by overcoming the latter's inhibition of NK cells, and by stimulating
the production of VIP auto-antibodies which can also bind gp120 and prevent
it from binding to NK cells.
Finally, both VIP and the peptide NTM has been previously identified as possessing
sequence characteristics responsible for the interaction between HIV and the
CD4 receptor , which represents the first step in process of infection.
It has also been demonstrated that sera from HIV-negative asthma patients contains
high levels of natural anti-VIP antibodies with peptide NTM reactivity. A recent
study on sera from 393 HIV- blood donors found that approximately 5% (21/393)
contain significant levels of the anti-VIP/NTM antibodies, corresponding to
two standard deviations above average.
For HIV+ individuals, the amount of anti-VIP/NTM antibodies available appears
to strongly correlate with progression of HIV disease, suggesting that the immune
system is attempting to overcome the infection. HIV patients in the first stage
of illness (characterized by CD4 lymphocytes count greater than 500/ml), when
the immune system is efficiently controlling HIV, have very low levels of anti-VIP/NTM
reactive antibodies, similar to levels in normal HIV- people .
The level of these antibodies significantly increases in disease stages corresponding
to CD4 values between 200 and 500/ml. Below that CD4 level (less than 200/ml),
however, the amount of anti-VIP/NTM antibody sharply decreases. In the terminal
stages of AIDS disease, NTM-reactive antibodies in sera of HIV+ patients appear
to be significantly decreased.
Neurath and co-workers have also reported differences in the spectrum of antibodies
against HIV gp120 in two groups of HIV-infected individuals, those who remained
healthy for at least 10 years, and those who developed AIDS within 5 years of
the onset of infection . They found antibodies recognizing the peptide 280-306
of HIV-1 gp 120 (overlapping NTM) significantly more prevalent in asymptomatic
carriers than in AIDS patients. Thus, the absence or disappearance of these
antibodies may be a possible factor contributing to the development of AIDS
Exercise as a natural source of VIP/NTM reactive antibodies
A unique method to produce high titers of VIP/NTM reactive antibodies may be
available to both HIV- and HIV+ individuals. An article by Paul and Said in
1988  showed that auto-antibodies to VIP were present in plasma from 29.6%
of healthy (HIV-) human subjects who habitually performed aerobic muscular exercise,
compared to 2.3% of healthy subjects who did not. The exercise involves running,
cycling, swimming, aerobic dancing, and/or weight training, three or more workouts
per week for a year or more prior to the study. The antigenic stimulus for the
formation of these auto-antibodies could not be identified from their data.
However, acute exercise has been shown to be associated with a brisk increase
in plasma levels of VIP [22,23]. It is possible therefore that the antibodies
may have been produced in response to increased VIP levels during exercise.
Effect of aerobic exercise training on HIV-positive individuals
Several studies on aerobic exercise training in HIV-positive individuals have
demonstrated that it is safe, effective, and has a number of beneficial outcomes
[24-38]. The aerobic exercise fitness improvements include a 10-25% improvement
in lactic acidosis threshold (a sign of fatigue) and 5-10% increase in maximal
oxygen uptake depending on the exercise training intensity. In addition, despite
concerns about the stress of aerobic exercise on already damaged immune systems
(specifically, increases in infections, morbidity, or mortality), there have
been no documented adverse effects of aerobic exercise training in HIV-positive
patients at either moderate or heavy exercise training levels . The available
literature clearly supports the idea that aerobic exercise is well tolerated
by HIV-positive individuals.
With regards to immunologic improvement with aerobic exercise training, CD4
counts or viral loads may or may not improve during the exercise intervention
in exercise (see below), although skin test reactivity to Candida antigen has
been shown to improve with moderate exercise. The quality of life outcomes,
however, were found to have improved significantly with aerobic exercise training
relative to a non-exercising control group.
There are indications that exercise can stabilize CD4 cell count in HIV-infected
individuals. Studies showed that people with CD4 cells between 200 - 500
/ml seemed to benefit the most from an exercise program. A pilot study performed
by Olson and co-workers found that the mean change in CD4 percentage over the
24 months interval for weight lifters was -3.1% compared with -5.9%
for runners . According to these researchers, among HIV infected patients
motivated to and capable of regular strenuous exercise, weight training may
offer a salutary benefit superior to intense running. The same authors have
also reported a case of a long-term survivor (12 years HIV+) of a tri-athlete
with a rigorous daily exercise regimen demonstrating very low viral burden as
reflected in non-detectable HIV RNA quantitative PCR and increase in CD4 during
6 years from 3 to 50 /ml (usual CD4 cell count is > 800 /ml) . There
was a report that exercise facilitated a return of the CD4 cell count to more
normal levels .
In a large study involving 415 individuals (156 HIV positive and 259 HIV negative)
Mustafa and co-workers demonstrated that exercising 3 - 4 times/week had
a more protective effect than daily exercise . Exercise in the HIV positive
group covered by this study showed an increase in CD4 count during a year by
a factor of 7%. It should be noted that some authors have reported moderate
training can be sustained without any large change in CD4 cell count [30-32].
Exercise for the masses
Aerobic exercise training has been shown to be a promising, non-toxic, non-drug
adjunct therapy to improve physical fitness, increase quality of life, and potentially
improve the immune status (as indicated by reactivity to Candida skin test)
of HIV-positive individuals. If aerobic exercise training can also be shown
to increase the titer of anti-VIP/NTM antibodies in normal individuals (potential
to decrease the risk of HIV transmission) and in HIV-positive individuals (potential
to slow disease progression), it would strengthen its case to serve as a widely
available and affordable intervention that is non-toxic and free of drug interactions.
It would be applicable worldwide, in both developed and developing countries.