HIV,
human immunodeficiency virus, infection is one of the largest public health
problems we face today. The WHO estimates that currently over 35 million people
worldwide are infected with HIV. HIV primarily infects and kills helper T
cells, cells that have the critical role of activating and supporting other cells
of the immune system, thus impairing the immune response on a broad level. It
is well known for causing AIDS, the acquired immunodeficiency syndrome, which
severely weakens the body’s immune response and leaves it open to attack by
foreign antigens. However, less widely known, HIV also causes neurocognitive
impairment and encephalitis (swelling of the brain), estimated by Heaton et al
to affect one third of individuals infected with HIV. This facet of HIV
infection, which affects a whopping 10 million people worldwide, is an important
concern and is now receiving more attention.
Recently,
the Section of Infectious Diseases of the Nervous System at NIH, led by Dr.
Avindra Nath, and their colleagues at Johns Hopkins School of Medicine have discovered
possible mechanisms for HIV-mediated neurocognitive impairment. In a recent
paper in the Journal of Neurovirology, these researchers looked at the
impairment of adult neurogenesis and neurite outgrowth in the hippocampus using
a HIV mouse model. They believe that the growth patterns of neurons in this
part of the brain, which deals with processes such as memory consolidation, may
be disrupted during HIV infection and underlie the cognitive dysfunction seen
in HIV infected patients. While previous research had found that HIV infects
glial cells and not neurons, it was shown that HIV infection lead to synaptic
pruning and apoptosis (Ellis et al 2007).
The
investigators used a transgenic mouse model that expressed the HIV envelope glycoprotein
gp120 under the control of the GFAP promoter (glial fibrillary acidic protein,
a protein expressed by glial cells in the brain). HIV gp120 is part of the HIV
viral envelope “spike,” a device used to bind host cell receptors and enter the
cell. Briefly, the spike consists of three gp120 units bound to three gp41
units; gp120 binds to the CD4 co-receptor on a helper T cell, allowing the HIV
envelope glycoprotein gp41 to contact the host cell membrane and promote viral
fusion. Thus, the investigators used this mouse model to simulate HIV
infection, during which gp120 would be circulating in the body.
These
investigators first looked at the proliferation of neural progenitor cells
(NPCs) in the hippocampus that give rise to neurons (and other neural cell
types) using an assay where only newly divided cells incorporate a modified
nucleotide, BrdU, into their DNA during DNA synthesis. They found that the HIV
gp120 mice showed significantly fewer proliferating NPCs compared to control
mice. They also found decreased neurogenesis in the transgenic mice. This means
that not only are NPCs proliferating less during HIV infection, fewer NPCs are
differentiating into neurons. On the other hand, the authors of this article
found more elaborate dendritic trees and longer dendritic length in the
transgenic mice; dendrites are the processes that extend from neurons and link
onto other neurons. You might ask why increased dendritic growth and complexity
is bad, since dendrites mediate neuronal activity; however, we must keep in
mind that the brain is very sensitive to changes, and a balance must be
established. Thus, more dendrites may overcrowd brain regions and may even
interfere with normal neuronal communication . Along with structural
differences, the authors saw decreased BDNF levels in the whole brain and
hippocampus of the transgenic animals and increased Cdk5 kinase activity; BDNF
promotes neuronal survival and growth and Cdk5, along with other proteins,
promotes neuronal maturation and stabilization. Thus, the authors showed that
during HIV infection, neuronal structures changed, possibly caused by the
negative impact on the proteins that regulate neural. These findings are backed
by the finding of others, who have seen similar changes in neural structure or
protein (such as Cdk5) in both mouse models of HIV and in HIV-infected
patients.
However,
these investigators also found a silver lining, a possible treatment for these
aberrant processes that occur in the brain during HIV infection. They decided
to put their transgenic and control mice on exercise regimens, which have been
shown to improve cognitive function in other diseases and promote general
health. After a 20 day running regimen, NPC proliferation, neurogenesis, and
neuronal survival increased in both the transgenic and control animals. Similarly,
this exercise regimen increased BDNF levels and normalized Cdk5 activity to
that of control mice in the HIV gp120 mice. Lastly, this exercise regimen was
able to normalize dendritic development in the transgenic mice to levels
comparable to control mice. Surprisingly, a 10 day running-10 day resting
exercise regimen only showed positive effects during the running phase, which
was promptly abolished after the mice stopped exercising.
The
findings these investigators present have elucidated some of the possible
mechanisms and effects of HIV infection of the brain that may lead to cognitive
dyfunction seen in over 10 million HIV infected individuals. The authors showed
that HIV infection alters brain chemistry and cellular activity, which may lead
to the altered brain structuring seen in HIV mouse models and patients.
However, they also propose a significant solution that may ameliorate some of
these negative neural effects: exercise. The benefits of exercise regimens as a
treatment for HIV cognitive decline are very evident. Exercise is a natural
process that is cost-effective to implement and can be performed throughout a
patient’s lifetime; as a natural process, exercise is less likely to interfere
with brain chemistry as pharmacological agents and promotes brain health in a
more controlled manner, not to mention its beneficial effects for general
health. However, the downside of this treatment for HIV infected individuals is
simply their impaired health and their ability to exercise. For patients who
have progressed to AIDS and are constantly assaulted by foreign invaders
(viruses, bacteria, etc.), patient health may not allow strict exercise
regimens. Even those who have not converted fully to AIDS, many hard-to-control
factors such as location, willpower, occupation, and free time limit the
implementation of exercise regimens. While the exact mechanisms behind HIV
induction of neural chemical and structural dysfunction need further elucidation,
and future studies are needed to confirm the effects of exercise found by these
investigators, we may now have another, more natural way to combat the
neurocognitive dysfunction caused by HIV infection.
Main article:
Lee, M. H., Amin,
N. D., Venkatesan, A., Wang, T., Tyagi, R., Pant, H. C., & Nath, A. (2013).
Impaired neurogenesis and neurite outgrowth in an HIV-gp120 transgenic model is
reversed by exercise via BDNF production and Cdk5 regulation. Journal of
Neurovirology,
REFERENCES
Ellis
R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain:
neuronal injury and repair. Nat Rev Neurosci 8:33–44
http://www.who.int/hiv/en/ (WHO
general HIV/AIDS page)
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