|NIAID Scientists Identify New Cellular Receptor for HIV
A cellular protein that helps guide immune cells to the gut has
been newly identified as a target of HIV when the virus begins
its assault on the body's immune system, according to researchers
from the National Institute of Allergy and Infectious Diseases
(NIAID), part of the National Institutes of Health (NIH).
"The identification of this new receptor opens up new
avenues of investigation that may help further elucidate the complex
mechanisms of the pathogenesis of HIV infection" says NIAID
Director Anthony S. Fauci, M.D., chief of the Institute's
Laboratory of Immunoregulation (LIR) and senior author of the new
Several other immune cell receptors bind to HIV. Most important
among these, the CD4 molecule, identified as an HIV receptor in
1984, functions as the principal receptor for HIV. The CCR5 and
CXCR4 molecules, discovered in 1996, serve as co-receptors that
HIV uses to enter its target cells. In the new study, which appears
online Feb. 10, 2008 in Nature Immunology, NIAID scientists
identify a cell adhesion molecule known as integrin alpha 4 beta
7 as another potentially important
receptor for HIV.
Early in the course of HIV infection, the virus rapidly invades
and replicates in gut-associated lymphoid tissue (GALT), the immune
cells of the gut. Once seeded with HIV, the gut is rapidly depleted
of CD4+ T cells, the main target of HIV, triggering the process
that ultimately leads to AIDS.
"In the very early days of infection, it is in the GALT
where most of the damage caused by HIV occurs," says Elena
Martinelli, Ph.D., a lead author of the paper and a fellow in Dr.
Fauci's laboratory. "The gut is where the virus really
takes hold. We found that integrin alpha 4 beta 7, whose natural
function is to direct T cells to the GALT, is also a receptor for
HIV. It is very unlikely that this is a coincidence."
Dr. Martinelli, along with Claudia Cicala, Ph.D., James Arthos,
Ph.D., and their colleagues found that the gp120 protein, part
of the HIV envelope, binds to integrin alpha 4 beta 7 on CD4+ T
cells, which promotes the formation of a stable junction, or synapse,
between neighboring cells.
"A synapse is a junction that allows two cells to adhere
in a stable way," says Dr. Arthos. "Many viruses have
found a way to trick cells into forming these stable junctions.
Now it appears that HIV can also trigger synapse formation."
Specifically, a short piece of the HIV gp120 protein in a region
known as the V2 loop recognizes the alpha 4 chain of the integrin
molecule on host cells. This stretch of the V2 loop is similar
to part of the naturally occurring molecules that bind integrin
alpha 4 beta 7. Thus, it appears that HIV is mimicking the natural
molecular partners, or ligands, that normally bind to the receptor.
The authors note, however, that some HIV isolates react more strongly
to integrin alpha 4 beta 7 than others.
"The ability of a particular virus to bind to integrin alpha
4 beta 7 may determine whether it will have a major impact in targeting
the gut lymphoid tissue," says Dr. Fauci. "This finding
could be a significant determinant in the pathogenic mechanisms
that lead to AIDS."
As part of the natural homing process, integrin alpha 4 beta 7
binds to its natural ligands and activates a protein known as LFA-1.
According to Dr. Arthos, HIV can co-opt this process by mimicking
the cells' alpha 4 beta 7 receptor natural ligands. When
HIV gp120 protein binds to the alpha 4 beta 7 receptor it
facilitates the formation of a synapse. Thus, HIV tricks an infected
cell into binding to an uninfected cell, enabling HIV to readily
gain access to the uninfected cell.
"While this study provides important new information concerning
the various mechanisms by which HIV debilitates the human immune
system, it also raises new questions and challenges that our laboratory
and others will pursue," notes Dr. Cicala.
For more information on HIV/AIDS, see http://www3.niaid.nih.gov/healthscience/healthtopics/HIVAIDS/overview.htm.
NIAID is a component of the National Institutes of Health. NIAID
supports basic and applied research to prevent, diagnose and treat
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infections, influenza, tuberculosis, malaria and illness from potential
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diseases, asthma and allergies.
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J Arthos et al. HIV-1 envelope protein binds to and signals through integrin alpha 4 beta 7, the gut mucosal homing receptor for peripheral T cells. Nature Immunology DOI: 10.1038/ni1566 (2008).