A research study by scientists from Massachusetts
General Hospital (MGH) has shown that, not only does HIV infect and destroy CD4
T cells, but also appears to use those
cells to travel through the body and infect other CD4 T cells. In this study
which is the first to visualize the behavior of HIV-infected human T cells
within a lymph node of a live animal, using a recently developed
"humanized" mouse model of HIV infection, the researchers have found
that HIV disseminates in the body of an infected individual by 'hitching a
ride' on the T cells it infects. As the Infected T cells continue to migrate
within and between tissues such as lymph nodes, HIV gets a ride to remote
locations that are usually not accessible to free viruses.
The scientists used the humanized BLT
mouse model for their experiments, the only non-primate that can be infected
with HIV. Upon confirming that human T cells enter and normally migrate within
the animals' lymph nodes, the
researchers injected the animals with HIV that is engineered to express green
fluorescent protein (GFP), to track the movement of infected cells within
living animals using intravital microscopy. They first observed that, within
two days, infected T cells continued to migrate and were uniformly distributed
within lymph nodes but remained in nodes closest to the site of injection.
As the HIV-infected cells actively moved within lymph nodes, they did not
move as quickly as comparable but uninfected T cells. Moreover, about 10 to 20%
of the HIV-infected T cells formed abnormally long and thin extensions that
appeared to trail behind moving cells, often exhibiting branches.
The researchers thus hypothesized that the HIV
envelope protein, expressed on the surface of infected T cells before they
release new virus particles, might cause infected cells to form tethering
contacts with uninfected cells, causing these extensions. A series of
experiments verified that the elongated shape of some infected cells requires
the presence of the envelope protein and that many of the elongated cells
contained multiple nuclei, suggesting they had been formed by the fusion of
several cells. Further, to test the role of T cell
migration in HIV infection, the researchers injected another group of BLT mice
with HIV and at the same time treated them with an agent that prevents T cells
from leaving lymph nodes. Two months later, levels of HIV in the bloodstream and
in lymph nodes distant from the site of injection were much lower than in
untreated HIV-infected animals, supporting the importance of T cell migration
to carry virus throughout the body. Treatment with the migration-suppressing
agent, however, did not reduce viral levels in animals with already established
HIV infection.
While this observation of tethering
interactions between infected and uninfected CD4-expressing cells suggest that
HIV may be transmitted between T cells by direct contact, further future
studies are needed to explore further and to investigate previously unexplored aspects
of HIV pathogenesis.
Reference:
Murooka TT, Deruaz M, Marangoni F, Vrbanac VD,
Seung E, von Andrian UH, et al. HIV-infected T cells are migratory vehicles for
viral dissemination. Nature [Internet]. 2012 online;advance online publication.
Available from: http://dx.doi.org/10.1038/nature11398
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