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Researchers say this is puzzling because the immune cells that first encounter HIV-1 on
genital surfaces, called Langerhans cells, should be susceptible to infection from both forms of
the virus. And yet, previous work has shown that after sexual transmission, the T-tropic virus
stays locked out of Langerhans cells. Researchers would like to know why this happens, saying
the answer could provide important new clues for vaccine development or other HIV treatments.
In the December issue of Nature Medicine, a team of scientists report that they now have
an answer.* They say that while in the skin--a site that closely reflects what happens on genital surfaces--Langerhans
cells fail to produce a surface protein that the T-tropic virus needs to chemically unlock the cell membrane
and come inside.
Just as significantly, they found that Langerhans cells produce adequate levels of another
surface protein that the M-tropic virus uses, like a key in a lock, to enter these immune cells and
infect them. "We hypothesized that this might be the case, but there was no direct evidence to
support this hypothesis," said Andrew Blauvelt, M.D., an author on the paper and a scientist in
the Dermatology Branch at the National Cancer Institute. "We now have that direct evidence."
Blauvelt said the findings of he and his colleagues at the Center for Biological Evaluation
and Research at the Food and Drug Administration (FDA) build on recent work showing that
HIV-1 enters immune cells using two distinct receptors. The M-tropic virus, which gets its name
for its affinity for white blood cells called macrophages, anchors to the well-known CD4 protein
that sits on the cell surface. But it also attaches to a second receptor called CCR5.
The T-tropic virus, which has an affinity for T cells and is associated with more advanced
HIV infection, also anchors to CD4. But, it attaches to a different coreceptor on the cell surface,
Marina Zaitseva, Ph.D., an FDA scientist and lead author on the paper, noted that
Langerhans cells are capable of expressing both CCR5 and CXCR4, making it a potential target
for both forms of the virus. But determining if it is a dual target had been problematic because
previous work, for technical reasons, had focused on dendritic cells cultured from the blood, not
the skin or genital surfaces. Langerhans cells are just one of several types of dendritic cells in the
"Dendritic cells from elsewhere in the body behave differently than those in the skin,"
said Hana Golding, Ph.D., an FDA scientist and senior author on the paper. "It's a little like
trying to determine what happens at point A by looking at point X or Y. The comparisons can be
To get around this problem, Zaitseva and colleagues isolated Langerhans cells and
macrophages, both of which are also suspected of initially interacting with HIV-1 on genital
surfaces. Blauvelt said Langerhans cells from the skin act much like they do in the genital
mucosa, making it possible to draw much closer correlations with receptor expression patterns on
the genital surface than in the previous models.
The FDA scientists generated two polyclonal antibodies--one with specificity against
CCR5 and the other targeting CXCR4. The idea being that the antibodies would recognize the
individual receptors, allowing Zaitseva and colleagues to quantify levels of their expression on
the cell surface.
The researchers found in 10 separate experiments that fresh Langerhans cells from the
skin expressed the M-tropic co-receptor CCR5, at levels ranging in each experiment from 24
percent to 49 percent. In contrast, they found no indication that T-tropic receptors are present in
the cell membrane.
These experiments raised another question. Would outer segments of the M and T-tropic
virus, known as protein envelopes, also fuse to Langerhans cells in a similar pattern? If so, it
would corroborate their previous antibody work and provide strong direct evidence that
Langerhans cells can restrict the type of HIV-1 that it ferries to the lymph nodes, where the virus
establishes its home base for further attacks on the immune system.
The researchers found that there was a correlation. Within three hours of exposure to the
M-tropic envelopes, Langerhans cells expressing the CCR5 receptor began fusing together,
called syncytia, a common characteristic of cells in culture that have been infected with HIV-1.
The fusion continued over the duration of the 18-hour experiment. Meanwhile, Langerhans cells
exposed to T-tropic envelopes failed to form syncytia, meaning the envelopes failed to fuse with
The researchers next turned to macrophages. Using macrophages derived from
monocytes, or undifferentiated immune cells, they found high levels of both receptors expressed
on the cell surface. But when they tested whether HIV-1 envelopes fused with the macrophages,
the scientists found that fusion had occurred only for the M-tropic virus. Golding said she and
her colleagues do not have an explanation for this, but they are now investigating the finding
Based on this month's paper, the scientists said it may be possible for researchers to focus
on developing agents that block HIV-1 infection on the surface of immune cells, before the virus
infects them. Golding pointed out that current drug therapy attacks HIV-1 inside immune cells,
where it already has established an active infection. "Our data suggest that nature has provided a
selective defense against some HIV-1 strains on the cell surface," said Golding. "It may be
possible to begin thinking about how to develop a drug or vaccine that blocks these doorways
from HIV-1 entry."
* The title of the study is, "Expression and Function of CCR5 and CXCR4 on Human
Langerhans Cells and Macrophages: Implications for HIV Primary Infection." The authors are
Marina Zaitseva, Andrew Blauvelt, Shirley Lee, Cheryl K. Lapham, Vera Klaus-Kovtun,
Howard Mostowski, Jody Manischewitz, and Hana Golding.
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