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| I.
The CTL Recognition of HIV-1 and the CTL-escape mechanism
of HIV-1 |
When a virus infection is established,
helper T cells recognize it via antigen presenting cells, inducing
CTL responses and production of specific antibodies. Usually, induction
of CTLs takes place at least in a week after the infection. By the
time, production of antibodies is seen reaching its peak in 2 weeks
in many cases of viral infections. CTLs recognize and kill virus-infected
cells, preventing viral replication. Antibodies, on the other hand,
particularly neutralizing antibodies, inactivate a virus, by binding
to virus particles in blood and on tissues. Also, NK cells are known
to recognize and kill virus-infected cells. Thus, a virus is being
eliminated from the body.
Meanwhile, in HIV-1 infection, there is a temporary fall in CD4+ T
cell count during the early stage of infection. This is because CD4+
T cells are target cells of HIV-1. The number, however, gets back
to its normal in most cases since CTLs eradicate HIV-1-infected CD4+
T cells. Production of antibodies is seen relatively late, sometimes,
in a month or two after the infection. What makes HIV-1 infection
unique is that the virus cannot be completely eradicated by the immune
system, persisting in the body, eventually increasing viral loads,
and thus developing AIDS. Persisting low level of viral loads may
explain that cellular immunity partially inhibits viral replication.
Nevertheless, the immune system is unable to eradicate a virus completely,
and the virus reverts to replicating after a certain period of time.
The mechanism to explain these is yet to be clarified. For this reason,
we are trying to clarify the mechanism by which cellular immunity
recognizes HIV-1, and HIV-1 evades cellular immunity. Based on the
results of these researches, we will promote establishment of AIDS
therapy and vaccine development. |
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| II.
Human CD8 T cell differentiation |
| There is a hypothesis to explain CTL escape
mechanism of HIV-1 that functional disorder due to abnormality of HIV-1
specific CD8 T cell differentiation may be the culprit. The mechanism of
peripheral CD8 T cell differentiation, however, has not been completely
clarified to understand differences in differentiation between normal CD8
T cells and HIV-specific CD8 T cells. Therefore, we first made a differentiation
or maturation analysis on normal human peripheral CD8 T cell, and from there
we attempted to examine the possibility of differentiation or maturation
abnormality of HIV-1-specific CD8 T cells in HIV-1 infected patients. |
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| Ⅲ．Molecular
recognition of virus antigenic epitopes by T cell receptor |
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Viruses including HIV-1 are processed
into peptides and presented to CD8 T cells via HLA class I molecules,
leading to T cell recognition. T cells recognize virus peptides combined
with HLA class I molecules on cell surface with T cell receptor. We
are studying T cell receptor-mediated recognition of the peptides
binding to HLA class I molecules to reveal recognition mechanism against
diverse viruses in human. |
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| Ⅳ．CTL
recognition of hepatitis virus |
Many cases of HCV co-infection among
HIV-1 positive patients have been reported, particularly among those
infected by transfusion of blood and serum products.
Concerns of developing chronic hepatitis, cirrhosis, and liver cancer
are growing for patients who show certain progress in controlling
the onset of AIDS after receiving HAART. For this reason, we studied
the CTL recognition of hepatitis B/C to identify the mechanism by
which hepatitis becomes chronic.
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