1,720,992 research outputs found
A dual defensive role of CIITA against retroviral infections
Full text linkWe describe how CIITA exerts a dual role against retroviral
infection. The first, classical role is the upregulation of MHC
class II expression and thus the capacity to present viral antigens
to CD4+ T cells. The other, evolutionary new and fundamental
role is to inhibit viral replication by blocking specifically the
function of the viral transactivators. HIV-1 Tat is inhibited
through the competition for cyclin T1 of the P-TEFb complex,
whereas HTLV-2 Tax-2 is inhibited through a concerted action
which may increase the binding affinity of the CIITA-NFY
complex for Tax-2, displacing it from the viral LTR promoter. As
expected, two distint sequences in the N-term region of CIITA
mediate the inhibitory action on Tat and Tax-2, respectively. Of
note, Tax-1 from HTLV-1 seems also to be inhibited by the same
sequence that inhibits HTLV-2 Tax-2. Interestingly, only those
CIITA fragments containing the minimal inhibitory domains that
localize into the nucleus could exert an effective suppressive
action. Taken together, our results indicate that CIITA is an
extant molecular tool endowed with distinct evolving functions
against retroviruses. These distinct properties of CIITA will
shed new light on the molecular mechanisms of adaptive
coevolution of hosts and pathogens and may be exploited to
envisage novel therapeutic strategies aimed at counteracting
retroviral infections
HTLV-II infection exerts a protective role against AIDS progression in IDUs coinfected with HIV-1
No full textHTLV-II influence on AIDS progression and changes in response to antiretroviral therapy in Italian IDUs coinfected with HIV-1
No full textInsight into the molecular mechanism of CIITA-mediated inhibition of HIV-1 and HTLV transactivators
No full textThe AIR-1-encoded MHC class II trans-activator (CIITA) blocks the function of the HTLV-2 transactivator Tax-2 and inhibits viral replication.
No full textThe molecular basis of the inhibition of HTLV-2 retroviral replication by the MHC class II transactivator (CIITA)
No full textThe transcriptional activator CIITA is the master regulator of the
expression ofMHC class II genes. In addition to this major role, we
found that CIITA exerts an important inhibitory effect on the
HTLV-2 replication. This inhibition is mediated by the N-terminal
1–321 region where we identified a minimal fragment of 80 aminoacids that specifically blocks the activity of the viral transactivator Tax2. To unveil the biochemical basis of the CIITA-mediated inhibition of Tax2 we first focussed on the identification of the cellular cofactors used by Tax2 to transactivate the viral promoter.
Preliminary data indicate that the transactivation activity of Tax2
and Tax1, the HTLV-1 homologous of Tax2, is differently influenced
by the hystone acetyltransferases CBP, p300 and PCAF
providing new informations on the biology of HTLV-2.
Furthermore, none of these factors was able to reverse the inhibitory
action of CIITA on Tax2 function. Interestingly, we found that the
B and, to a lesser extent, the A subunits of the NFY complex inhibit
Tax2 activity when iper-expressed in cells. On the basis of our results
and of the reported physical interactions between NFY and both
CIITA and Tax1, a possible mechanism for the CIITA-mediated
inhibition of Tax2 activity would be the binding of the CIITA-NFY
complex to Tax2. When expressed in cells, CIITA interacts with the
NFY complex; this interaction changes the conformation of NFY
increasing its binding affinity for Tax2. Following this model the
inhibition of Tax2 by CIITA it is not due to the squelching of a
transcriptional positive co-activator, but instead to the recruitment
of a cellular factor, NFY, with a negative regulatory action on Tax2.
On the whole these results confirm that CIITA may represent a
physiologic tool for novel therapeutic strategies aimed at counteracting
HLTV-2 replication and spreading
Inhibition of HTLV-2 viral replication by the MHC class II transcriptional activator (CIITA)
No full textThe replication of HTLV-2 and the expression of HLA class II transcriptional activator (CIITA) are inversely correlated
No full textBackground: HTLV-2 is mitogenic for CD341 hematopoietic
precursors and this effect is inhibited by HLA class II molecules
(HLA-II) on the envelope. The aim of this study was to
investigate the role of HLA-II in the phases of infection.
Methods: The experimental system was designed by using
HLA-II-positive and HLA-II-negative cells as targets for infection.
As HLA-II negative targets, T-cell lines and B-cell mutants
that have lost expression of HLA-II were used. To understand
CIITA/HTLV-2 Tax interaction a transfection system
was optimized in HeLa cells.
Results: The extent of HTLV-2 replication is correlated with
low or absent expression of HLA-II. HLA-II negative mutants
segregated into two distinct clusters: permissive and non permissive
for viral replication. Closer analysis revealed a correlation
between the rate of expression of the AIR-1 encoded CIITA
and inhibition of viral replication.On the contrary,HLA-II
negative mutants supported HTLV-2 replication, this correlates
with CIITA expression but not with HLA expression.Analysis
of CIITA/HTLV-2 Tax interactions revealed that transcription
of HTLV-LTR increased in HeLa cells only in the presence of
Tax-2 and was reduced in a dose-dependentway by increasing
CIITA.
Conclusions: These results indicate that sustained expression
of CIITA in HTLV-2-susceptible targets may down-regulate
viral expression and open new ways to study the retrovirus
replication in man
HTLV2 influence on pathways regulating proliferation and death in B cell line BJAB
No full textBackground: We have demonstrated that T cell derived
HTLV-2 Mo strain is anti-apoptotic and mitogenic for CD34!
hematopoietic precursors (Casoli et al., Blood 91:2296-2304,
1998). This property is lost when the Mo strain is adapted to
grow in a B cell host by the presence of large amounts of HLAII
molecules. The interplay between regulation of HLA-II expression
and viral replication is related to CIITA/Tax interactions
(Casoli et al., Blood 103:995-1001, 2004).
Methods: In order to study the HTLV virus/host cell interaction,
the B cell line BJAB, expressing HLA-II molecules, and
its Gu HTLV-2-infected counterpart are chosen as model systems.
Both cell lines were tested for their cell surface expression
of HLA-II and CIITA mRNA levels. Apoptotic phases and
cell cycle were also investigated by flow cytometry.
Results: In comparison of uninfected cells, BJAB-infected
cells showed a drammatic decrease of HLA-DR expression in
association with a low amount of CIITA transcript. HTLV-2-
infected cells undergo G1 arrest and apoptosis, that reflect p19
Ag production. Both early and late apoptotic cells are detected
in high percentage (40%).
Conclusions: On BJAB cells HTLV-2 infection downregulates
HLA-II expression by blocking CIITA gene transcription.
In this cell line HTLV-2 replication induced G1 arrest and enhances
apoptosis
Inibizione della replicazione virale di HIV-1 e HTLV-2 da parte di CIITA il regolatore trascrizionale dell'espressione dell'HLA-II
No full text- …
