Activation of HMOX1 expression by an HBZ-small Maf complex as a potential therapeutic target for HTLV-1 associated diseases. - Human T-cell Leukemia Virus type 1 (HTLV-1) is the etiologic agent of a fatal form of leukemia and a
progressive neurodegenerative disease and is also linked to a spectrum of immunoinflammatory disorders.
These diseases arise from infected T-cells undergoing pathogenic reprogramming in response to complex
virus-mediated processes that are not yet fully understood. To date, HTLV-1-associated diseases have proven
to be highly refractory to a wide array of therapeutic strategies. Recently, however, a molecularly targeted
therapy showed promise for some HTLV-1 leukemia patients. This observation highlights the importance of
devising therapeutic approaches that disrupt or exploit specific viral processes as a means of sensitizing
infected cells for elimination or rendering them innocuous. Considering this goal, we have focused on
characterizing functions of the viral protein, HTLV-1 basic leucine zipper (bZIP) factor (HBZ), which is
implicated in pathogenic reprogramming of infected cells. HBZ localizes to the nucleus and affects
transcription. It contains an N-terminal activation domain that binds the homologous cellular coactivators, p300
and CBP, and a C-terminal bZIP domain. Through the leucine zipper (ZIP) sub-domain, HBZ is able to
dimerize with a subset of cellular bZIP transcription factors. These interactions generally block the cellular
factors from binding DNA and activating transcription. This effect is consistent with the current view that HBZ
does not bind to DNA due to its lack of certain amino acid motifs normally found in other bZIP factors. Despite
this property, HBZ is frequently involved in activating gene expression, but how it does so remains largely
unresolved. The preliminary data in this application show that HBZ binds to a group of cellular bZIP
transcription factors known as small Mafs (sMafs). Strikingly, the HBZ/sMaf complex displays DNA-binding
activity. These observations led to the hypothesis that HBZ/sMaf heterodimers recognize specific DNA
sequences and, through HBZ-mediated recruitment of p300/CBP, activate transcription. The objective of
Specific Aim 1 is to characterize HBZ/sMaf/DNA complexes. The preliminary data in this application also define
HMOX1 as a gene that is specifically activated by HBZ/sMaf complexes. HMOX1 produces heme oxygenase-
1, an enzyme that modulates cellular detoxification events such as the elimination of reactive oxygen species
(ROS). This function may play a role in the survival of HTLV-1-infected cells, as the activities of other viral
proteins trigger production of ROS that, in turn, can induce apoptosis. These observations support the
hypothesis that elevated HMOX1 expression in infected cells reduces oxidative stress caused by other viral
proteins and exposure to chemotherapeutic agents. The objective of Specific Aim 2 is to determine whether
inhibition of HMOX1 activity deters the survival and proliferation of HTLV-1-infected T-cells. Results from these
studies will elucidate a novel mechanism used by HBZ to activate certain cellular genes. This information will
be useful for advancing molecularly targeted approaches against HTLV-1-associated diseases.
