About Us
|
Laboratory of Human Retrovirology and Immunoinformatics
|
1. Mission
2. Research Interest
3. Address
4. Campus Map
5. Ask Questions
6. LHRI Group
|
|
1. Mission
|
|
The mission of the Laboratory of Human Retrovirology and Immunoinformatics (LHRI)
is to investigate the mechanism of immune and viral responses in infected
individuals utilizing microbiological, biochemical and immunological
techniques, and bioinformatics analysis.
top
|
2. Research Interest
|
|
The Laboratory of Human Retrovirology and Immunoinformatics (LHRI) has investigated
mechanism of multiple-class drug resistant (MDR) in HIV infection. Goals of the studies
are to define salvage therapies for each patient-infected with MDR strains and to develop
novel anti-viral therapies for each MDR strain using either chemical
compounds (nucleotide, peptides or others) or immune regulatory
proteins (cytokines or other proteins). LHRI has cloned multiple MDR strains from the
infected patients and profiled drug sensitivity of each strain against FDA approved and
experimental drugs in vitro. LHRI has also characterized pathogenesis and innate immune
response to MDR infection. LHRI has first reported that Interleukin-27 possesses anti-HIV
property and discovered four novel none-coding RNAs as novel anti-viral nucleotides;
those are potential anti-MDR reagents. The second LHRI research area is the mechanism of
human innate immune response via Ku70, a component of the DNA repair complex protein, as a
cytosolic DNA sensor. Upon transfection with DNA or infection with DNA virus, Ku70 in the
cytosol detects the invaded DNA and then predominately induces interferon lambda1
(IFN-λ1) rather than IFN-α or IFN-β, through a STING-dependent signaling
pathway. Accumulation of cytoplasmic translocation of Ku70 only occurred in DNA-triggered
IFN-λ1 inducible cells and enhances the innate immune response. Recently, LHRI found
that Herpes Simplex Virus type-1 (DNA virus) infection induces IFN-λ1 via Ku70, but
it is strain-dependent; HSV-1 McKrae, but not MacIntyre strain induces IFN-λ1
(Figure 1).
Figure 1. The cytoplasmic translocation of Ku70 in DNA transfected or HSV-1 virus
(McKrae and MacIntyre strain) infected HEK cells. The localization of Ku70 was
visualized under confocal microscope. HEK cells were seeded on coverslip-inserted 12-well
plates, and then were transfected with MFP488-labelled DNA (green) or infected by HSV-1 at
MOL of 1.6 h after DNA transfection or 16 h after infection, the cells were fixed and
stained with anti-Ku70 (red) antibody or anti-HSV-1 (green) antibody. Nuclei were
visualized by DAPI (blue). Original magnification was x40. Scale bar: 10 μm.
The mechanism was further confirmed by that the inhibition of Ku70 translocation
also inhibited IFN-λ1 induction, and enhancing the acetylation status of the cells
promotes Ku70's cytoplasmic accumulation, increases DNA-mediated IFN-λ1 induction.
These findings provide insights into the molecular mechanism by which the versatile sensor
detects pathogenic DNA in a localization-dependent manner (Figure 2).
Figure 2. Working model for the cytosolic DNA sensing activity of Ku70. Ku70
undergoes a translocation from the nucleus to the cytoplasm to recognize cytosolic viral
DNA or other form of DNA followed by interacting with STING and activating the downstream
IFN-λ1 signaling pathway. Acetylation modulates DNA-mediated Ku70-dependent
IFN-λ1 induction. Ku80 colocalizes with Ku70 during Ku70 translocation from
the nucleus to the cytoplasm, but not directly involving in Ku70's cytosolic DNA activity.
The third research
area is to study the host genetic determinants that affect HIV pathogenesis and
progression. Genome-wide associate study have identified eleven loci associated with three
biomarker levels (six loci known in the general population and five novel loci associated
with D-dimer and IL-6 levels) in people living with HIV (PLWH) of three ethnic groups:
African (AFR), Admixed American (AMR), European (EUR). Three of them are ethnic specific
and other eight loci have been identified by transethnic meta-analyses (Figure 3).
Figure 3. Manhattan plots of transethnic meta-analyses results for genetic associations
with three biomarkers. (A). hsCRP levels, (B). D-dimer levels, (C). IL-6 levels.
Loci are labeled by the closest genes. Each point represents one SNP and is plotted by
chromosomal location (x-axis) and -log10(P) (y-axis). The dashed red line represents
genome-wide significance (P = 5 x 10-8) and SNPs meeting this threshold
are colored red.
The findings support the hypothesis that host genetics may partially contribute to chronic
inflammation in PLWH and help to identify potential targets for intervention of serious
non-AIDS complications. LHRI also has a strong bioinformatics team supporting the research
in the basic and translational research sections in LHRI, other laboratories in ADRD at
Frederick National laboratory, NIAID and other NIH institutes. The bioinformatics team is
also responsible for updating and maintaining the Database for Annotation, Visualization
and Integrated Discovery (DAVID), an important bioinformatics resource system.
top
|
|
3. Address
|
|
310 Wood Street
Building 315, Room 8
Laboratory of Human Retrovirology and Immunoinformatics
Applied/Developmental Research Directorate
Frederick National Laboratory for Cancer Research
Frederick, MD 21702
top
|
4. Campus Map
|
|
pdf version
jpg version
top
|
5. Ask Questions
|
|
DAVID Bioinformatics Questions? Contact the DAVID Bioinformatic Team
top
|
|
6. LHRI Group
|
|
Laboratory of Human Retrovirology and Immunoinformatics (LHRI)
|
Tomozumi Imamichi, Ph.D.
Sr. Principal Investigator
timamichi@mail.nih.gov
(301) 846-5450
|
| Basic Research |
Translational Research |
Bioinformatics |
| Hongyan Sui, Ph.D. |
| Scientist II |
|
| Suranjana Goswami, Ph.D. |
| Scientist I |
|
| Qian Chen, M.D. |
| Research Associate III |
|
| Jun Yang, M.S. |
| Bioinformatics Analyst V |
|
| Two Postdoctoral Positions Available |
|
|
| Sylvain Laverdure, Ph.D. |
| Scientist I |
|
| Francesca Scrimieri, Ph.D. |
| Scientist I |
|
| Sharada Paudel, Ph.D. |
| Research Associate II |
|
| Whitney Bruchey, B.S. |
| Research Associate II |
|
|
| Weizhong Chang, Ph.D. |
| Sr. Bioinformatics Scientist |
| weizhong.chang@nih.gov |
| (301) 846-6295 |
|
| Brad T Sherman, M.S. |
| IT Manager I |
|
| Xiaoli Jiao, Ph.D. |
| Computational Scientist |
|
| Ming Hao, Ph.D. |
| Bioinformatics Analyst III |
|
| Ju Qiu, M.S. |
| Bioinformatics Analyst II |
|
top
|
|
Last edited on February 22, 2021
|
|
