Research interests of
our laboratory are directed at understanding the mechanisms underlying
HIV pathogenesis with the hope of designing novel antiviral therapies
and an effective AIDS vaccine.
Virus Studies: Biologic, serologic, and molecular characterization
of several HIV-1 and HIV-2 strains are revealing their extensive heterogeneity
and have demonstrated that viruses may evolve differently in the same
individual in the immune system, bowel, and the brain. Molecular studies
with intraviral recombinants of HIV-1 have shown that very few envelope
gene changes can affect tissue tropism, cytopathicity and serum antibody
sensitivity. Current anti-HIV experiments are evaluating siRNA approaches.
Immune Studies: Recent emphasis in the laboratory has been
on anti-HIV innate immune responses. We are evaluating the role of
plasmacytoid dendritic cells (PDC), major producers of type 1 interferons.
Studies are directed at understanding how HIV-infected cells induce
interferon production from PDC and what cell surface molecules, including
toll-like receptors, are involved in this process. Another innate
response we have defined is the ability of CD8+ lymphocytes to suppress
HIV replication without killing the cells. This CD8+ cell noncytotoxic
antiviral response (CNAR) is mediated by a novel as yet unidentified
CD8+ cell antiviral factor (CAF). CNAR and CAF block HIV transcription.
Certain cytokines such as IL-2, IL-15 and IFN-a as well as co-stimulation
with CD3 and CD28 antibodies and co-culture with mature dendritic
cells can enhance this antiviral response.
The identity of CAF is being determined by protein purification procedures
involving mass spectrometry, and molecular analyses, using microarray
techniques. Other studies focus on why the CD8+ cell anti-HIV response
decreases with time in HIV-infected individuals. In acute HIV infection,
we have found that antiviral drugs that reduce HIV plasma loads, decrease
the CD8+ cell antiviral response. New treatment directions being evaluated
are IL-2 therapy, immunization, and structured treatment interruptions
in attempts to restore the host anti-HIV immune response.
Vaccine Studies: Experiments towards deriving an AIDS vaccine
involve an HIV-2 DNA vaccine with genetic adjuvants (GM-CSF, B7.2).
Immunized baboons are monitored for anti-HIV-2 neutralizing antibodies
as well as cell-mediated anti-HIV immune responses. These studies
will hopefully pave the way for the development of an effective HIV
vaccine for humans. |
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Levy JA. HIV and the Pathogenesis of AIDS (Third Edition) . Washington, DC: ASM Press, 2007
Martinez-Mariño B, Foster H, Hao Y, Levy JA. Differential gene expression in CD8+ cells from HIV-1 infected subjects showing suppression of HIV replication. Virology, 362 : 217-225, 2007.
Diaz LS, Foster H, Stone MR, Fujimura S, Relman DA, Levy JA. VCAM-1expression on CD8+ cells correlates with enhanced anti-HIV suppressing activity. Journal of Immunology, 174 :1574-1579, 2005.
Schmidt B, Ashlock BM, Foster H, Fujimura SH, Levy JA. HIV-infected cells are major inducers of plasmacytoid dendritic cell interferon production, maturation, and migration. Virology, 343 :256-266, 2005.
Stranford SA, Ong JC, Martinez-Mariño B, Busch
M, Hecht FM, Kahn J, Levy JA. Reduction in CD8+ cell noncytotoxic
anti-HIV activity in subjects receiving HAART therapy during primary
infection. Proc Natl Acad Sci (USA) 98:597-602, 2001.
Soumelis VS, Scott I, Gheyas F, Bouhour D, Cozon G, Cotte L, Huang
L, Levy J, Liu Y-J. Depletion of circulating natural type 1 interferon-producing
cells in HIV-infected AIDS patients. Blood 98:906-912, 2001.
Locher CP, Witt SA, Herdier BG, Abbey NW, Tenner-Racz K, Racz P, Kiviat
NB, Murthy KK, Brasky K, Leland M, Levy JA. Increased viral replication
and virulence after serial passage of human immunodeficiency virus
type-2 in baboons. J Virol. 77: 77-88, 2003.
Mackewicz CE, Craik CS, Levy JA. The CD8+ cell noncytotoxic anti-HIV
response can be blocked by protease inhibitors. Proc Natl Acad Sci
(USA), 100, 3433-3438, 2003.
Diaz L, Stone M, Mackewicz CE, Levy JA. Differential gene expression
in CD8+ cells exhibiting non-cytotoxic anti-HIV activity. Virology.
311: 400-405, 2003.
Schmidt B, Scott I, Whitmore RG, Foser H, Fujimura, S, Schmitz J, Levy JA. Low-level HIV infection of plasmacytoid dendritic cells (PDC): Onset of cell death after PDC maturation. Virology. 329:280-288, 2004
information last updated May 2007 |
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Biomedical Sciences (BMS) Graduate Program
