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Description of Research: Kathleen
Collins
HIV Disease Pathogenesis
HIV establishes a chronic infection, and leads inexorably
to the development of AIDS despite the acquisition
of an anti-HIV immune response. My laboratory is interested
in understanding the factors that allow HIV to thwart
the immune system. Thus far, we have found that HIV
evades the cytotoxic T lymphocyte (CTL) arm of the
immune response by limiting presentation of viral
antigens. This is accomplished by downmodulating MHC-I
protein, which is required for immune recognition.
Downmodulation of MHC-I occurs through the action
of the HIV Nef protein. Work from our laboratory has
indicated that the HIV Nef protein downmodulates MHC-I
by physically interacting with specific amino acid
sequences located in the MHC-I cytoplasmic tail. The
specificity of this interaction allows Nef to selectively
downmodulate MHC-I allotypes important for CTL recognition,
while maintaining the expression of MHC-I allotypes
that protect cells from natural killer cell recognition.
Once bound, Nef allows the transport of MHC-I molecules
into the Golgi apparatus, but then prevents their
expression on the cell surface by recruiting a cellular
adaptor protein, AP-1, which targets the complex to
lysosomes for degradation. We have also learned that
the effects of Nef are cell-type-specific in that
Nef is much more active in T cells, a natural target
for HIV infection. We have discovered that this results
from the fact that The Nef-MHC-I complex recruits
AP-1 much more efficiently in T cells. This observation
is important because current models derived from non-T
cell systems, have led to the incorrect conclusion
that Nef functions exclusively by accelerating MHC-I
enodocytosis. Thus, our studies have uncovered a key,
previously overlooked mechanism for MHC-I downmodulation
and immune evasion by HIV.
In addition, we have found that HIV limits antigen
expression through the action of HIV Rev. The Rev
protein normally functions by allowing late gene product
mRNAs to exit the nucleus. Thus, the amount of Rev
activity in the cell determines the relative amount
of late gene product expression, the main source of
CTL antigens. We have found that naturally occurring
Rev alleles vary in their activity level and that
those with less activity result in infected cells
that are resistant to CTL lysis. These alleles are
selected early in disease when the immune system is
more active. Later on in disease, more active alleles
emerge once the immune system has been destroyed and
selective pressure wanes. In sum, the combined effects
of Nef and Rev dramatically limit antigen presentation
early in HIV disease when HIV must combat a highly
active anti-HIV immune response.
Honors and Awards
1998 Biomedical Scholars Program Award, University
of Michigan
1998 Massachusetts Infectious Disease Society Maxwell
Finland Young Investigator Award for Excellence in
Research
1999 Pew Scholars Award
2000 Center For AIDS Research Development Award
2001 Plenary speaker, American Association of Immunology
Symposium on Microbial Invasion
2003 Padykula Lecturer, Wellesley College, Wellesley,
MA
2003 Plenary speaker, 2004 Keystone Symposia on Molecular
Mechanisms of HIV Pathogenesis
2004 Chair of the plenary session, Nef Function, 2004
Keystone Symposia on Molecular Mechanisms of HIV Pathogenesis
2004 Elizabeth C. Crosby Award
2005 Plenary speaker, 2005 ASM Symposia on Viral Immune
Evasion
2005 Chair of the plenary session, Viral Regulation
of Antigen Presentation, 2005 ASM Symposia on Viral
Immune Evasion
2005 Plenary speaker, 91st International Titisee Conference
"Cell biology meets the immune system: molecular
aspects of host pathogen interactions"
2005 Elizabeth C. Crosby Award
Professional and University Service Contributions
Associate Director, Cellular and Molecular Biology
Graduate Program
Member, CMB, MMMP, TTI, Experimental Immunology and
Genetics training grants
Member, CMB and Immunology graduate training programs
Member, Editorial board of Journal of Virology and
Current HIV Research
Ad Hoc Referee, Immunity, Journal of Virology, Journal
of Clinical Investigation, Journal of Experimental
medicine, Virology, EMBO, PLoS
Member, NIH AIP Study Section
Member, American Society for Microbiology
Member, American Society for Clinical Investigation
Recent Publications
Collins, K.L. Resistance of HIV-infected cells to
cytotoxic T lymphocytes. Microbes Infect 5; 494-500,
2004.
Roeth, J.F., Kasper, M.R., Williams, M., Filzen,
T.F., and Collins, K. L. HIV-1 Nef re-directs MHC-I
from the TGN to lysosomes by stabilizing an interaction
between MHC-I and AP-1. J Cell Biol 167(5); 903-913,
2004.
Williams, M., Roeth, J.F., and Collins, K.L. HIV-1
Nef domains required for disruption of MHC-I trafficking
are also necessary for co-precipitation of Nef with
HLA-A2. J Virol 79(1);632-636, 2005.
Kasper, M.R., Williams, M., Xie, D., Fleis, R. and
Collins, K.L. HIV-1 Nef disrupts viral antigen presentation
early in the secretory pathway by preferentially binding
hypo-phosphorylated MHC-I cytoplasmic tails. J Biol
Chem 280(13): 12840-12848, 2005.
Roeth JF, Collins KL. Human immunodeficiency virus
type 1 Nef: Adapting to intracellular trafficking
pathways. Microbiol Molec Biol Rev 70: 548, 2006.
Thammavongsa V, Raghuraman G, Filzen TM, Collins
KL, Raghavan M. HLA-B44 polymorphisms at position
116 of the heavy chain influence TAP complex minding
via an effect on peptide occupancy. J Immunol 177
(5): 3150-3161, 2006.
Wonderlich ER, Williams M, Collins KL. The tyrosine
binding pocket in the adaptor protein 1 (AP-1) mu
1 subunit is necessary for nef to recruit AP-1 to
the major histocompatibility complex class I cytoplasmic
tail. J Biol Chem 283 (6): 3011-3022, 2008.
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