Description of Research: Kathleen
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.
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.
Schaefer MR, Wonderlich ER, Roeth JF, Leonard JA,
Collins KL. HIV-1 Nef targets MHC-I and CD4 for degradation
via a final common beta-COP-dependent pathway in T
cells - art. no. e1000131. PLOS Path 4 (8): 131-131,
Collins KL. This Bud's for Vpu. Cell Host Microbe
5 (3): 217-219, 2009.
Thammavongsa V, Schaefer M, Filzen T, Collins KL,
Carrington M, Bangia N, Raghavan M. Assembly and intracellular
trafficking of HLA-B*3501 and HLA-B*3503. Immunogenetics
61 (11-12): 703-716, 2009.
Carter CC, Onafuwa-Nuga A, McNamara LA, Riddell J, Bixby D, Savona MR, Collins KL. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nature Med 16 (4): 446-U127, 2010.
Garcia-Perez JL, Morell M, Scheys JO, Kulpa DA, Morell S, Carter CC, Hammer GD, Collins KL, O'Shea KS, Menendez P, Moran JV. Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells. Nature 466 (7307): 769-773, 2010.
Onafuwa-Nuga A, McNamara LA, Collins KL. Towards a cure for HIV: the identification and characterization of HIV reservoirs in optimally treated people. Cell Res 20 (11): 1185-1187, 2010.
Carter CC, McNamara LA, Onafuwa-Nuga A, Shackleton M, Riddell J, Bixby D, Savona MR, Morrison SJ, Collins KL. HIV-1 Utilizes the CXCR4 Chemokine Receptor to Infect Multipotent Hematopoietic Stem and Progenitor Cells. Cell Host Microbe 9 (3): 223-234, 2011.
Leonard JA, Filzen T, Carter CC, Schaefer M, Collins KL. HIV-1 Nef Disrupts Intracellular Trafficking of Major Histocompatibility Complex Class I, CD4, CD8, and CD28 by Distinct Pathways That Share Common Elements. J Virol 85 (14): 6867-6881, 2011.
Kulpa DA, Collins KL. The emerging role of HLA-C in HIV-1 infection. Immunology 134 (2): 116-122, 2011.
Norman JM, Mashiba M, McNamara LA, Onafuwa-Nuga A, Chiari-Fort E, Shen WW, Collins KL. The antiviral factor APOBEC3G enhances the recognition of HIV-infected primary T cells by natural killer cells. Nature Immunol 12 (10): 975-NIL_83, 2011.
McNamara LA, Collins KL. Hematopoietic stem/precursor cells as HIV reservoirs. Current Open HIV AIDS 6 (1): 43-48, 2011.
Wonderlich ER, Leonard JA, Kulpa DA, Leopold KE, Norman JM, Collins KL. ADP Ribosylation Factor 1 Activity Is Required To Recruit AP-1 to the Major Histocompatibility Complex Class I (MHC-I) Cytoplasmic Tail and Disrupt MHC-I Trafficking in HIV-1-Infected Primary T Cells. J Virol 85 (23): 12216-12226, 2011.
Heigele A, Schindler M, Gnanadurai CW, Leonard JA, Collins KL, Kirchhoff F. Down-Modulation of CD8 alpha beta is a Fundamental Activity of Primate Lentiviral Nef Proteins. J Virol 86 (1):36-48, 2012.