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.
Garcia-Perez, J.L., Morell, M., Scheys, J.O., Kulpa, D.A., Morell, S., Carter, C.C.,
Kim, J.K., Hammer, G.D., Collins, K.L., Andrews, P.W., O’Shea, K.S.,
Menendez, P., and Moran, J.V., (2010) Epigenetic silencing of LINE-1
retrotransposition events in human embryonic carcinoma cell lines, Nature, Aug
Carter, C.C., McNamara, L.A., Onafuwa-Nuga, A., Shackleton, M., Riddell, J.,
Bixby, D., Morrison, S.J., and Collins, K.L., (2011) HIV-1 utilizes the CXCR4
chemokine receptor to infect multi-potent hematopoietic stem cells, Cell Host &
Microbe, Mar 17;9(3):223-34.
Leonard, J.A., Filzen, T., Carter, C.C., Schaefer, M., Collins, K.L., (2011) The
HIV-1 Nef protein disrupts intracellular trafficking of MHC-I, CD4, CD8 and
CD28 by distinct pathways that share common elements, J. Virol. Jul
85(14):6867-81. Epub 2011 May 4. PubMed PMID: 21543478, PubMed Central
Norman, J.M., McNamara, L.A., Onafuwa-Nuga, Mashiba, M., Chiari, E. and
Collins K.L., (2011) The antiviral factor APOBEC3G enhances the recognition of
HIV-infected primary T cells by natural killer cells, Nature Immunology, Aug
28;12(10):975-83. doi: 10.1038/ni.2087. [Epub ahead of print] PubMed PMID:
Wonderlich, E.R. Kulpa, D.A., Leonard, J.A., Leopold, K. and Collins, K.L.,
(2011) ARF-1activity is required to recruit AP-1 to the MHC-I cytoplasmic tail
and disrupt MHC-I trafficking in HIV-1 infected primary T cells, J. Virol.
Dec;85(23):12216-26. Epub 2011 Sep 14. PubMed PMID: 21917951; PubMed
Central PMCID: PMC3209341.
Heigele, A., Schindler, M., Gnanadurai, C.W., Leonard, J.A., Collins, K.L. Frank
Kirchhoff, F., (2012) Down-modulation of CD8αß is a fundamental activity of
primate lentiviral Nef proteins. J. Virol. Jan;86(1):36-48. Epub 2011 Oct 19.
PubMed PMID: 22013062; PubMed Central PMCID: PMC3255914.
McNamara L.A, Ganesh J.A., Collins K.L., (2012) Latent HIV-1 Infection Occurs
in Multiple Subsets of Hematopoietic Progenitor Cells and Is Reversed by NF-kB
Activation. J Virol. 2012 Jun 20.
McNamara, L.A., Onafuwa-Nuga, A., Sebastian, N., Riddell, J, Bixby, D., and
Collins, K.L., (2013) CD133+ HPCs harbor HIV genomes in a subset of optimally
treated people with long-term viral suppression. J Infect Dis., Apr 22. [Epub
ahead of print] PubMed PMID: 23554378.
Kulpa, D.A., Del Cid, N., Peterson K., and Collins, K.L., (2013) Adaptor protein
1 directs MHC-I into a cross-presentation pathway, J. Virol. May 14. [Epub ahead
of print] PubMed PMID: 23678182.
Mashiba, M., Collins, David R., and Collins, K.L., (2014) Vpr utilizes DCAF1-
DDB1-CUL4 E3 ubiquitin ligase to overcome macrophage-specific restriction of
Env expression and virion production. Cell Host & Microbe, revision requested