My lab studies the molecular pathogenesis of HIV-1 infection.
HIV-1 utilizes the chemokine receptors CCR5 and CXCR4 to
enter target cells, including lymphocytes and macrophages.
CCR5-using strains (R5) are responsible for person-to-person
transmission, but virus evolves over time in infected people
to use both CCR5 and CXCR4 (R5X4), in association with disease
progresses.
Our work is directed at defining how these receptors are
used by HIV-1 to enter target cells, how the viral Envelope
glycoprotein regulates target cell tropism, and the molecular
evolution of virus over time. We have found that virus isolates
differ in their ability to use these entry pathways on target
cells taken from different tissues, such as macrophages,
blood lymphocytes, and tissue-derived lymphocytes. We are
working to understand how the cellular context affects the
manner in which virus uses the receptors, and how this influences
disease progression.
A second area of interest is directed at understanding how
HIV can lead to immune dysfunction independent of infection.
In addition to serving as viral entry coreceptors, CCR5
and CXCR4 are potent signaling molecules. We have shown
that the viral Envelope glycoprotein can act as a functional
ligand for these receptors on macrophages, triggering intracellular
signaling responses and cytokine secretion. We are working
to determine the pathways activated by HIV-1 through these
receptors, and how they alter macrophage function and contribute
to disease.
Twigg, H.L., Weiden, M., Valentine, F., Schnizlein-Bick,
C.T., Bassett, R., Wheat, J., Day, R.B., Rominger-Grubbs,
H., Collman, R.G., Fox, L., Brizz, B., Dragavon, J., Coombs,
R.W., Bucy, R.P. Effect of highly active antiretroviral
therapy on viral burden in the lungs of HIV-infected subjects.
J. Infectious Diseases. (in press).
Tomkowicz, B., Lee, C., Ravyn, V., Cheung, R., Ptasznik,
A., Collman, R.G. The Src kinase lyn is required for CCR5
signaling in response to MIP-1 and R5 HIV-1 gp120 in human
macrophages. Blood. 108(4):1145-50, 2006.
Goodenow, M.M., Collman, R.G. HIV-1 coreceptor preference
is distinct from target cell tropism: A dual parameter nomenclature
to define viral phenotypes. J. Leukocyte Biol. 80:965-972,
2006.
Lee, C., Tomkowicz, B., Freedman, B.D., Collman, R.G. HIV-1
gp120-induced TNF- production by primary human macrophages
is mediated by phosphatidylinositol-3 kinase and mitogen-activated
protein kinase pathways. J. Leuk. Biol. 78:1016-1023, 2005.
Yi, Y., Shaheen, F., Collman, R.G. Preferential use of CXCR4
by R5X4 HIV-1 isolates for infection of primary lymphocytes.
J. Virol. 79:1480-1486, 2005.
Tomkowicz B, Collman RG. HIV-1 entry inhibitors: Closing
the front door. Expert Opinion in Therapeutic Targets. 8:65-78,
2004.
Yi Y, Singh A, Shaheen F, Louden A, Lee C, Collman RG. Contrasting
use of CCR5 structural determinants by R5 and R5X4 variants
within an HIV-1 primary isolate quasispecies. J. Virol.
77;12057-12066, 2003.
Novina CD, Murray MF, Dykzhoorn D, Beresford PJ, Zhang
D, Riess J, Collman RG, Lieberman J, Shankar P, Sharp PA.
siRNA-directed host and viral gene silencing inhibits HIV
infection. Nature Med. 8:681-686, 2002.
