Molecular Mechanisms of HIV Immune Evasion
The human immunodeficiency virus (HIV) causes a lethal syndrome (acquired immunodeficiency syndrome) characterized by CD4+ T cell depletion and resultant immunodeficiency. HIV has caused a worldwide epidemic that has killed millions of people and continues to infect about 40,000 people each year in this country. The long-term goal of our research program is to provide improved treatments for people withHIV/AIDS. Existing therapies are highly effective at rendering viral particles non-infectious and thus reducing viral loads. However none of the current drugs are capable of destroying infected cells. Many infected cells have short half-lives and die within days or months.Others, however, remain in a state that is resistant to the immune system and can persist for years. To provide better therapies, our focus has been on understanding the molecular mechanisms of viral persistence within cellular reservoirs. The development of drugs that will inhibit these pathways will bring us closer to a cure.
To this end, our research program focuses on major viral mechanisms of resistance to the cell mediated immune (CMI) response, which normally eradicates infected cells by direct lysis. To maintain a chronic infection HIV must evade lysis by both cytotoxic T lymphocytes (CTLs), and natural killer (NK) cells. CTLs recognize infected cells with receptors that detect foreign peptide antigens presented in associationwith host major histocompatibility class I protein (MHC-I). NK cells recognize cells with abnormally low MHC-I levels and/or those that have upregulated NK activating ligands. Our goals are to better understand viral mechanisms of immune evasion and to ultimately inhibit these processes.
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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. (Highlighted in Cell Hostand Microbe, Nature Reviews Microbiology and Cell podcast.)
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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: 21874023. (Highlighted with News and Views in Nature Immunology; selected as Nature Immunology article of the month).
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 Sep 14. [Epub ahead of print] PubMed PMID: 21917951.