Areas of Interest
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.
Jay Lubow, David R. Collins, Mike Mashiba, Brian Peterson, Maria C Virgilio, Kathleen L Collins. Mannose receptor is a restriction factor of HIV in macrophages and is counteracted by the accessory protein Vpr. bioRxiv 742197; doi: https://doi.org/10.1101/742197 pre-print (2019)
Zaikos TD, Terry VH, Sebastian Kettinger NT, Lubow J, Painter MM, Virgilio MC, Neevel A, Taschuk F, Onafuwa-Nuga A, McNamara LA, Riddell J 4th, Bixby D, Markowitz N, Collins KL. Hematopoietic Stem and Progenitor Cells Are a Distinct HIV Reservoir that Contributes to Persistent Viremia in Suppressed Patients. Cell Rep. 2018 Dec 26;25(13):3759-3773.e9. doi: 10.1016/j.celrep.2018.11.104. PubMed PMID: 30590047.
Zaikos TD, Painter MM, Sebastian Kettinger NT, Terry VH, Collins KL. Class 1-Selective Histone Deacetylase (HDAC) Inhibitors Enhance HIV Latency Reversal while Preserving the Activity of HDAC Isoforms Necessary for Maximal HIV Gene Expression. J Virol. 2018 Mar 15;92(6). doi: 10.1128/JVI.02110-17. Print 2018 Mar 15. PubMed PMID: 29298886; PubMed Central PMCID: PMC5827401.
Painter MM, Zaikos TD, Collins KL. Quiescence Promotes Latent HIV Infection and Resistance to Reactivation from Latency with Histone Deacetylase Inhibitors. J Virol. 2017 Dec 15;91(24). doi: 10.1128/JVI.01080-17. Print 2017 Dec 15. PubMed PMID: 29021396; PubMed Central PMCID: PMC5709582.
Sebastian NT, Zaikos TD, Terry V, Taschuk F, McNamara LA, Onafuwa-Nuga A, Yucha R, Signer RAJ, Riddell J IV, Bixby D, Markowitz N, Morrison SJ, Collins KL. CD4 is expressed on a heterogeneous subset of hematopoietic progenitors, which persistently harbor CXCR4 and CCR5-tropic HIV proviral genomes in vivo. PLoS Pathog. 2017 Jul;13(7):e1006509. doi: 10.1371/journal.ppat.1006509. eCollection 2017 Jul. PubMed PMID: 28732051; PubMed Central PMCID: PMC5540617.
Collins DR, Lubow J, Lukic Z, Mashiba M, Collins KL. Vpr Promotes Macrophage-Dependent HIV-1 Infection of CD4+ T Lymphocytes. PLoS Pathog. 2015 Jul;11(7):e1005054. doi: 10.1371/journal.ppat.1005054. eCollection 2015 Jul. PubMed PMID: 26186441; PubMed Central PMCID: PMC4506080.
Carter CC, Onafuwa-Nuga A, McNamara LA, Riddell J 4th, Bixby D, Savona MR, Collins KL. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med. 2010 Apr;16(4):446-51. doi: 10.1038/nm.2109. Epub 2010 Mar 7. PubMed PMID: 20208541; PubMed Central PMCID: PMC2892382.
Collins KL, Chen BK, Kalams SA, Walker BD, Baltimore D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature. 1998 Jan 22;391(6665):397-401. doi: 10.1038/34929. PubMed PMID: 9450757.
Sebastian NT, Collins KL. Targeting HIV latency: resting memory T cells, hematopoietic progenitor cells and future directions.Expert Rev Anti Infect Ther. 2014 Oct;12(10):1187-201. doi: 10.1586/14787210.2014.956094. Epub 2014 Sep 4. Review. PubMed PMID: 25189526; PubMed Central PMCID: PMC4291319.
Zaikos TD, Collins KL. Long-lived reservoirs of HIV-1. Trends Microbiol. 2014 Apr;22(4):173-5. doi: 10.1016/j.tim.2014.02.015. Epub 2014 Mar 15. PubMed PMID: 24641995; PubMed Central PMCID: PMC4048589.
Collins DR, Collins KL. HIV-1 accessory proteins adapt cellular adaptors to facilitate immune evasion. PLoS Pathog. 2014 Jan;10(1):e1003851. doi: 10.1371/journal.ppat.1003851. Epub 2014 Jan 23. Review. PubMed PMID: 24465204; PubMed Central PMCID: PMC3900642.