Elizabeth Connick

Elizabeth Connick

Professor, Medicine
Division Chief, Infectious Disease
Professor, Immunobiology
Professor, BIO5 Institute
Primary Department
Department Affiliations
(520) 626-6887

Work Summary

Dr. Connick is a physician scientist who has dedicated her career to the improvement of health of individuals living with or at risk for HIV-1 infection. Her research ranges from laboratory based investigations of HIV-1 immunopathogenesis to clinical and epidemiological studies of novel immunotherapies and other interventions to improve health outcomes in people living with HIV-1.

Research Interest

Elizabeth Connick, M.D.'s laboratory focuses on the immunopathogenesis of HIV infection, particularly strategies employed by the virus to evade cellular immunity. Because most HIV replication occurs in secondary lymphoid tissues, much of her work has been focused on understanding the biology of HIV replication within lymphoid tissues and unique features of the host immune response at those sites. Other areas of interest include investigation of sex differences in HIV-1 infection as well as factors that promote accelerated cardiovascular disease in HIV-infected individuals.


Miller, S. M., Miles, B., Guo, K., Folkvord, J., Meditz, A. L., McCarter, M. D., Levy, D. N., MaWhinney, S., Santiago, M. L., & Connick, E. (2017). Follicular Regulatory T Cells Are Highly Permissive to R5-Tropic HIV-1. Journal of virology, 91(17).

Follicular regulatory T (TFR) cells are a subset of CD4+ T cells in secondary lymphoid follicles. TFR cells were previously included in the follicular helper T (TFH) cell subset, which consists of cells that are highly permissive to HIV-1. The permissivity of TFR cells to HIV-1 is unknown. We find that TFR cells are more permissive than TFH cells to R5-tropic HIV-1 ex vivo TFR cells expressed more CCR5 and CD4 and supported higher frequencies of viral fusion. Differences in Ki67 expression correlated with HIV-1 replication. Inhibiting cellular proliferation reduced Ki67 expression and HIV-1 replication. Lymph node cells from untreated HIV-infected individuals revealed that TFR cells harbored the highest concentrations of HIV-1 RNA and highest levels of Ki67 expression. These data demonstrate that TFR cells are highly permissive to R5-tropic HIV-1 both ex vivo and in vivo This is likely related to elevated CCR5 levels combined with a heightened proliferative state and suggests that TFR cells contribute to persistent R5-tropic HIV-1 replication in vivoIMPORTANCE In chronic, untreated HIV-1 infection, viral replication is concentrated in secondary lymphoid follicles. Within secondary lymphoid follicles, follicular helper T (TFH) cells have previously been shown to be highly permissive to HIV-1. Recently, another subset of T cells in secondary lymphoid follicles was described, follicular regulatory T (TFR) cells. These cells share some phenotypic characteristics with TFH cells, and studies that showed that TFH cells are highly permissive to HIV-1 included TFR cells in their definition of TFH cells. The permissivity of TFR cells to HIV-1 has not previously been described. Here, we show that TFR cells are highly permissive to HIV-1 both ex vivo and in vivo The expression of Ki67, a marker of proliferative capacity, is predictive of expression of viral proteins, and downregulating Ki67 leads to concurrent decreases in expression of viral proteins. Our study provides new insight into HIV-1 replication and a potential new cell type to target for future treatment.

Connick, E., Melanson, E. L., Ritchie, H. K., Dear, T. B., Catenacci, V., Shea, K., Moehlman, T. M., Stothard, E. R., Higgins, J., McHill, A. W., & Wright Jr., K. P. (2017). Daytime Bright Light Exposure, Metabolism, and Individual Differences in Wake and Sleep Energy Expenditure During Circadian Entrainment and Misalignment.. Neurobiology of Sleep and Circadian Rhythms.
Li, S., Folkvord, J. M., Rakasz, E. G., Abdelaal, H. M., Wagstaff, R. K., Kovacs, K. J., Kim, H. O., Sawahata, R., MaWhinney, S., Masopust, D., Connick, E., & Skinner, P. J. (2016). Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8+ Cells In Vivo. Journal of virology, 90(24), 11168-11180.

Human immunodeficiency virus (HIV)- and simian immunodeficiency virus (SIV)-specific CD8(+) T cells are typically largely excluded from lymphoid B cell follicles, where HIV- and SIV-producing cells are most highly concentrated, indicating that B cell follicles are somewhat of an immunoprivileged site. To gain insights into virus-specific follicular CD8(+) T cells, we determined the location and phenotype of follicular SIV-specific CD8(+) T cells in situ, the local relationship of these cells to Foxp3(+) cells, and the effects of CD8 depletion on levels of follicular SIV-producing cells in chronically SIV-infected rhesus macaques. We found that follicular SIV-specific CD8(+) T cells were able to migrate throughout follicular areas, including germinal centers. Many expressed PD-1, indicating that they may have been exhausted. A small subset was in direct contact with and likely inhibited by Foxp3(+) cells, and a few were themselves Foxp3(+) In addition, subsets of follicular SIV-specific CD8(+) T cells expressed low to medium levels of perforin, and subsets were activated and proliferating. Importantly, after CD8 depletion, the number of SIV-producing cells increased in B cell follicles and extrafollicular areas, suggesting that follicular and extrafollicular CD8(+) T cells have a suppressive effect on SIV replication. Taken together, these results suggest that during chronic SIV infection, despite high levels of exhaustion and likely inhibition by Foxp3(+) cells, a subset of follicular SIV-specific CD8(+) T cells are functional and suppress viral replication in vivo These findings support HIV cure strategies that augment functional follicular virus-specific CD8(+) T cells to enhance viral control.

Miles, B., Miller, S., & Connick, E. (2016). CD4 T Follicular Helper and Regulatory Cell Dynamics and Function in HIV Infection. Frontiers in Immunology, https://doi.org/10.3389/fimmu.2016.00659. doi:https://doi.org/10.3389/fimmu.2016.00659
Kohler, S. L., Pham, M. N., Folkvord, J. M., Arends, T., Miller, S. M., Miles, B., Meditz, A. L., McCarter, M., Levy, D. N., & Connick, E. (2016). Germinal Center T Follicular Helper Cells Are Highly Permissive to HIV-1 and Alter Their Phenotype during Virus Replication. Journal of immunology (Baltimore, Md. : 1950), 196(6), 2711-22.

HIV-1 replication is concentrated within CD4(+) T cells in B cell follicles of secondary lymphoid tissues during asymptomatic disease. Limited data suggest that a subset of T follicular helper cells (TFH) within germinal centers (GC) is highly permissive to HIV-1. Whether GC TFH are the major HIV-1 virus-producing cells in vivo has not been established. In this study, we investigated TFH permissivity to HIV-1 ex vivo by spinoculating and culturing tonsil cells with HIV-1 GFP reporter viruses. Using flow cytometry, higher percentages of GC TFH (CXCR5(high)PD-1(high)) and CXCR5(+)programmed cell death-1 (PD-1)(low) cells were GFP(+) than non-GC TFH (CXCR5(+)PD-1(intermediate)) or extrafollicular (EF) (CXCR5(-)) cells. When sorted prior to spinoculation, however, GC TFH were substantially more permissive than CXCR5(+)PD-1(low) or EF cells, suggesting that many GC TFH transition to a CXCR5(+)PD-1(low) phenotype during productive infection. In situ hybridization on inguinal lymph node sections from untreated HIV-1-infected individuals without AIDS revealed higher frequencies of HIV-1 RNA(+) cells in GC than non-GC regions of follicle or EF regions. Superinfection of HIV-1-infected individuals' lymph node cells with GFP reporter virus confirmed the permissivity of follicular cells ex vivo. Lymph node immunostaining revealed 96% of CXCR5(+)CD4(+) cells were located in follicles. Within sorted lymph node cells from four HIV-infected individuals, CXCR5(+) subsets harbored 11-66-fold more HIV-1 RNA than CXCR5(-) subsets, as determined by RT PCR. Thus, GC TFH are highly permissive to HIV-1, but downregulate PD-1 and, to a lesser extent, CXCR5 during HIV-1 replication. These data further implicate GC TFH as the major HIV-1-producing cells in chronic asymptomatic HIV-1 infection.