Elizabeth Connick
Division Chief, Infectious Disease
Professor, BIO5 Institute
Professor, Immunobiology
Professor, Medicine
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.

Publications

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.

Connick, E., Folkvord, J. M., Lind, K. T., Rakasz, E. G., Miles, B., Wilson, N. A., Santiago, M. L., Schmitt, K., Stephens, E. B., Kim, H. O., Wagstaff, R., Li, S., Abdelaal, H. M., Kemp, N., Watkins, D. I., MaWhinney, S., & Skinner, P. J. (2014). Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL. Journal of immunology (Baltimore, Md. : 1950), 193(11), 5613-25.

We previously demonstrated that HIV replication is concentrated in lymph node B cell follicles during chronic infection and that HIV-specific CTL fail to accumulate in large numbers at those sites. It is unknown whether these observations can be generalized to other secondary lymphoid tissues or whether virus compartmentalization occurs in the absence of CTL. We evaluated these questions in SIVmac239-infected rhesus macaques by quantifying SIV RNA(+) cells and SIV-specific CTL in situ in spleen, lymph nodes, and intestinal tissues obtained at several stages of infection. During chronic asymptomatic infection prior to simian AIDS, SIV-producing cells were more concentrated in follicular (F) compared with extrafollicular (EF) regions of secondary lymphoid tissues. At day 14 of infection, when CTL have minimal impact on virus replication, there was no compartmentalization of SIV-producing cells. Virus compartmentalization was diminished in animals with simian AIDS, which often have low-frequency CTL responses. SIV-specific CTL were consistently more concentrated within EF regions of lymph node and spleen in chronically infected animals regardless of epitope specificity. Frequencies of SIV-specific CTL within F and EF compartments predicted SIV RNA(+) cells within these compartments in a mixed model. Few SIV-specific CTL expressed the F homing molecule CXCR5 in the absence of the EF retention molecule CCR7, possibly accounting for the paucity of F CTL. These findings bolster the hypothesis that B cell follicles are immune privileged sites and suggest that strategies to augment CTL in B cell follicles could lead to improved viral control and possibly a functional cure for HIV infection.

Connick, E., 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). Impact of Daytime Blue-Enriched Light Exposure on Cognition During the Workday. SLEEP.
Connick, E., Almodovar, S., Swanson, J., Giavedoni, L. D., Kanthaswamy, S., Long, C. S., Voelkel, N. F., Edwards, M. G., Folkvord, J. M., Westmoreland, S. V., Luciw, P. A., & Flores, S. C. (2017). Lung Vascular Remodeling, Cardiac Hypertrophy and Inflammatory Cytokines in SHIV nef-infected macaques. Viral Immunology.
Miles, B., Miller, S. M., Folkvord, J. M., Kimball, A., Chamanian, M., Meditz, A. L., Arends, T., McCarter, M. D., Levy, D. N., Rakasz, E. G., Skinner, P. J., & Connick, E. (2015). Follicular regulatory T cells impair follicular T helper cells in HIV and SIV infection. Nature communications, 6, 8608.

Human and simian immunodeficiency viruses (HIV and SIV) exploit follicular lymphoid regions by establishing high levels of viral replication and dysregulating humoral immunity. Follicular regulatory T cells (TFR) are a recently characterized subset of lymphocytes that influence the germinal centre response through interactions with follicular helper T cells (TFH). Here, utilizing both human and rhesus macaque models, we show the impact of HIV and SIV infection on TFR number and function. We find that TFR proportionately and numerically expand during infection through mechanisms involving viral entry and replication, TGF-β signalling, low apoptosis rates and the presence of regulatory dendritic cells. Further, TFR exhibit elevated regulatory phenotypes and impair TFH functions during HIV infection. Thus, TFR contribute to inefficient germinal centre responses and inhibit HIV and SIV clearance.