Elizabeth Connick

Elizabeth Connick

Professor, Medicine
Division Chief, Infectious Disease
Professor, Immunobiology
Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(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

Moore, C. M., MaWhinney, S., Forster, J. E., Carlson, N. E., Allshouse, A., Wang, X., Routy, J. P., Conway, B., & Connick, E. (2017). Accounting for dropout reason in longitudinal studies with nonignorable dropout. Statistical methods in medical research, 26(4), 1854-1866.

Dropout is a common problem in longitudinal cohort studies and clinical trials, often raising concerns of nonignorable dropout. Selection, frailty, and mixture models have been proposed to account for potentially nonignorable missingness by relating the longitudinal outcome to time of dropout. In addition, many longitudinal studies encounter multiple types of missing data or reasons for dropout, such as loss to follow-up, disease progression, treatment modifications and death. When clinically distinct dropout reasons are present, it may be preferable to control for both dropout reason and time to gain additional clinical insights. This may be especially interesting when the dropout reason and dropout times differ by the primary exposure variable. We extend a semi-parametric varying-coefficient method for nonignorable dropout to accommodate dropout reason. We apply our method to untreated HIV-infected subjects recruited to the Acute Infection and Early Disease Research Program HIV cohort and compare longitudinal CD4+ T cell count in injection drug users to nonusers with two dropout reasons: anti-retroviral treatment initiation and loss to follow-up.

Connick, E., Webb, G. M., Li, S., Mwakalundwa, G., Folkvord, J. M., Greene, J. M., Reed, J. S., Stanton, J. J., Legasse, A. W., Hobbs, T., Martin, L. D., Park, B. S., Whitney, J. B., Jeng, E. K., Wong, H. C., Nixon, D. F., Jones, R. B., Skinner, P. J., & Sacha, J. B. (2018). The human IL-15 superagonist ALT-80 directs SIV-specific CD8+ T cells into B cells follicles. Blood Advances.
Miles, B., Miller, S. M., Folkvord, J. M., Levy, D. N., Rakasz, E. G., Skinner, P. J., & Connick, E. (2016). Follicular Regulatory CD8 T Cells Impair the Germinal Center Response in SIV and Ex Vivo HIV Infection. PLoS pathogens, 12(10), e1005924.

During chronic HIV infection, viral replication is concentrated in secondary lymphoid follicles. Cytotoxic CD8 T cells control HIV replication in extrafollicular regions, but not in the follicle. Here, we show CXCR5hiCD44hiCD8 T cells are a regulatory subset differing from conventional CD8 T cells, and constitute the majority of CD8 T cells in the follicle. This subset, CD8 follicular regulatory T cells (CD8 TFR), expand in chronic SIV infection, exhibit enhanced expression of Tim-3 and IL-10, and express less perforin compared to conventional CD8 T cells. CD8 TFR modestly limit HIV replication in follicular helper T cells (TFH), impair TFH IL-21 production via Tim-3, and inhibit IgG production by B cells during ex vivo HIV infection. CD8 TFR induce TFH apoptosis through HLA-E, but induce less apoptosis than conventional CD8 T cells. These data demonstrate that a unique regulatory CD8 population exists in follicles that impairs GC function in HIV infection.

Connick, E., Bronnimann, M. P., & Skinner, P. J. (2018). The B-cell Follicle in HIV Infection: Barrier to a Cure. Frontiers in Immunology.
Miles, B., & Connick, E. (2016). TFH in HIV Latency and as Sources of Replication-Competent Virus. Trends in microbiology, 24(5), 338-44.

During untreated disease, HIV replication is concentrated within T follicular helper cells (TFH). Heightened permissiveness, the presence of highly infectious virions on follicular dendritic cells (FDCs), low frequencies of virus-specific cytotoxic T lymphocytes (CTLs) in B cell follicles, expansions in TFH, and TFH dysfunction, all likely promote replication in TFH. Limited data suggest that memory TFH play a role in the latent or subclinical reservoir of HIV during antiretroviral therapy (ART), potentially for many of the same reasons. A better understanding of the role of memory TFH and FDC-bound virions in promoting recrudescent viremia in the setting of ART cessation is essential. Studies that target follicular virus reservoirs are needed to determine their role in HIV latency and to suggest successful cure strategies.