IHV > Research : T Cells & Viral Pathogenesis Laboratory
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T Cells & Viral Pathogenesis Laboratory

Associated Faculty 

HIV infects and depletes CD4+ T cells during disease. Loss of this T cell subset lowers resistance to other pathogens and promotes HIV disease. HIV also depletes cells that do not express CD4 and are not direct targets for virus infection. Termed “indirect depletion,” this component of viral pathogenesis impacts a broad spectrum of immune cells and likely accounts for reduced tumor immunity, poor levels of protective antibody and the emergence of opportunistic infections. We are interested in two major consequences of indirect cell depletion: the loss of gd T cells and the in ability to generate B cell memory and durable protective antibody responses.

HIV effects on gd T cells are targeted to a Vg2Vd2+ subset that comprises the majority of blood gd T cells in healthy individuals. The extent of gd T cell loss is proportion to clinical outcomes [1], with natural virus suppressors (long term control of HIV without antiretroviral therapy) being the only group that reconstitutes Vg2Vd2 cells to normal levels [2] after infection. In patients with progressing HIV infection, lost gd T cells [3] are not recovered even after therapy. The loss of gd T cells reduces natural tumor surveillance [4], prevents activation of NK cells [5, 6], and impacts an important source for pro-inflammatory cytokines. We are continuing the study of gd T cell biology and antigen recognition by this subset, in addition to understanding the interactions with NK and dendritic cells. Our goals are to exploit the ability to activate gd T cells with approved drugs, for treating HIV disease and for improving outcomes of cancer therapy. More recently, we showed that Envelope glycoprotein from CXCR5-tropic HIV strains causes activation-induced cell death of gd T cells, principally because they express high levels of of the chemokine receptor CCR5. Thus, Env glycoprotein (soluble or on infected cells) might be an important mediator of gd T cell death in HIV-infected individuals. We also showed that nonhuman primates suffered a significant loss of gd T cells after Env immunization, an example for the toxic effects of this protein in vivo. We also know from human clinical studies, that Env elicits only short half-life antibodies after immunization and this is perhaps the greatest obstacle to developing an effective vaccine. Based on our recent findings, we postulate that toxic effects of Env prevent the generation of memory B cells, possibly by eliminating critically important T helper cell subsets. Without adequate B cell memory, antibodies are transient and protective immunity is limited to a short interval after vaccination. We are focusing on modifications of Env glycoprotein that will eliminate the cell killing mechanism while preserving the integrity of protective B cell epitopes; these new molecules will be tested in immunization studies to show whether longer half-life responses are achieved. By direct therapy to increase gd T cell numbers and function or eliminating a toxic property of Env glycoprotein that decreases the half-life of vaccine-induced antibodies, my laboratory continues to focus on the indirect effects of HIV and how they impact the treatment and prevention of disease.

T-Cells and Viral Pathology graphic 

Relevant Publications

  1. Li, H., H. Peng, P. Ma, Y. Ruan, B. Su, X. Ding, C. Xu, C.D. Pauza, and Y. Shao, Association between Vgamma2Vdelta2 T cells and disease progression after infection with closely related strains of HIV in China. Clin Infect Dis, 2008. 46(9): p. 1466-72.
  2. Riedel, D.J., M.M. Sajadi, C.L. Armstrong, J.S. Cummings, C. Cairo, R.R. Redfield, and C.D. Pauza, Natural viral suppressors of HIV-1 have a unique capacity to maintain gammadelta T cells. Aids, 2009. 23(15): p. 1955-64.
  3. Hebbeler, A.M., N. Propp, C. Cairo, H. Li, J.S. Cummings, L.P. Jacobson, J.B. Margolick, and C.D. Pauza, Failure to restore the Vgamma2-Jgamma1.2 repertoire in HIV-infected men receiving highly active antiretroviral therapy (HAART). Clin Immunol, 2008. 128(3): p. 349-57.
  4. Cummings, J.S., C. Cairo, C. Armstrong, C.E. Davis, and C.D. Pauza, Impacts of HIV infection on Vgamma2Vdelta2 T cell phenotype and function: a mechanism for reduced tumor immunity in AIDS. J Leukoc Biol, 2008. 84(2): p. 371-9.
  5. Alexander, A.A., A. Maniar, J.S. Cummings, A.M. Hebbeler, D.H. Schulze, B.R. Gastman, C.D. Pauza, S.E. Strome, and A.I. Chapoval, Isopentenyl pyrophosphate-activated CD56+ {gamma}{delta} T lymphocytes display potent antitumor activity toward human squamous cell carcinoma. Clin Cancer Res, 2008. 14(13): p. 4232-40.
  6. Maniar, A., X. Zhang, W. Lin, B.R. Gastman, C.D. Pauza, S.E. Strome, and A.I. Chapoval, Human gammadelta T lymphocytes induce robust NK cell-mediated antitumor cytotoxicity through CD137 engagement. Blood. 116(10): p. 1726-33.