Biographical Sketch:
Dr. Lena Al-Harthi began her career in retrovirology in 1992 as a graduate student in the Department of Microbiology and Immunology at the George Washington University. Her doctoral research was performed on HIV pathogenesis in the laboratory of Dr. Robert C. Gallo (co-discoverer of the Human Immunodeficiency Virus {HIV}) at the National Cancer Institute. After earning her Ph.D. in 1996, she joined Rush University as a Mark Weiss Fellow in the Department of Immunology and Microbiology During her two years of post-doctoral work, her research was focused on immune reconstitution of HIV and cytokine modulation of HIV replication. Currently, she is an Associate Professor in the Department of Immunology/Microbiology and the Director of the Graduate Program in the Division of Immunology/Virology at Rush University Medical Center (Chicago, IL).

Description of Research:
Dr. Al-Harthi is currently pursuing two major areas of research relating to HIV neuro- and immuno-pathogenesis:

1. Mechanism of restricted HIV replication in astrocytes and role of cytokines in modulating this restriction: Approximately 25% of HIV infected individuals exhibit neurologic disorders that range from mild or moderate impairment of cognitive-motor skills to severe HIV-associated dementia (HAD) or encephalitis. Recently, sophisticated assessments of neurologic dysfunctions have demonstrated that a high prevalence of neurocognitive impairment still persist in a large cohort of HIV positive patients, despite the use of highly active antiretroviral therapy (HAART). Astrocyte dysregulation correlates with the severity and the rate of HAD progression, highlighting a pivotal role for astrocytes in HIV neuropathogenesis. Astrocytes, however, unlike resident microglia and infiltrating monocytes/macrophages are restricted to productive/robust HIV replication. This restriction to efficient HIV replication in astrocytes is reported to occur at multiple steps of the HIV life cycle, including restriction at HIV entry and post-entry events. My laboratory demonstrated that restriction to HIV replication in astrocytes can be modulated by priming astrocytes with IFNg, which is elevated in the cerebral spinal fluid (CSF) of HAD patients and is secreted by activated microglia and astrocytes themselves. Data from my laboratory further indicate that restricted HIV replication in astrocytes is associated with Wnt signaling through T cell factor (TCF)-4.  Astrocytes can serve as a model for restricted HIV replication that can be applied to other HIV permissive targets. The focus of this project is to define the relationship between Wnt signaling and restricted HIV replication in astrocytes and how IFNg can regulate this restriction. With the long-term goal towards animal and clinical studies to harness the power of the Wnt pathway to suppress HIV replication.

2. The functional role of CD4^dimCD8^bright T cells in anti-viral immunity: Considerable data from my laboratory and that of others indicate that CD4 expression can be de novo up-regulated on CD8+ T cells to generate a CD4^dimCD8^bright T cell phenotype. These cells represent 3-5% of CD8+ T cells in healthy individuals. We have shown that CD4^dimCD8^bright T cells constitute the activated phenotype of CD8+ T cells. In the context of anti-CMV immunity, CD4^dimCD8^bright T cells from CMV seropositive donors recognize CMV pp65 peptide 20-fold higher than CD4-CD8+ T cells and exhibit greater cytotoxic potential than CD4-CD8+ T cells.  Blocking CD4 on CD4^dimCD8^bright T cells or major histocompatability complex II (MHC-II) on antigen presenting cells (APCs) reduces CD4^dimCD8^bright T cell-mediated cytotoxic potential by approximately fifty percent. These data demonstrate that CD4^dimCD8^bright T cells constitute a major cytotoxic subset of CD8+ T cells requiring both CD4 and MHC-II for potent cytotoxic activity. Our effort is now focused on determining the mechanism of enhanced peptide recognition in CD4^dimCD8^bright T cells and their role in anti-HIV immunity.

Publications:

List of Peer-Reviewed Publications (in chronological order):

1. Coyne, V. E. and L. Al-Harthi. 1992. Induction of melanin biosynthesis in Vibrio cholerae. Appl Environ Microbiol 58:2861.

2. Rabbi, M. F., L. Al-H arthi, and K. A. Roebuck. 1997. TNFa cooperates with the protein kinase A pathway to synergistically increase HIV-1 LTR transcription via downstream TRE-like cAMP response elements. Virology 237:422.

3. Spear, G. T., L. Al-Harthi, B. Sha, M. N. Saarloos, M. Hayden, L. S. Massad, C. Benson, K. A. Roebuck, N. R. Glick, and A. Landay. 1997. A potent activator of HIV-1 replication is present in the genital tract of a subset of HIV-1-infected and uninfected women. AIDS 11:1319.

4. Al-Harthi, L., K. A. Roebuck, H. Kessler, and A. Landay. 1997. Inhibition of cytokine-driven human immunodeficiency virus type 1 replication by protease inhibitor. J Infect Dis 176:1175.

5. Rabbi, M. F., L. Al-Harthi, M. Saifuddin, and K. A. Roebuck. 1998. The cAMP-dependent protein kinase A and protein kinase C-beta pathways synergistically interact to activate HIV-1 transcription in latently infected cells of monocyte/macrophage lineage. Virology 245:257.

6. Rabbi, M. F., A. Finnegan, L. Al-Harthi, S. Song, and K. A. Roebuck. 1998. Interleukin-10 enhances tumor necrosis factor-alpha activation of HIV-1 transcription in latently infected T cells. J Acquir Immune Defic Syndr Hum Retrovirol 19:321.

7. Al-Harthi, L., K. A. Roebuck, and A. Landay. 1998. Induction of HIV-1 replication by type 1-like cytokines, interleukin (IL)-12 and IL-15: Effect on viral transcriptional activation, cellular proliferation, and endogenous cytokine production. J Clin Immunol 18:124.

8. Al-Harthi, L., G. T. Spear, F. B. Hashemi, A. Landay, B. E. Sha, and K. A. Roebuck. 1998. A human immunodeficiency virus (HIV)-inducing factor from the female genital tract activates HIV-1 gene expression through the kappaB enhancer. J Infect Dis 178:1343.

9. Al-Harthi, L., M. Owais, and S. K. Arya. 1998. Molecular inhibition of HIV type 1 by HIV type 2: effectiveness in peripheral blood mononuclear cells. AIDS Res Hum Retroviruses 14:59.

10. Al-Harthi, L., K. A. Roebuck, G. G. Olinger, A. Landay, B. E. Sha, F. B. Hashemi, and G. T. Spear. 1999. Bacterial vaginosis-associated microflora isolated from the female genital tract activates HIV-1 expression. J Acquir Immune Defic Syndr 21:194.

11. Al-Harthi, L., D. J. Wright, D. Anderson, M. Cohen, D. Matity Ahu, J. Cohn, S. Cu-Unvin, D. Burns, P. Reichelderfer, S. Lewis, S. Beckner, A. Kovacs, and A. Landay. 2000. The impact of the ovulatory cycle on cytokine production: evaluation of systemic, cervicovaginal, and salivary compartments. J Interferon Cytokine Res 20:719.

12. Al-Harthi, L., J. Siegel, J. Spritzler, J. Pottage, M. Agnoli, and A. Landay. 2000. Maximum suppression of HIV replication leads to the restoration of HIV-specific responses in early HIV disease. AIDS 14:761.

13. Al-Harthi, L., G. Marchetti, C. M. Steffens, J. Poulin, R. Sekaly, and A. Landay. 2000. Detection of T cell receptor circles (TRECs) as biomarkers for de novo T cell synthesis using a quantitative polymerase chain reaction-enzyme linked immunosorbent assay (PCR-ELISA). J Immunol Methods 237:187.

14. Steffens, C. M., L. Al-Harthi, S. Shott, R. Yogev, and A. Landay. 2000. Evaluation of thymopoiesis using T cell receptor excision circles (TRECs): differential correlation between adult and pediatric TRECs and naive phenotypes. Clin Immunol 97:95.

15. Steffens, C. M., K. Y. Smith, A. Landay, S. Shott, A. Truckenbrod, M. Russert, and L. Al-Harthi. 2001. T cell receptor excision circle (TREC) content following maximum HIV suppression is equivalent in HIV-infected and HIV-uninfected individuals. AIDS 15:1757.

16. Sullivan, Y. B., A. L. Landay, J. A. Zack, S. G. Kitchen, and L. Al-Harthi. 2001. Upregulation of CD4 on CD8+ T cells: CD4^dimCD8^bright T cells constitute an activated phenotype of CD8+ T cells. Immunology 103:270.

17. Al-Harthi, L., A. Kovacs, R. W. Coombs, P. S. Reichelderfer, D. J. Wright, M. H. Cohen, J. Cohn, S. Cu-Uvin, H. Watts, S. Lewis, S. Beckner, and A. Landay. 2001. A menstrual cycle pattern for cytokine levels exists in HIV-positive women: implication for HIV vaginal and plasma shedding. Aids 15:1535.

18. Al-Harthi, L., L. J. Guilbert, J. A. Hoxie, and A. Landay. 2002. Trophoblasts are productively infected by CD4-independent isolate of HIV type 1. AIDS Res Hum Retroviruses 18:13.

19. Steffens, C. M., E. Z. Managlia, A. Landay, and L. Al-Harthi. 2002. Interleukin-7-treated naive T cells can be productively infected by T-cell-adapted and primary isolates of human immunodeficiency virus 1. Blood 99:3310.

20. Al-Harthi, L. 2002. IL-7, naive T cell expansion, and HIV infection. Blood 100: 4676. (invited response).

21. Nokta, M. A., X. D. Li, L. Al-Harthi, J. Nichols, A. Pou, D. Asmuth, A. Landay, and R. B. Pollard. 2002. Entrapment of recent thymic emigrants in lymphoid tissues from HIV-infected patients: association with HIV cellular viral load. AIDS 16:2119.

22. Smith, K. Y., C. M. Steffens, A. Truckenbrod, A. Landay, and L. Al-Harthi. 2002. Immune reconstitution after successful treatment with protease inhibitor-based and protease inhibitor-sparing antiretroviral regimens. J Acquir Immune Defic Syndr 29:544.

23. Fleuridor, R., B. Wilson, R. Hou, A. Landay, H. Kessler, and L. Al-Harthi. 2003. CD1d-restricted natural killer T cells are potent targets for human immunodeficiency virus infection. Immunology 108:3.

24. Poirier, M., R. Divi, L. Al-Harthi, O. Olivero, V. Nguyen, B. Walker, A. Landay, V. Walker, M. Charurat, Blattner.WA, and for the WITS. 2003. Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. JAIDS 33:175.

25. Zloza, A.,YBS. Sullivan, E. Connick, AL. Landay, and L. Al-Harthi. 2003. CD8⁺ T cells that express CD4 on their surface (CD4^dimCD8^bright T cells) potently recognize an antigen-specific target, are detected in vivo, and can be productively infected by T-tropic HIV. Blood 102:215-64..

26. Al-Harthi, L., J. Voris, S. Becker, J. Eron, K. Smith, D. Mildvan, R. D'Amico, J. Snidow, B. Pobiner, L. Yau, and A. Landay. 2002. Evaluation of immune restoration parameters in antiretroviral naïve patients with CD4<500 cell/ml: Role of the thymus in naïve T cell rise. HIV medicine.5:55-65.

27. Jacobson JM, Lederman MM, Spritzler J, Valdez H, Tebas P, Skowron G, Wang R, Jackson JB, Fox L, Landay A, Gilbert MJ, O'Neil D, Bancroft L, Al-Harthi L, Jacobson MA, Merigan TC, Jr., Glesby MJ. Granulocyte-Macrophage Colony-Stimulating Factor Induces Modest Increases in Plasma Human Immunodeficiency Virus (HIV) Type 1 RNA Levels and CD4+ Lymphocyte Counts in Patients with Uncontrolled HIV Infection. J Infect Dis. 2003;188:1804-1814.

28. Bahbouhi, B. and L. Al-Harthi. Enriching for HIV infected cells using anti-gp41 antibodies indirectly conjugated to magnetic microbeads. BioTechnique. 2004; 36: 139-1347.

29. Bahbouhi, B, Landay, A., and Al-Harthi, L. Dynamics of cytokine expression within HIV productively infected primary CD4+ T cells. Blood. 2004 5: 55-65

30. De Vera, MJ, Al-Harthi, L. and Gewurz, AT. Assessing thymopoiesis in patients with common variable immunodeficiency as measured by T-cell receptor excision circles. Ann Allergy Asthma Immunol. Ann Allergy Asthma Immunol. 2004; 93:478-484.

31. Managlia, E.Z., Landay, A. and Al-Harthi, L. Interleukin-7 signaling is sufficient to phenotypically and functionally prime human CD4+ naïve T cells. Immunology. 2005; 114: 322-35.

32. Managlia, E. Z., A. Landay, and L. Al-Harthi. 2006. Interleukin-7 induces HIV replication in primary naive T cells through a nuclear factor of activated T cell (NFAT)-dependent pathway. Virology.

33. Zloza, A., and L. Al-Harthi. 2006. Multiple populations of T lymphocytes are distinguished by the level of CD4 and CD8 coexpression and require individual consideration. J Leukoc Biol 79:4.

34. Carroll-Anzinger, D., and L. Al-Harthi. 2006. Gamma interferon primes productive human immunodeficiency virus infection in astrocytes. J Virol 80:541.

35. Al-Harthi, L., J. Voris, W. Du, D. Wright, M. Nowicki, T. Frederick, A. Landay, and A. Kovacs. 2006. Evaluating the Impact of Hepatitis C Virus (HCV) on Highly Active Antiretroviral Therapy-Mediated Immune Responses in HCV/HIV-Coinfected Women: Role of HCV on Expression of Primed/Memory T Cells. J Infect Dis 193:1202.

36. Montoya, C. J., H. B. Jie, L. Al-Harthi, C. Mulder, P. J. Patino, M. T. Rugeles, A. M. Krieg, A. L. Landay, and S. B. Wilson. 2006. Activation of Plasmacytoid Dendritic Cells with TLR9 Agonists Initiates Invariant NKT Cell-Mediated Cross-Talk with Myeloid Dendritic Cells. J Immunol 177:1028-39.

37. Bahbouhi, B., A. Landay, A. Tenorio, and L. Al-Harthi. 2006. HIV infection of primary CD4+ Th2 cells, defined by expression of the Chemoattractant Receptor-Homologous (CRTH2), induces a Th0 phenotype. AIDS Res Hum Retroviruses In press.

List of Reviews and/or Book Chapters:

1. Kelleher, A. D., L. Al-Harthi, and A. L. Landay. 1997. Immunological effects of antiretroviral and immune therapies for HIV. AIDS 11:S149.

2. Al-Harthi, L., and K. A. Roebuck. 1998. Human immunodeficiency virus type-1 transcription: role of the 5'-untranslated leader region . Int J Mol Med 1:875.

3. Valdez, H., L. Al-Harthi, A. Landay, and M. M. Lederman. 1998. Rationale for immune-based therapies for HIV-1 infection. J Lab Clin Med 131:197.

4. Steffens, C. M., G. Marchetti, A. Landay, and L. Al-Harthi. 1999. The Human Thymus: A New Perspective on Thymic function, Aging, and HIV Infection. Clin Immun news letter 19:65.

5. Al-Harthi, L., and A. Landay. 2001. Alternative targets of productive HIV infection: Role of CD4 up-regulation on susceptibility of cells to HIV infection. AIDS Reviews 3:67.

6. Al-Harthi, L., and A. Landay. 2001. HIV in the female genital tract: Viral shedding and mucosal immunity. Clin Obstet Gynecol 44:144.

7. Al-Harthi, L., and A. Landay. 2002. Immune recovery in HIV disease: Role of the thymus and T cell expansion in immune reconstitution strategies. J Hematother Stem Cell Res 11:777.

8. Managlia, L., D. Carroll, A. Zloza, and L. Al-Harthi. Immune modulation of HIV replication. Current research in HIV. Current HIV Research 2004; 2: 395-401.

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