Although combination antiretroviral therapy (ART) has significantly improved the life span of people living with human immunodeficiency virus (HIV), cART alone is not able to eradicate the infection. Despite its high efficiency, cART must be maintained for life to prevent the resumption of virus replication and disease progression. This lifelong treatment, however, brings both health side effects for treated individuals and a significant economic burden to society. Considering that nearly 35 million people worldwide currently live with HIV, it becomes evident the importance of developing novel therapeutic interventions that could facilitate complete and durable remission of HIV infection. Failure to cure HIV is in part due to long-lived CD4+ T cells carrying an integrated, replication-competent form of the viral genome. These latently-infected cells can persist for long periods of time and are believed to be preserved by homeostatic mechanisms. The focus of Okoye’s laboratory is to develop novel strategies aimed at eliminating these latently-infected cells with the goal of facilitating remission from virus replication after cART cessation. A few projects are highlighted below:
HIV latency disruption
One strategy that has been proposed to enhance immune recognition of latently-infected CD4+ T cells is the use of a latency-reversing agents (LRA) to induce viral gene expression in the presence of suppressive cART, a strategy often referred to as “kick and kill”. The goal of this approach is to facilitate the clearance of cells with reactivating viral reservoirs by either viral cytopathic effects or immune cell-mediated killing. To date, several LRAs have been identified that can increase latent viral gene expression in in vitro models of HIV latency and in primary CD4+ T cells isolated from cART suppressed individuals. However, only a few studies using LRAs in vivo have reported a significant increase in virus production. Dr. Okoye’s lab is actively engaged in evaluating novel LRAs for their potential to disrupt HIV latency in vivo.
Therapeutic HIV vaccination
In most HIV-infected individuals, post-cART immune-mediated control of HIV replication is often limited, in part, due to the lack of potent and sustained anti-viral CD8+ T cell responses that can effectively eliminate the vast majority of HIV-producing cells. To date, immunologic interventions that can elicit and maintain such potent cytotoxic T cell responses in cART-suppressed HIV infections are yet to be defined. One approach currently under intense investigation is the use of therapeutic vaccines to boost pre-existing immune responses in HIV+ individuals on suppressive cART and/or to generate completely new responses to epitopes not previously elicited by the virus. Dr. Okoye’s lab is evaluating the potential of a number of vaccine-platforms to enhance cellular immunity in the setting of a previously established, cART-suppressed infection, with the goal of establishing long-term control of HIV replication after cART cessation.
Dr. Okoye graduated from University of Nigeria, Nsukka with a B.Sc. in Microbiology in 1998. He then went on to Nottingham Trent University, UK, to receive a M.Sc. in Biotechnology in 1999. His Ph.D. was achieved in Virology from the University of Glasgow, Scotland in 2004. He is currently a Research Associate Professor at VGTI with a joint faculty appointment at the Oregon National Primate Research Center.
- Okoye AA, Hansen SG, Vaidya M, Fukazawa Y, Park H, Duell DM, Lum R, Hughes CM, Ventura AB, Ainslie E, Ford JC, Morrow D, Gilbride RM, Legasse AW, Hesselgesser J, Geleziunas R, Li Y, Oswald K, Shoemaker R, Fast R, Bosche WJ, Borate BR, Edlefsen PT, Axthelm MK, Picker LJ, Lifson JD. Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound. Nat Med. 2018 Sep;24(9):1430-1440. doi: 10.1038/s41591-018-0130-7. Epub 2018 Aug 6. PubMed PMID: 30082858.
- Chomont N, Okoye AA, Favre D, Trautmann L. Wake me up before you go: a strategy to reduce the latent HIV reservoir. AIDS. 2018 Jan 28;32(3):293-298. doi: 10.1097/QAD.0000000000001695. PubMed PMID: 29135580; PubMed Central PMCID: PMC5758429.
- Thompson HL, Smithey MJ, Uhrlaub JL, Jeftić I, Jergović M, White SE, Currier N, Lang AM, Okoye A, Park B, Picker LJ, Surh CD, Nikolich-Žugich J. Lymph nodes as barriers to T-cell rejuvenation in aging mice and nonhuman primates. Aging Cell. 2019 Feb;18(1):e12865. doi: 10.1111/acel.12865. Epub 2018 Nov 14. PubMed PMID: 30430748; PubMed Central PMCID: PMC6351843.
- Rasmussen TA, McMahon J, Chang JJ, Symons J, Roche M, Dantanarayana A, Okoye A, Hiener B, Palmer S, Lee WS, Kent SJ, Van Der Weyden C, Prince HM, Cameron PU, Lewin SR. Impact of alemtuzumab on HIV persistence in an HIV-infected individual on antiretroviral therapy with Sezary syndrome. AIDS. 2017 Aug 24;31(13):1839-1845. doi: 10.1097/QAD.0000000000001540. PubMed PMID: 28514279; PubMed Central PMCID: PMC5990417.
- DeGottardi MQ, Okoye AA, Vaidya M, Talla A, Konfe AL, Reyes MD, Clock JA, Duell DM, Legasse AW, Sabnis A, Park BS, Axthelm MK, Estes JD, Reiman KA, Sekaly RP, Picker LJ. Effect of Anti-IL-15 Administration on T Cell and NK Cell Homeostasis in Rhesus Macaques. J Immunol. 2016 Aug 15;197(4):1183-98. doi: 10.4049/jimmunol.1600065. Epub 2016 Jul 18. PubMed PMID: 27430715; PubMed Central PMCID: PMC4976006.
- Fukazawa Y, Lum R, Okoye AA, Park H, Matsuda K, Bae JY, Hagen SI, Shoemaker R, Deleage C, Lucero C, Morcock D, Swanson T, Legasse AW, Axthelm MK, Hesselgesser J, Geleziunas R, Hirsch VM, Edlefsen PT, Piatak M Jr, Estes JD, Lifson JD, Picker LJ. B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat Med. 2015 Feb;21(2):132-9. doi: 10.1038/nm.3781. Epub 2015 Jan 19. PubMed PMID: 25599132; PubMed Central PMCID: PMC4320022.
- Okoye AA, Picker LJ. CD4(+) T-cell depletion in HIV infection: mechanisms of immunological failure. Immunol Rev. 2013 Jul;254(1):54-64. doi: 10.1111/imr.12066. Review. PubMed PMID: 23772614; PubMed Central PMCID: PMC3729334.
- Okoye AA, Rohankhedkar M, Abana C, Pattenn A, Reyes M, Pexton C, Lum R, Sylwester A, Planer SL, Legasse A, Park BS, Piatak M Jr, Lifson JD, Axthelm MK, Picker LJ. Naive T cells are dispensable for memory CD4+ T cell homeostasis in progressive simian immunodeficiency virus infection. J Exp Med. 2012 Apr 9;209(4):641-51. doi: 10.1084/jem.20112071. Epub 2012 Mar 26. PubMed PMID: 22451717; PubMed Central PMCID: PMC3328373.
- Leone A, Rohankhedkar M, Okoye A, Legasse A, Axthelm MK, Villinger F, Piatak M Jr, Lifson JD, Assouline B, Morre M, Picker LJ, Sodora DL. Increased CD4+ T cell levels during IL-7 administration of antiretroviral therapy-treated simian immunodeficiency virus-positive macaques are not dependent on strong proliferative responses. J Immunol. 2010 Aug 1;185(3):1650-9. doi: 10.4049/jimmunol.0902626. Epub 2010 Jul 9. PubMed PMID: 20622118; PubMed Central PMCID: PMC3050806.
- Okoye A, Park H, Rohankhedkar M, Coyne-Johnson L, Lum R, Walker JM, Planer SL, Legasse AW, Sylwester AW, Piatak M Jr, Lifson JD, Sodora DL, Villinger F, Axthelm MK, Schmitz JE, Picker LJ. Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis. J Exp Med. 2009 Jul 6;206(7):1575-88. doi: 10.1084/jem.20090356. Epub 2009 Jun 22. PubMed PMID: 19546246; PubMed Central PMCID: PMC2715089.
- Okoye A, Meier-Schellersheim M, Brenchley JM, Hagen SI, Walker JM, Rohankhedkar M, Lum R, Edgar JB, Planer SL, Legasse A, Sylwester AW, Piatak M Jr, Lifson JD, Maino VC, Sodora DL, Douek DC, Axthelm MK, Grossman Z, Picker LJ. Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection. J Exp Med. 2007 Sep 3;204(9):2171-85. Epub 2007 Aug 27. Erratum in: J Exp Med. 2007 Oct;204(10):2493. PubMed PMID: 17724130; PubMed Central PMCID: PMC2118701.