- Ph.D. Candidate
Laboratory of Dr. Jason Kimata
Department of Molecular Virology and Microbiology
Baylor College of Medicine
Houston, TX US
- Department of Molecular Virology and Microbiology (Lab)
One Baylor Plaza, RM 811D
Houston, TX 77030
- BS from The University of Texas at Austin
- 05/2017 - Austin, Texas US
- Public Health Infectious Diseases
- HIV Functional Cures
- Molecular Virology
Professional StatementHuman Immunodeficiency Virus (HIV) is a major burden of morbidity and mortality. There are more than 75 million people that have been infected with HIV worldwide, with 37.9 million currently living with infection and 2 million deaths per year (1). HIV optimally replicates in CD4 T cells leading to their progressive depletion causing immunologic deficiency if left untreated (2, 3). HIV is a part of the Retroviridae family and a member of the Lentivirus genus. It is an enveloped single stranded positive RNA virus that utilizes reverse transcriptase to generate a copy of viral DNA that subsequently integrates into the host genome. Integration establishes a stable and latent proviral reservoir in infected cells (4). Transcriptionally silent, long-lived resting memory CD4 T cells are the largest proviral reservoir and presents a major challenge for viral eradication (5). Continuous adherence to combination antiretroviral therapy (cART) is highly effective at restricting HIV replication and improving immunologic outcomes. However, interruption of cART results in the reemergence of virus and is not curative in eradication of virus from the host (6, 7). The invariable rebound of viral loads after treatment interruption requires lifelong adherence to cART.
Currently, there are only two documented cases of patients attaining HIV-1 remission (8, 9). Both cases reported patients that had comorbidities of non-HIV related hematologic malignancies. Both patients received 1) allogenic hematopoietic stem-cell transplants after total body irradiation and 2) donor cells that were homozygous mutant deletions for the HIV co-receptor, CCR5. Remarkably, these patients demonstrated sustained HIV-1 remission in the absence of antiretroviral therapy. While these achievements have energized the field and this cell-based strategy has been the only method that resulted in HIV-1 cure, there are considerable challenges to their universal adoption. Limitations include rarity of homozygous mutant donors, toxicities post transplantation from graft versus host disease, increased rates of infection, and a higher risk of death post transplantation (10). Characterization of viral reservoirs upon early introduction of cART in pediatric patients reported that the size of latent reservoirs is inversely related to the duration remission. Additionally, long term remission after treatment interruption has been demonstrated in very early treatment of cART in patients and resulted in improved immune function, effective suppression of virus, and perturbing the expansion of viral reservoirs (11). Together, these data suggest that early introduction of cART preserves immune function that may contribute to improved outcomes and that reducing viral reservoirs to attain long-term viral remission is achievable (12). A functional cure capable of achieving durable viral remission in the absence of cART must 1) reduce the size of HIV reservoirs and 2) effectively restrict residual HIV upon reactivation to preserve immune function.
Alternative approaches to eradicating cures include functional cure strategies of HIV and are defined by sustained viral remission in the absence of cART. Towards that end, immunotherapy remains a promising strategy for controlling HIV infection. Previous work in our lab has demonstrated potent inhibition of HIV-1 at multiple stages of viral replication in vitro using an anti-Env monoclonal antibody single-chain variable fragment (ScFv) anchored to target cell surfaces by a glycosyl-phosphatidylinositol (GPI) attachment. Cell anchored antibody fragments derived from broadly neutralizing antibodies against HIV-1 have demonstrated potent anti-viral activity in vitro. However, the mechanism of cell anchored antibody fragments contributing to clearance after receptor binding is not well understood. Additionally, while natural killer cells play an important roll in facilitating initial control of acute HIV infection, enhancing their ability using cell anchored broadly neutralizing antibody fragments has not yet been investigated. Finally, our preliminary studies have demonstrated potent restriction of HIV and reduction of latent reservoirs using modified HIV specific T cells in vitro; but their efficacy in vivo has not yet been evaluated.
Research in the Kimata lab seeks to understand and characterize the mechanism of how antibody fragments anchored on T cell surfaces may contribute toward virus suppression. Specifically, we will investigate the events following HIV binding to cell anchored antibody fragments. In addition, we seek to characterize the role of displaying neutralizing proteins on natural killer cell surfaces and its effect on cytotoxicity in vitro. Finally, we will investigate the effects of deploying neutralizing proteins on CD8 HIV specific T cells in vivo in a cART as well as a cART free environment during HIV-1 infection. Answering these questions will advance our understanding of achieving long-term remission of HIV in the absence of cART and contribute to our knowledge of attaining a functional cure for HIV.
1. HIV/AIDS: World Health Organization; 2019 [updated November 2017]. Available from: https://www.who.int/en/news-room/fact-sheets/detail/hiv-aids.
2. Moir S, Chun TW, Fauci AS. Pathogenic mechanisms of HIV disease. Annu Rev Pathol. 2011;6:223-48. Epub 2010/11/03. doi: 10.1146/annurev-pathol-011110-130254. PubMed PMID: 21034222.
3. McCune JM. The dynamics of CD4+ T-cell depletion in HIV disease. Nature. 2001;410(6831):974-9. Epub 2001/04/20. doi: 10.1038/35073648. PubMed PMID: 11309627.
4. Deeks SG, Overbaugh J, Phillips A, Buchbinder S. HIV infection. Nat Rev Dis Primers. 2015;1:15035. Epub 2015/01/01. doi: 10.1038/nrdp.2015.35. PubMed PMID: 27188527.
5. Kimata JT, Rice AP, Wang J. Challenges and strategies for the eradication of the HIV reservoir. Curr Opin Immunol. 2016;42:65-70. Epub 2016/10/30. doi: 10.1016/j.coi.2016.05.015. PubMed PMID: 27288651; PMCID: PMC5086301.
6. Zhen A, Peterson CW, Carrillo MA, Reddy SS, Youn CS, Lam BB, Chang NY, Martin HA, Rick JW, Kim J, Neel NC, Rezek VK, Kamata M, Chen ISY, Zack JA, Kiem HP, Kitchen SG. Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS. PLoS Pathog. 2017;13(12):e1006753. Epub 2017/12/29. doi: 10.1371/journal.ppat.1006753. PubMed PMID: 29284044; PMCID: PMC5746250.
7. Leibman RS, Richardson MW, Ellebrecht CT, Maldini CR, Glover JA, Secreto AJ, Kulikovskaya I, Lacey SF, Akkina SR, Yi Y, Shaheen F, Wang J, Dufendach KA, Holmes MC, Collman RG, Payne AS, Riley JL. Supraphysiologic control over HIV-1 replication mediated by CD8 T cells expressing a re-engineered CD4-based chimeric antigen receptor. PLoS Pathog. 2017;13(10):e1006613. Epub 2017/10/13. doi: 10.1371/journal.ppat.1006613. PubMed PMID: 29023549; PMCID: PMC5638568.
8. Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, Schneider T, Hofmann J, Kucherer C, Blau O, Blau IW, Hofmann WK, Thiel E. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360(7):692-8. Epub 2009/02/14. doi: 10.1056/NEJMoa0802905. PubMed PMID: 19213682.
9. Gupta RK, Abdul-Jawad S, McCoy LE, Mok HP, Peppa D, Salgado M, Martinez-Picado J, Nijhuis M, Wensing AMJ, Lee H, Grant P, Nastouli E, Lambert J, Pace M, Salasc F, Monit C, Innes AJ, Muir L, Waters L, Frater J, Lever AML, Edwards SG, Gabriel IH, Olavarria E. HIV-1 remission following CCR5Delta32/Delta32 haematopoietic stem-cell transplantation. Nature. 2019;568(7751):244-8. Epub 2019/03/06. doi: 10.1038/s41586-019-1027-4. PubMed PMID: 30836379.
10. Kuritzkes DR. Hematopoietic stem cell transplantation for HIV cure. J Clin Invest. 2016;126(2):432-7. Epub 2016/01/06. doi: 10.1172/JCI80563. PubMed PMID: 26731468; PMCID: PMC4731181.
11. Rainwater-Lovett K, Luzuriaga K, Persaud D. Very early combination antiretroviral therapy in infants: prospects for cure. Curr Opin HIV AIDS. 2015;10(1):4-11. Epub 2014/11/18. doi: 10.1097/COH.0000000000000127. PubMed PMID: 25402708; PMCID: PMC4351817.
12. Riley JL, Montaner LJ. Cell-Mediated Immunity to Target the Persistent Human Immunodeficiency Virus Reservoir. J Infect Dis. 2017;215(suppl_3):S160-S71. Epub 2017/05/19. doi: 10.1093/infdis/jix002. PubMed PMID: 28520969; PMCID: PMC5853458.
Log In to edit your profile