Diagnostics and Treatments for HIV

Understanding the persistence of HIV viral reservoirs

Technology Overview

Dr. Lisa FrenkelThe development of anti-retroviral therapy (ART) revolutionized HIV treatment, but discontinuing ART leads to reactivation of the infection due to persistence of viral reservoirs. Broadly, Lisa Frenkel’s research is focused on diagnostic tools for HIV, the mutations that confer resistance to ART, and the mechanisms that allow for viral persistence.

Discovering the mechanisms for viral persistence, despite effective ART, is necessary for the potential development of a curative therapy for HIV. When the virus infects a cell, the viral genome integrates into the host cell genome. Dr. Frenkel has shown that the integration site of the virus influences the ability of the infected cell to survive and proliferate because of the disruption of a gene within the host genome. The result is clonal populations of infected cells with various viral integration sites that become the reservoirs of viral persistence, despite otherwise effective ART. Ongoing projects are focused on determining the cell phenotypes and tissue sources of HIV reservoirs and how HIV reservoir cells interact with other types of cells in the immune system.

Another ongoing area of Dr. Frenkel’s research involves the connection between HIV and cervical dysplasia caused by Human Papilloma Virus (HPV) infection. In conjunction with the Uganda Cancer Institute, Dr. Frenkel is working with patients who have both HPV and HIV infections. This project is centered on determining if HIV in the immune cells of the cervix prevents the immune system from eliminating cervical cancer caused by HPV.

Dr. Frenkel is also interested in the interaction of microchimerism and thymic presentation. While in utero, the fetus exchanges a small number of cells with the mother, which is called microchimerism. At the same time, the fetus is undergoing thymic presentation – the process that allows the immune system to identify self-antigens. Some babies recognize maternal cells as self, which allows the maternal cells to remain. Other babies do not recognize maternal cells as self and the immune system eliminates the maternal cells. Dr. Frenkel is collaborating with experts in microchimerism and cellular immunity to determine if babies that tend to recognize maternal cells as self also recognize maternally-transmitted HIV as self, allowing for immune tolerance of the virus, increased viral persistence and worse prognosis for these babies.

Dr. Frenkel would be interested in working with industry partners in development of therapies and diagnostics for HIV, including point-of-care assays to detect mutations conferring HIV drug resistance. In the future, by identifying drug-resistant mutations, and by discovering the mechanisms that allow for the persistence of virus reservoirs within different contexts and populations, Dr. Frenkel’s research may help improve treatment or move toward a curative therapy for HIV.

Stage of Development

• Pre-clinical ex vivo

Partnering Opportunities

• Collaborative research opportunity
• Sponsored research agreement
• Consultation agreement
• Tissue sample access

Publications

1. Beck IA, Levine M, McGrath CJ, Bii S, Milne RS...Frenkel LM.  Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: A cohort study in Kenya. EClinicalMedicine. 2020 Jan 14;18:100239. doi: 10.1016/j.eclinm.2019.100239. eCollection 2020 Jan.  PMID:  31956856
2. Panpradist N, Beck IA, Vrana J, Higa N, McIntyre D...Frenkel LM, Lutz BR. OLA-Simple: A software-guided HIV-1 drug resistance test for low-resource laboratories.  EBioMedicine. 2019 Dec;50:34-44. doi: 10.1016/j.ebiom.2019.11.002. Epub 2019 Nov 22.
3. Chung MH, McGrath CJ, Beck IA, Levine M, Milne RS...Frenkel LM.  Evaluation of the management of pretreatment HIV drug resistance by oligonucleotide ligation assay: a randomised controlled trial.  Lancet HIV. 2019 Dec 6. pii: S2352-3018(19)30337-6. doi: 10.1016/S2352-3018(19)30337-6.
4. Milne RS, Silverman RA, Beck IA, Mckernan-Mullin J, Deng W, Sibley TR, Dross S, Kiarie JN, Sakr SR, Coombs RW, Chung MH, Frenkel LM. Minority and majority pretreatment HIV-1 drug resistance associated with failure of first-line nonnucleoside reverse-transcriptase inhibitor antiretroviral therapy in Kenyan women. AIDS. 2019;33(6):941-951.
5. Duarte HA, Beck IA, Levine M, Kiptinness C, Kingoo JM, Chohan B. Sakr SR, Chung MH, Frenkel LM. Implementation of a point mutation assay for HIV drug resistance testing in Kenya. AIDS. 2018;32(16):2301-2308. doi: 10.1097/QAD.0000000000001934.
6. Beck IA, Deng W, Payant R, Hall R, Bumgarner RE, Mullins JI, Frenkel LM. Validation of an oligonucleotide ligation assay for quantification of human immunodeficiency virus type 1 drug-resistant mutants by use of massively parallel sequencing. J Clin Microbiol. 2014;52(7):2320-7. doi: 10.1128/JCM.00306-14.
7. Jourdain G, Wagner TA, Ngo-Giang-Huong N, Sirirungsi W, Klinbuayaem V...Frenkel LM, Lallemant M. Association between detection of HIV-1 DNA resistance mutations by a sensitive assay at initiation of antiretroviral therapy and virologic failure. Clin Infect Dis. 2010; 50:1397-1404.

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• Lisa Frenkel, MD