HIV is a lentivirus that enters and infects leukocytes, including CD4-expressing T cells, dendritic cells, and macrophages. The virus uses a protein on its surface known as gp120 to bind CD4 on the surface of host cells to gain entry. Once inside, HIV integrates its genetic code into the DNA of the cell, where it can actively replicate or lie dormant for long periods. Infected cells containing dormant HIV can be found in other tissues, such as lymphoid tissue and gut, where they are able to evade CD8 T cells and therapeutics. Broadly neutralizing antibodies (bNAbs), which can bind to many different strains of the human immunodeficiency virus (HIV), have great potential in reducing HIV replication. While bNAbs have shown to be effective in reducing the amount of HIV present in patients, they must be administered often due to their short half-life in vivo. The laboratory of Dr. Hans-Peter Kiem (Clinical Research Division) published a study led by Dr. Anne-Sophie Kuhlmann in the journal Molecular Therapy demonstrating that hematopoietic stem and progenitor cells (HSPCs) could be genetically modified to secrete bNAbs long-term in a preclinical model.
Two of the bNAbs studied in the paper, PGT128 and VRC01, work by binding to gp120 and blocking the viral particles’ attachment to host cells. The authors genetically modified two sets of human CD34+ cells to either secrete PGT128 or VRC01. They then infused the cells into the immunodeficient NSG mice and were able to detect their engraftment up to nine months following infusion. The researchers also found that the cells developed into progenitor cells of myeloid and lymphoid lineage despite gene modification.
Dr. Kuhlmann and the team hypothesized that because these HSPCs were able to differentiate into myeloid and lymphoid cells they would be able to traffic to reservoirs of HIV. “HIV has proven difficult to eradicate in part because of its capacity to infect cells that will remain quiescent in the tissue reservoirs but can reactivate and produce virus later on,” Dr. Kuhlmann said. “Antibodies by themselves might not traffic to these tissues while the modified secreting-hematopoietic cells will. For example, B and T cells will migrate to lymphoid tissues, or monocytes to the brain.” The authors were able to observe the modified cells in several tissues through immunohistochemistry.
To test whether HSPCs would be effective at suppressing HIV, the researchers challenged the mice with HIV after HSPC engraftment. They found that mice engrafted with PGT128 secreting HSPCs had delayed viremia despite low levels of serum bNAbs. “This might be due to the fact that the modified cells can traffic to the reservoir tissues of HIV,” Dr. Kuhlmann said. “By delivering the bNAbs to the tissues of interest, we might not need such high concentrations in the blood. The antibodies are available in the reservoirs tissues to address any viral rebound as soon as it happens.”
The researchers also tested which cell types might be responsible for this protection. They found that CD3+ (T cells) and CD20+ (B cells) cells recovered from the mice expressed bNAb mRNA, suggesting that both T and B cells derived from HSPCs could be producing bNAbs.
Dr. Kuhlmann explained how bNAb secreting HSPCs might change the way HIV patients are treated: “Antiretroviral therapy (ART) is the only FDA-approved treatment for HIV patients. Despite its great efficiency, the virus replication quickly rebounds following treatment interruption and this daily treatment has some side effects that can significantly alter the quality of life for the patients. If efficient on its own, antibody secretion could allow ART treatment interruption and maintain virus suppression.”
Funding for this research was provided by the National Institutes of Health and the Fred Hutch Core Center Grant.
Fred Hutch/UW Cancer Consortium author Hans-Peter Kiem contributed to this work.
Kuhlmann A-S, Haworth KG, Barber-Axthelm IM, Ironside C, Giese MA, Peterson CW, Kiem H-P. 2018. Long-Term Persistence of Anti-HIV Broadly Neutralizing Antibody-Secreting Hematopoietic Cells in Humanized Mice. Molecular Therapy. doi: 10.1016/j.ymthe.2018.09.017. [Epub ahead of print]