A new study out of Tufts University suggests new experimental systems may be useful in studying how HIV integration can affect normal cells' growth properties in vivo.
The persistence of HIV-1 in CD4 T cells during antiretroviral therapy is thought to be associated with T cells that contain a transcriptionally silent form of the virus that is not affected by antiretroviral drugs. Studies have shown that proviral integration in the human genome has led to the development of lymphomas in patients with AIDS. Integrated HIV-1 proviruses may activate cellular gene expression, can replicate with the host cell, and can be transmitted from one cell generation to the next.
Clonal expansion of cells is often associated with proviral integration in a few specific genes. Scientists from Tufts University conducted in vitro experiments to determine the role of proviral integration in infected T-cell expansion and the specific genes involved. The researchers obtained human primary naïve CD4+ T cells from 2 donors and infected the cells with an HIV-1 vector. The cells were cultured for approximately 2 months, then the frequency and location of HIV proviral DNA integration into genomic DNA were assessed.
Large clusters of integration sites were detected, and the clusters mapped to a small region within the signal transducer and activator of the transcription 3 (STAT3) gene. STAT3 is a transcription factor that can translocate into cell nuclei, combine with DNA, and regulate the expression of genes including those involved in cell proliferation, differentiation, apoptosis, and metastasis. Cells with STAT3-related proviruses increased 100-fold over the course of the study. By day 57 of the study, the cells increased at a rate of 18% per day.
The presence of hybrid HIV-STAT3 sequences suggests that STAT3 overexpression induced by HIV-1 viral integration into host STAT3 DNA may drive the overgrowth of HIV-infected T cells. Although the current study involved cells taken from two donors, the data show that the studied approach may help determine how HIV-1 proviral DNA integration can affect previously normal cells’ T cell growth. Using this study system could also help understand how proviral integration promotes AIDS-related cancers.
HemaCare offers a wide variety of human-derived cellular products for research and the advancement of medicine. If you are conducting research and need help finding cellular material, please contact us.
Yoon, J., Holloway, J., Wells, D., Kaku, M., Jetton, D., Brown, R., & Coffin, J. (2020). HIV proviral DNA integration can drive T cell growth ex vivo. Proceedings Of The National Academy Of Sciences, 117(52), 32880-32882. doi: 10.1073/pnas.2013194117