Abbas Mohammadi, MD
Post Doctoral Research Fellow
Abbas Mohammadi, Behzad Etemad, Xin Zhang, Yijia Li, Radwa Sharaf, Gregory Bedwell, Autumn Kittilson, Meghan Melberg, Colline Wong, Jesse Fajnzylber, Nikolaus Jilg, Francoise Giguel, Xiaodong Lian, Rinki Deo, Elisabeth Gillespie, Rida Chishti, Sara Abrha, Taylor Adams, Abigail Siagian, Alex Rosenthal, Daniel Worrall, Alan Engelman, Steven G. Deeks, Michael M. Lederman, Sigal Yawetz, Daniel R. Kuritzkes, Mathias D. Lichterfeld, Athe N. Tsibris, Mary N. Carrington, Zabrina l. Brumme, Jose Castillo-Mancilla, Gaurav D. Gaiha, Jonathan Z. Li
Jonathan Z. Li
Research Category: Allergy, Immunology, Inflammation, and Infectious Diseases
Introduction: Persistent low-level HIV-1 viremia (pLLV) can occur despite adherence to antiretroviral therapies (ART) and without drug resistance. We evaluated the viral, host and immune mechanisms of pLLV.
Methods: We enrolled 8 ART-treated participants with ≥3 HIV-1 RNA between 40-1000 copies/mL over 24 months. We performed proviral and plasma HIV sequencing, HIV integration site analysis, CD4+ T cell transcriptomic profiling and evaluated HIV-specific CD8 T-cell activity. We defined intact proviruses that contribute to plasma viremia as “producers”, and those that did not as “non-producers”.
Results: Plasma pLLV sequences were comprised primarily of large identical clones. 38% of participant sequences demonstrated unusual 5’ deletions. pLLV participants had a significantly larger intact reservoir (p=0.001). The chromosomal integration site of producer proviruses was in closer proximity to key heterochromatin markers H3K9me3 and H3K36me3. pLLV demonstrated significant upregulation of anti-apoptotic genes, with downregulation of type I/II interferon-related genes. There were no significant differences in HIV-specific CD8 T cell activity between pLLV and ART-suppressed participants. Producer proviruses harbored more HLA escape mutations compared to non-producers (p=0.04).
Conclusion: Our findings suggest that persistent low-level HIV viremia is driven by the intersection of factors at the viral genetic, epigenetic and cellular level.
HIV can persist in human body for lifetime despite the most contemporary treatment, owing to their ability to integrate into human immune cells named CD4+ T cells. Most people with HIV (PWH) can suppress active viral replication when taking their HIV medications. A small group of people, however, could not suppress despite great adherence to the HIV medications they are taking. We aim to understand the mechanisms behind this phenomenon to better serve this group of people. We enrolled 8 PWH with this condition and did thorough sequencing assays. We also performed comprehensive immunological assays to understand the role of immune system. We found that big clones of identical HIV viruses integrated into certain hotspots in human genome releasing viruses in the blood over years. They tend to integrate into certain genome areas that allows them to hide from immune system killing. The CD4+ T cells carrying these viruses could survive long enough, since their cell-death signal was dialed down. Furthermore, these viruses evolved to escape the surveillance of killer cells that are supposed to eradicate them. In conclusion we identified several mechanisms that allow HIV persist despite this group of people are taking their medications as prescribed. Novel therapeutics targeting these mechanisms could help us suppress these recalcitrant viruses.