Defective, but not silent
A recent study shows why HIV persists in the body for decades despite effective therapy. The findings could pave the way for new strategies to combat the virus.
10/21/2026 · News · Leibniz-Institut für Virologie · Lebenswissenschaften · Forschungsergebnis
HIV may be suppressed by antiretroviral therapy, but its genetic material remains in the body. New research by scientists at the Leibniz Institute of Virology (LIV) suggests that some of these viral remnants may be doing more than simply lingering: integration of HIV in specific genes, such as the BACH2 master regulator, can change the biology of the cell carrying it. This pushes CD4 T cells towards a state that favours long-term survival, continued division and altered immune activity. This observation may explain why HIV is able to persist for so long in the body of infected people. The results were published in the journal PLOS Pathogens.
Antiretroviral therapy has transformed HIV from a once-deadly infection into a manageable chronic condition. While treatment prevents the virus from multiplying, it cannot remove viral DNA that has already become part of the genome of infected immune cells. In people who have lived with HIV for many years, these so-called proviruses are generally defective and cannot produce new viruses. A large proportion, however, remain transcriptionally active, continuing to produce viral RNA and proteins. The new study by the BMFTR Junior research group “Genomics of Retroviral Infections” lead by PD Dr. Dr. Ulrike Lange, shows that these defective proviruses do more than simply generating “background noise” — they can also influence the biology of the cells in which they reside.
In people with long-term treated HIV, proviruses are frequently found integrated in selected gene hotspots. One of these hotspots is BACH2, a gene that plays an important role in regulating immune-cell development and function. HIV integrations involving BACH2 have been detected in up to 40% of people living with HIV.
“We wanted to understand, what their presence means for the cells that carry the integration,” says Lange.
To investigate, researchers from the Genomics of Retroviral Infections group at LIV recreated a HIV integration site found in people living with HIV. Using the genome-editing technique CRISPR-Cas9, they introduced an HIV sequence into a specific region of the BACH2 gene in CD4 T-like cells.
Defective HIV DNA can change the properties of infected cells
The researchers found that activity of the integrated HIV sequence increased the production of BACH2 protein. Normally, the cell tightly regulates BACH2 through feedback mechanisms. But in the presence of the integrated HIV sequence, these controls were bypassed, leading to maintenance of unusually high levels of BACH2 and widespread changes in gene activity.
“Modeling these effects in primary T cells, we found that genes involved in immune activation and inflammatory responses became less active in affected cells. At the same time, genes associated with the maintenance and survival of long-lived T cells became more active. In agreement, the cells also showed increased proliferation rates”, says Lisa Brauckmann, co-first author of the study and PhD-Student at LIV. The resulting molecular immune profile closely resembled one previously observed in expanded clones of HIV-infected cells from people living with HIV. “We observed that the integrated HIV sequence can disrupt the normal regulation of BACH2 and push the cell towards a state that favours long-term survival and continued division,” says Dr. Martin Hamann, co-first author of the study and postdoctoral researcher at LIV.
“Interestingly, the immune state of the cells was also altered and we found signs that these cells might inhibit innate mechanisms that keep the HIV reservoir in check. Our findings therefore not only offer an explanation for how defective viral sequences can persist for years, but also highlight a mechanism how these sequences may contribute to an altered immune homeostasis that can impact HIV persistence,” says Lange.
In view of potential therapeutic translation, the researchers found that reducing transcriptional activity of the integrated HIV sequence diminished the observed changes associated with its presence in BACH2 gene. These results raise the possibility that suppressing the activity of persistent viral sequences – along the proposed ‘block and lock’ strategy for HIV cure - could in the future, offer a therapeutic way to limit virus-driven immune modulatory effects.
The study was funded primarily by the German Federal Ministry of Research, Technology and Space (BMFTR), with additional support from the German Center for Infection Research (DZIF) and the National Institutes of Health (NIH).