AHRI scientists have used a combination of experimental and computational approaches to show that partially inhibiting HIV with antiretroviral therapy can actually result in more infected cells.
The results, published in eLife, suggest that such an increase in the number of HIV-infected cells could potentially result in long-term persistence and increased transmission of disease.
During infection, a virus needs to balance making enough copies of itself while ensuring that its host cell survives to allow the new virus copies to spread. This suggests that more cells will be successfully infected if virus replication is reduced.
Lead author Dr Alex Sigal, Faculty at the Africa Health Research Institute (AHRI) and Group Leader at the Max Planck Institute for Infection Biology Research, Germany, describes a computational model of cell-to-cell transmission of HIV. This model predicts the chance of a cell being infected, the chance of an infected cell dying, and the effects of different strengths of an antiretroviral therapy, efavirenz (EFV), on the likelihood of these scenarios.
Using the model, Sigal and colleagues found two possible outcomes of partially inhibiting infection with EFV: “Where cells were infected by a single attempt, inhibition with EFV would lead to a decline in the number of live infected cells – because it reduced the number of infections per cell from one to zero,” he explains. “But in the case of multiple infection attempts we saw the possibility that inhibition with EFV would reduce the number of HIV copies in the cell, but would not extinguish infection completely.” In fact, reducing the number of HIV copies would be more likely to reduce the chances of cell death, and increase the number of infected live cells.
The team investigated these scenarios in both a cell line and in primary lymph-node cells, the preferred target cells for HIV. In both settings they found a peak in the number of live infected cells at intermediate concentrations of EFV, which would partially inhibit infection. They also found a reduced number of viral copies per cell.
Increasing the concentration of EFV in some cases increased the number of infected cells. Likewise, when a mutant drug-resistant HIV strain was used, the number of live cells only increased when a higher concentration of EFV was used.
This is of note because the concentrations of EFV at which the optimum level of infection is reached in EFV-resistant HIV is similar to that observed in the lymph nodes. EFV also stays in the body for longer than the other antiretroviral drugs it is formulated with, which means there is more opportunity for it to provide a growth advantage. This may allow people whose therapy is no longer working to better transmit drug-resistant strains.
“Our model reproduced the essential behaviour of the experimental results and we think it can be further refined to give even more accurate predictions of HIV infection dynamics,” says co-lead author Laurelle Jackson, a PhD student in Sigal’s group at AHRI. “The study is, to our knowledge, the first to address the question of whether attempting to reduce the severity of HIV infection actually increases the number of infected cells, and has important implications for the use of antiretroviral therapies.”
The paper ‘Incomplete inhibition of HIV infection results in more HIV infected lymph node cells by reducing cell death’ can be freely accessed online at https://doi.org/10.7554/eLife.30134. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.
Top photo: Dr Alex Sigal
Story by eLife’s Emily Packer