Persistent cell-associated HIV-1 RNA in virally suppressed individuals on INSTI-based ART

Area of Science:

• Virology
• Immunology
• Infectious Diseases

Background:

• Integrase strand transfer inhibitors (INSTIs) are key in modern antiretroviral therapy (ART) for HIV-1 suppression.
• Previous studies focused on HIV DNA, not active transcription, in the HIV reservoir.
• Assessing reservoir activity is crucial for understanding HIV persistence and cure strategies.

Purpose of the Study:

• To functionally compare HIV reservoir activity between INSTI-based and non-INSTI-based ART regimens.
• To measure cell-associated (CA) short HIV-1 RNA transcripts as a marker of active HIV transcription.
• To evaluate the impact of INSTIs on ongoing HIV transcription from the latent reservoir.

Main Methods:

• Measured cell-associated (CA) short HIV-1 RNA and HIV-1 DNA in white blood cells from 92 virally suppressed individuals.
• Compared participants on INSTI-based ART (n=73) versus non-INSTI-based ART (n=19).
• Analyzed the association between prior plasma HIV-1 RNA 'blips' and reservoir size/activity.

Main Results:

• CA short RNA transcripts were detected in all participants; HIV-1 DNA in 99%, despite undetectable plasma viremia.
• Individuals with prior 'blips' had significantly higher CA RNA and HIV DNA.
• No significant difference in reservoir size or transcriptional activity between INSTI and non-INSTI groups was observed.

Conclusions:

• INSTIs effectively block new HIV integration but do not suppress transcription from the established latent reservoir.
• Ongoing HIV transcription persists even with long-term ART, indicating a need for novel therapeutic targets.
• Cure-oriented HIV research should prioritize strategies that directly target and inhibit HIV transcription.