Origin and Correlates of Viral Rebound in SIV-Infected Rhesus Macaques Following ART Discontinuation
Irena King1,2,3, Malika Aid1, Emek Kose4
1Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Biorxiv : the Preprint Server for Biology
|September 5, 2025
Summary
Viral rebound after stopping antiretroviral therapy (ART) is initiated by limited clonal lineages replicating in tissues, particularly the gastrointestinal tract. This leads to systemic expansion and further replication, offering insights for HIV-1 cure strategies.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Antiretroviral therapy (ART) suppresses HIV-1 replication but does not eliminate the virus.
- Discontinuation of ART in most individuals leads to viral rebound, with underlying tissue-level mechanisms poorly understood.
Purpose of the Study:
- To investigate the origin, dynamics, and correlates of viral rebound following ART discontinuation in a SIV-infected non-human primate model.
- To identify specific tissue sites and molecular pathways involved in initiating viral rebound.
Main Methods:
- Utilized molecular barcoding to track viral lineages in SIV-infected rhesus macaques (RMs) undergoing ART.
- Analyzed plasma and tissue samples post-ART discontinuation using barcode sequencing, transcriptomics, and proteomics.
- Correlated viral RNA expression in tissues with systemic viral dynamics.
Main Results:
- Identified 1-38 rebounding viral lineages per animal post-ART discontinuation.
- Determined that 1-4 lineages initiate the first detectable rebound viremia.
- Found significant enrichment of viral lineage origins in the gastrointestinal tract and associated lymph nodes.
- Observed upregulation of T cell signaling, cytokine response, and metabolic pathways in peripheral blood before rebound.
Conclusions:
- Viral rebound is initiated by local replication of a few clonal lineages within tissues, primarily the GI tract.
- Systemic expansion and subsequent initiation of additional lineages contribute to sustained viremia.
- These findings provide crucial mechanistic insights for developing next-generation HIV-1 cure strategies.
More Related Videos
Related Concept Videos
01:10Retrovirus Life Cycles
46.7K
Retroviruses have a single-stranded RNA genome that undergoes a special form of replication. Once the retrovirus has entered the host cell, an enzyme called reverse transcriptase synthesizes double-stranded DNA from the retroviral RNA genome. This DNA copy of the genome is then integrated into the host’s genome inside the nucleus via an enzyme called integrase. Consequently, the retroviral genome is transcribed into RNA whenever the host’s genome is transcribed, allowing the...
46.7K
01:26Size and Structure of Viral Genomes
132
Viral genomes exhibit remarkable diversity in size, structure, and composition, influencing their replication strategies and interactions with host cells. These genomes consist of either DNA or RNA and may be linear or circular. Additionally, they can be single-stranded or double-stranded, with each configuration affecting how the virus propagates within a host. RNA viruses, for instance, generally have smaller genomes than DNA viruses, a factor that contributes to their high mutation rates and...
132
02:33Retroviruses
12.7K
Retroviruses and retrotransposons both insert copies of their genetic elements into the genome of the host cell. Thus, the viral genes are passed on when the host genome is replicated or translated. A typical retroviral DNA sequence contains 3-4 genes that encode the different proteins required for its structural assembly and function as a molecular parasite. This DNA is transcribed into a single mRNA, which is very similar in structure to conventional mRNAs, i.e., it is capped at the 5’...
12.7K