Prolonged non-suppressible viremia sustained by a clonally expanded, genomically defective provirus with an immune-evasive HIV protein expression profile
Bibliographic record
Abstract
Abstract Antiretroviral therapy (ART) potently inhibits HIV replication but does not eliminate HIV proviruses integrated within the genomes of infected cells. Though ART normally suppresses HIV to clinically undetectable levels in blood, some individuals experience non-suppressible viremia (NSV) that is not attributable to suboptimal drug exposure ( e.g. due to incomplete medication adherence or pharmacological issues) nor emerging HIV drug resistance, and that does not resolve following regimen modification. We now understand that NSV can originate from expanded cell clones harboring genetically identical proviruses that reactivate en masse to produce clinically detectable viremia. NSV can even originate from proviruses with genomic defects, particularly in HIV’s major splice donor (MSD) site, that render the viremia non-infectious. But, because only a limited number of such cases have been described, all in HIV subtype B, the mechanisms that allow cells harboring such proviruses to produce prolonged viremia without being eliminated remain incompletely understood. We characterized a case of MSD-defective, replication-impaired NSV that lasted >4 years in an individual with non-B HIV. Our results reveal that proviruses with MSD deletions can persist by integrating into minimally differentiated CD4+ T-cell subsets that then give rise to the full spectrum of memory and effector subpopulations, and by exhibiting an HIV protein expression profile that would allow these cells to evade cellular and humoral immunity. Our results highlight the need to better understand the biological implications of persistent HIV protein and virion production by genomically defective, clonally expanded proviruses, and for clinical guidelines to acknowledge this type of viremia. Importance HIV cure efforts focus on eliminating the viral reservoir, strictly defined as cells harboring proviruses that can produce infectious HIV. But this definition excludes proviruses with defects in HIV’s major splice donor site (MSD), which persist readily. Our results confirm that clonally expanded, MSD-defective proviruses can produce HIV transcripts, proteins and clinically-detectable viremia over long periods, underscoring the need to investigate the potential long-term biological consequences of these activities. Our findings also have clinical implications. Most HIV treatment guidelines don’t acknowledge that persistent viremia during ART can originate from clonally-expanded proviruses, and all recommend that viremia >200 HIV RNA copies/mL be managed as virologic failure. Clear clinical frameworks should be developed to discriminate persistent viremia that is due to drug adherence, pharmacokinetics or emerging drug resistance (that is clinically actionable), from NSV (that is not). Genotyping of HIV’s MSD could also help assess potential transmission risk during NSV.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".