The role of Nef in the long-term persistence of the replication-competent HIV reservoir in South African women
Bibliographic record
Abstract
ABSTRACT HIV-1 Nef mediates immune evasion and viral pathogenesis in part through the downregulation of cell surface cluster of differentiation 4 (CD4) and major histocompatibility complex class I (MHC-I) on infected cells. While the Nef function of circulating viral populations found early in infection has been associated with reservoir size in early-treated cohorts, there is limited research on how its activity impacts reservoir size in people initiating treatment during chronic infection. In addition, there is little research on its role in the persistence of viral variants during long-term antiretroviral therapy (ART). Phylogenetically distinct nef genes ( n = 82) with varying estimated times of reservoir entry were selected from viral outgrowth variants stimulated from the reservoir of South African women living with HIV who initiated ART during chronic infection ( n = 16). These nef genes were synthesized and used in a pseudovirus infection assay that measures CD4 and MHC-I downregulation via flow cytometry. Downregulation measures were compared to the size of the replication-competent viral reservoir (RC-VR), estimated by quantitative viral outgrowth assay at 5 years after treatment initiation, as well as proviral survival time. Maximum Nef-mediated MHC-I downregulation was significantly associated with RC-VR size ( P = 0.034), but this association was not observed for CD4 downregulation. Conversely, we did not find a consistent association between intraparticipant MHC-I or CD4 downregulation and the variant timing of entry into the reservoir. These data support a role for Nef-mediated MHC-I downregulation in determining RC-VR size, but more work is needed to determine Nef’s role in the survival of individual viral variants over time. IMPORTANCE Rational design of HIV cure interventions requires an understanding of the viral determinants of reservoir dynamics. For an equitable cure, it needs to be broadly applicable. While African women bear the greatest burden of HIV globally, most cure research has focused on men in the global North. Our study aims to elucidate viral determinants of HIV persistence in South African women on antiretroviral therapy. We hypothesized that the HIV protein Nef subverts immune clearance of infected cells by downregulating surface levels of two cellular proteins, CD4 and MHC-I. We compared this downregulation capacity with reservoir size and variant survival in the reservoir. We found a positive association between an individual’s reservoir size and MHC-I downregulation, but there was little evidence for a survival benefit with stronger MHC-I reduction. These data support earlier work and suggest that Nef’s interaction with MHC-I may be a target to restrict the latent reservoir in cure strategies.
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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 | 0.002 |
| 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 | 0.000 | 0.000 |
| 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".