Novel Mechansims for Pk (Gb3) Inhibition of HIV Infection.
Bibliographic record
Abstract
Abstract Many blood group antigens belong to a class of lipid-sugar conjugate molecules known as glycosphingolipids (GSLs), including ABH, Lewis and P blood group systems. GSLs are implicated in HIV-host cell fusion, and several bind to HIV-gp120 in vitro. In addition, inhibiting glycolipid biosynthesis has been shown to prevent HIV membrane fusion. The Pk blood group antigen, also known as globotriaosylceramide (Gb3), has been shown to augment HIV fusion in in vitro models; however its exact role in HIV infection is not known. We have previously developed a soluble analogue of Pk, a highly effective gp120 ligand, which inhibits HIV-1 and HIV-2 membrane fusion. We hypothesize that Pk influences susceptibility to HIV infection, inhibiting at the level of membrane fusion and entry. We have presently investigated the effects of soluble and expressed Pk on HIV-1 infection in vitro. Soluble Pk effects were considered by pre-treating monocyte (M)-tropic HIV-1Ba-L or T-cell (T)-tropic HIV-1IIIB with soluble Pk prior to infection of PHA or PHA/IL2 activated peripheral blood-derived mononuclear cells (PBMCs) or Jurkat T-cells. Productive M-tropic and/or T-tropic HIV-1 infection of PBMCs and Jurkat cells was inhibited by more than 90%. Inhibition of membrane fusion and entry was visualised by transmission electron microscopy. Soluble Pk had minimal effects on cell viability or HIV receptor (CD4) and co-receptor (CCR5 or CXCR4) expression as measured by flow cytometry. Exogenously introduced Pk in Jurkat T-cells was accomplished by liposome fusion, and susceptibility to T-tropic HIV-1IIIB infection was determined. Pk transfer in Jurkat T-cells also reduced productive HIV-1 infection by 50%, without affecting cell viability or HIV receptor and co-receptor expression. Effects of differential Pk expression on HIV susceptibility was investigated using PBMCs with Pk accumulation, from patients with Fabry disease and P1k blood group individuals, or which lack Pk, from p blood group individuals. PBMCs representative of these two groups were infected with M-tropic HIV-1Ba-L or T-tropic HIV-1IIIB. PBMCs with Pk accumulation from patients with Fabry disease were resistant to productive M-tropic, but not T-tropic HIV-1 infection. These PBMCs had significantly decreased expression levels of the M-tropic HIV-1 co-receptor CCR5. Pk accumulation in P1k blood group PBMCs shows resistance to T-tropic and M-tropic HIV-1 infection, unrelated to levels of chemokine receptors. PBMCs lacking Pk from p blood group individuals were hypersensitive to M-tropic HIV-1 infection, while T-tropic HIV-1 infection levels were variable. Interestingly, p blood group PBMCs showed significantly higher levels of the CCR5 co-receptor. Our findings suggest Pk is inhibitory to HIV infection, which may translate into natural resistance in individuals that express high levels of Pk. This may be linked to interactions with CCR5, through receptor trafficking to the cell surface, or associations within lipid rafts. Furthermore, soluble Pk or potential mechanisms to increase cellular Pk expression, provide novel strategies for prevention of HIV infection.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".