Adaptive NK Cell Frequency and Function in Cytomegalovirus Infected People Living with HIV
Notice bibliographique
Résumé
The majority of people living with HIV (PLWH) are cytomegalovirus (CMV) co-infected. Infection with both of these viruses is associated with immune activation and a higher risk of health complications such as cardiovascular disease (CVD). CMV infection expands a population of natural killer (NK) cells having adaptive properties. Adaptive NK (adapNK) cells are positive for NKG2C, CD57 and CD16. Most AdapNK cells have potent antibody dependent (AD) responses such as AD cellular cytotoxicity (ADCC) and AD NK cell activation (ADNKA). I hypothesized that adapNK cells play a role in HIV pathogenesis in the context of CMV co-infection. To test this hypothesis, I addressed the following research questions: 1) Does NKG2C genotype influence protection from HIV infection and/or HIV control? 2) Is the frequency of adapNK cells a determinant of total plaque volume (TPV) in CMV+PLWH and CMV+HIV- subjects? 3) Does age or time on antiretroviral treatment (ART) influence the frequency and functionality of adapNK cells in CMV+PLWH? 4) Does HIV infection compromise adapNK cell functionality? In chapter II, I genotyped subjects from an HIV primary infection (PI, i.e. HIV susceptible) cohort and HIV exposed seronegative (HESN i.e. HIV resistant) persons for three possible NKG2C genotypes where the gene product of the NKG2C- allele is not cell surface expressed. When I compared the distribution of the three possible NKG2C genotypes in PI and HESNs, I found no NKG2C-/- carriers in HESNs. Thus, the NKG2C-/- genotype was associated with HIV susceptibility in HIV exposed persons. I next compared the viral load (VL) setpoint in carriers of the three NKG2C genotypes finding no significant between-genotype differences in the VL set point in PLWH. I also showed that there was no correlation between the frequency of NKG2C+ adapNK cells and mean fluorescent intensity (MFI) of NKG2C+ expression on adapNK cells and VL set point. Thus, these genotypes played no role in HIV control. In chapter III, I investigated the frequency of adapNK cells in four groups enrolled in the Canadian HIV and Aging Cohort Study (CHACS): CMV+PLWH, CMV+HIV-, CMV-PLWH, and CMV-HIV- persons. All CHACS participants were >40 yrs of age; all PLWH were on ART. The frequency of adapNK cells was significantly higher in CMV+ than in CMV- persons, while there was no significant difference in the frequency of these cells in CMV+PLWH compared to CMV+HIV- persons. High frequencies of adapNK cells were associated with a reduced prevalence of coronary atherosclerotic plaque in CMV+PLWH and CMV+HIV- persons, suggesting a protective role in this pre-clinical CVD setting.In chapter IV, I showed that the frequency of adapNK cells was higher in CMV+PLWH than in CMV+HIV- persons aged <40 yrs but did not differ significantly in these two groups when from persons aged >40 yrs. However, in the PLWH there was a significant positive associated between age and time on ART. Experiments dissociating age and ART duration revealed that time on ART was the parameter that negatively influenced not only the frequency of adapNK cells but also the frequency of adapNK cells secreting IFN-γ and TNF-α upon AD stimulation in an ADNKA assay. A higher frequency of adapNK than cNK cells from CMV+PLWH and CMV+HIV responded to AD stimulation by secreting IFN-γ and TNF-α indicating that treated HIV infection did not compromise the function of adapNK cells. The results presented in this thesis show that NKG2C+ adapNK play a role at the level of susceptibility to HIV infection in those exposed to HIV but plays no role in HIV control in those infected. AdapNK cells play a role in reducing the risk of pre-clinical atherosclerosis in CMV+ persons. The AD functionality of adapNK and cNK cells is maintained in in the setting of treated HIV infection. The duration of ART impacts the frequency and likely also the functionality of adapNK in CMV+PLWH
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».