Adaptive NK Cell Frequency and Function in Cytomegalovirus Infected People Living with HIV
Bibliographic record
Abstract
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
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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 | 0.001 |
| 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) | 0.002 | 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".