The impact of antiretroviral therapy on the evolution of Fc region mediated humoral immunity toward HIV infection
Bibliographic record
Abstract
Secondary analyses of RV144, the only vaccine trial ever shown to provide significant protection against human immunodeficiency virus (HIV) infection, have revealed that immunoglobulin G (IgG) antibody (Ab) dependent cellular cytotoxicity (ADCC) activity correlated with vaccinee protection from HIV (Haynes et al., 2012). ADCC is a humoral immune response that depends on the use of Ab fragment crystallizable (Fc) regions to direct HIV lysis through the engagement of Natural Killer (NK) cells. Therefore, RV144 provides an impetus to further characterize immune responses like ADCC that require Ab Fc regions to attract immune system components capable of lysing extracellular HIV virions and HIV infected cells. Antiretroviral therapy (ART), accessed by approximately half the current HIV+ population and recommended immediately upon HIV infection for the vast majority of people by the International Antiviral Society (IAS), is one such factor that has not been assessed for its ability to impact Ab Fc region mediated (Fcm) immunity, despite its ubiquity (Günthard et al., 2016; WHO, 2016). This study investigated the evolution of IgG Fcm immunity over the course of early HIV infection in ART naive individuals and also in individuals who began receiving ART treatment within six months of HIV infection. The ability of blood plasma donated by HIV+ patients in the Montreal Primary Infection Cohort (MPIC) to mediate ADCC and other HIV antigen specific Fcm immune functions, including Ab dependent phagocytosis (ADCP), Ab dependent complement deposition (ADCD) and Ab dependent trogocytosis (ADCT) was assessed. Total and HIV envelope (Env) gp120 glycoprotein specific IgG titers were quantified in the plasma samples. Comparing equal levels of IgG between the plasma samples, ADCP activity was measured toward an Env gp120 target, while ADCD, ADCC and ADCT activities were measured toward target CCR5+ NK cell resistant CEM (CEM.NKr.CCR5) cells infected with bonafide HIV. These particular HIV infected target cells do not expose cluster of differentiation (CD)4 induced (CD4i) epitopes, which are susceptible to Fcm immunity and are protected by the virus during physiological infection. ADCC, ADCP and ADCT were found to mount significantly over time during untreated HIV infection, yielding Spearman correlation coefficients (rs) of rs=0.3836, rs=0.3532 and rs=0.1975, respectively (corresponding to probability [p] values of p=0.0005, p=0.0013 and p=0.0494, respectively), while ADCD activity did not increase as infection progressed. Analysis of covariance (ANCOVA) was calculated between ART treated and ART naive individuals to determine whether ART administration affected the evolution of Fcm immune responses over time. F-scores of 4.72394 (p=0.0313) and 11.6545 (p=0.0008) portrayed that ART administration did indeed mitigate the evolution of ADCC and ADCD responses, unlike ADCP and ADCT. Generalized linear mixed models (GLMMs) and the variance weighted least squares (VWLS) method were then able to deduce the impact of ART initiation timing on the evolution of ADCC, ADCP, ADCD and ADCT responses, after separating the treated patients into three groups, based on whether their ART administration started within 69 days, between 70 to 124 days, or after 124 days post HIV infection. These statistical analyses revealed that early treatment timing did not affect the evolution of ADCC or ADCP responses in the MPIC plasma donors investigated and actually preserved ADCD and ADCT responses over time, as compared to later ART initiation. Collectively, these results do not reject the current IAS consensus that immediate ART treatment initiation is ideal for the preservation of health in people who become infected with HIV. The results do show however, that ADCC, ADCP, ADCD and ADCT activities can be directed towards HIV epitopes that do not require gp120 binding to CD4.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".