Evolution of anti-HIV Envelope-specific antibody concentration and antibody-dependent functionality in HIV primary infection before and after ART initiation

When the Fc portion of antibody (Ab) molecules binds to Fc Receptors (FcR) on an array of innate immune cells, signals are transmitted that modulate their function. Fc-dependent functions (FcDFs) include antibody dependent (AD) cellular cytotoxicity (ADCC), AD cellular trogocytosis (ADCT), AD cellular phagocytosis (ADCP), and AD complement deposition (ADCD). The only vaccine trial to date demonstrating significant (31.2%) protection against HIV-1 infection was the RV144 trial that identified anti-Env Abs and Fc-dependent ADCC as correlates of protection. At present, anti-retroviral therapy (ART) remains the standard of care for HIV infection though only 62% of HIV-1 infected people worldwide are receiving ART. While the timing of the appearance of HIV-specific Abs in acute infection has been defined, less is known about the effect of starting ART at various times during acute infection on the evolution of FcDF responses. Plasma samples from subjects in the Montreal HIV Primary Infection cohort were collected at time points up to 34 months post-treatment. A plate-based enzyme-linked immunosorbent assay (ELISA) was used to quantify total immunoglobulin G (IgG) and HIV Envelope (Env) gp120-specific Ab levels in the plasma samples of untreated and treated subjects. The samples’ anti-Env Ab concentrations were quantified using a new cell-based quantitative assay that employs uninfected CEM (uniCEM) cells and sorted Env-expressing HIV infected CEM.NKR.CCR5 (siCEM) cells. Our siCEM cell model expresses HIV Nef and Vpu and hence downregulates CD4, allowing for accurate quantification of the binding of anti-Env Abs in a model exemplifying Env’s conformation in genuinely infected cells. Subject samples were also used to quantify and characterize four FcDFs including ADCC, ADCT, ADCP, and ADCD. siCEM cells were the target for the ADCC, ADCT, and ADCD assays while gp120 coated beads were used as the target in the ADCP assay. In untreated subjects there was an increase in Ab concentration over time that was significantly different from “0” for total IgG, anti-gp120, and anti-Env Abs. There was a 46.1x higher concentration of anti-gp120 Abs on average than anti-Env Abs in subject plasma. This ratio was enhanced in treated subjects compared to untreated subjects and in those treated <90 DPI compared to those treated > 90 DPI. The activity of all four FcDFs increased with days post-infection (DPI), with statistically significant increases in ADCC and ADCP. Differences in Ab concentration and FcDF activity were observed between subjects who initiated treatment less than vs. greater than 90 DPI. Anti-gp120 and anti-Env Ab concentrations declined with a significantly steeper slope of decline in the late compared to early treatment group. At treatment initiation, there was a significantly higher concentration of anti-Env Abs as well as higher ADCT and ADCP activity in the late compared to the early treatment group. Correlation analyses demonstrated stronger correlations between anti-Env Ab concentration than anti-gp120 Ab concentration with the functional assays. The work described in my thesis contributes to our understanding of Fc-mediated immune activity. This work may inform strategies on the ideal time to initiate ART that balance allowing development of persistent anti-HIV immune responses before starting ART, while still controlling the size of the HIV reservoir

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