KEYSTONE 2023
HIV Vaccines, Immunoprophylaxis and Drugs (Z6)
Gregory Whitehill project was selected for a short oral and poster presentation.
HIV-Specific Neutralizing Antibody Responses after Acute and Early ART Initiation
CROI 2023
Conference on Retroviruses and Opportunistic Infections
The Bar Lab presented two posters at CROI 2023.
Click on the images below to download the PDF version of each presented poster. BEAT2: PEG-IFN-ALPHA + 3BNC117 + 10-1074 REBOUND VIRUS PHENOTYPE AND EVOLUTION
Jaimy Joy, Francesco Elia Marino, Ryan Krause, Christos J. Petropoulos, Emmanouil Papasavvas, Matthew Fair, Karam Mounzer, Pablo Teba1, Luis J. Montaner, Katharine J. Bar.
University of Pennsylvania, Philadelphia, US, Monogram Biosciences, San Francisco, US, Wistar Institute, Philadelphia, US, Philadelphia FIGHT, Philadelphia, US.
Background: BEAT2 (NCT03588715) tested combined peg-IFN-α2b with two broadly neutralizing antibodies (bnAbs) (3BNC117 and 10-1074) at antiretroviral treatment interruption (ATI) in 14 people living with HIV. Entry criteria included bnAb sensitivity by PhenoSense HIV mAb Assay (IC90< 2.0 µg/mL (3BNC117) and < 1.5 µg/mL (10-1074)). Primary clinical outcomes are presented elsewhere; here, we report the plasma rebound virus phenotype and evolution.
Methods: HIV-1 env single genome sequencing (SGS) was performed at rebound and longitudinally through ATI. Rebound lineage consensus Envs were tested for neutralization sensitivity by TZM.bl assay and compared with PhenoSense results. Two participants withdrew during the study, 12 were analyzed.
Results: SGS of the first detectable rebound virus (n=210 sequences) revealed a median of 1 (range 1-3) reactivating virus populations. Two participants rebounded with high levels of both bnAbs during the 26-week period of immunotherapy. Early rebound Envs had complete resistance to 10-1074 (IC90 >10µg/ml), and increased resistance to 3BNC117 compared to entry criteria (median IC90 of 5.9 µg/ml). Eight participants rebounded after cessation of immunotherapy, between 26- and 30-weeks post-ATI, with waning 10-1074 and 3BNC117 plasma levels (median of 71.0 and 8.1 µg/ml, respectively). Rebound Envs in 6/8 participants were resistant to 10-1074, while 5/8 retained sensitivity to 3BNC117 (median IC90 of 1.52 µg/ml). Finally, 2 participants with rebound >50 weeks post-ATI as both bnAb levels fell to < 5 µg/ml, retained sensitivity (median IC90s=0.63 to 10-1074 and 0.28 µg/ml to 3BNC117). Rebound Env neutralization sensitivities largely agreed with PhenoSense cutoffs obtained from similar samples (100% concordance for 10-1074, 92% for 3BNC117). Rebound Env resistance to 3BNC117 correlated with time to rebound (rs=0.82, p=0.013) and weakly correlated with concurrent 3BNC117 plasma levels (rs=0.67, p=0.069). Longitudinal sequencing over ATI showed increasing env diversity via within-lineage evolution and addition of new rebound lineages, both of which led to further increases in resistance to 3BNC117 (median 2.5-fold increase in IC50).
Conclusions: Parallel analyses of rebound Env sensitivity to administered bnAbs using independent research and commercial assays gave similar results. Rebound Env lineages revealed a high frequency of resistance to both bnAbs (10-1074 > 3BNC117), which increased over the duration of ATI and correlated with time to rebound and diminishing bnAb levels.
AUTOLOGOUS NEUTRALIZING ANTIBODIES DEVELOP AFTER EARLY BUT NOT ACUTE ART INITIATION
Gregory Whitehill, Ryan Krause, Francesco Elia Marino, Jaimy Joy, Suvadip Mallick, Rebecca Hoh, Steven G. Deeks, Rebecca Lynch, Sulggi Lee, Katharine J. Bar.
University of Pennsylvania, Philadelphia, US, University of California, San Francisco, CA, USA, George Washington University, Washington DC, USA
Background: ART initiation (ARTi) in acute/early HIV limits reservoir size and diversity, preserves host immunity, and limits transmission risk, but may also limit development of HIV-specific immune responses. While the kinetics of HIV-specific immunity with ongoing viremia is described, the effect of early ARTi on autologous neutralizing antibody (anAb) development and persistence is less clear. Here, we tested for antibody responses to the identified transmitted/founder (TF) or early virus populations in individuals with acute/early ARTi.
Methods: Among 15 participants from the UCSF Treat Acute HIV study of individuals with acute/early ARTi, plasma was obtained at day of ARTi and longitudinally for 6-36 months. Single genome sequencing (SGS) of early plasma virus was used to identify TF viruses or representative early viruses, which were cloned and pseudotyped. Plasma IgG from longitudinal timepoints was used to test for autologous neutralization by TZM.bl assay. In parallel, plasma IgG was assessed for gp120-specific binding antibodies by ELISA and neutralization of tier 1 MN and SF162 strains.
Results: SGS of gp160 env was performed on first available plasma from 15 participants with ARTi in Fiebig stages I-V and estimated date of diagnostic infection (EDDI) ranging from 17-128 days. SGS (n=311 total, median=22/participant) identified 8 single and 7 multiple virus transmissions. In all 15 participants, plasma IgG from the day of diagnosis/ARTi did not neutralize the contemporaneous autologous TF/early virus. In 7 participants with ARTi < 60 days from EDDI who maintained suppression on ART, no anAbs developed in up to 3 years of sampling. In contrast, 2 of 3 participants with EDDI < 60 days who experienced viral rebound (weeks 16 and 96 after ARTi) subsequently developed anAbs. In participants with ARTi at EDDI >60 days, 5 of 6 developed anAbs 12-80 weeks post-ARTi, which increased in potency on continued ART. AnAb potency at week 24 post-ARTi correlated with time to ARTi (r=-0.69, p=0.006), and with binding antibodies at ARTi (r=-0.79, p< 0.001) and 24 weeks later (r=-0.86, p< 0.0001).
Conclusions: AnAbs developed only in those initiating ART >60 days after EDDI or following rebound viremia after initial ARTi, suggesting that anAb development is dependent on a threshold of viral exposure. In participants for whom this virus exposure threshold was met, anAb potency increased over years of suppressive ART. Results have implications for humoral immunotherapy approaches in PLWH with early ARTi.