Kammers K, Chen A, Monaco DR, Hudelson SE, Grant-McAuley W, Moore RD, Alter G, Deeks SG, Morrison CS, Eller LA, Blankson JN, Laeyendecker O, Ruczinski I, Eshleman SH, Larman HB. *Frontiers in Immunology* · August 26, 2021 · DOI: [10.3389/fimmu.2021.740395](https://doi.org/10.3389/fimmu.2021.740395) How to cite ### AMA Kammers K, Chen A, Monaco DR, et al. HIV antibody profiles in HIV controllers and persons with treatment-induced viral suppression. *Front Immunol*. 2021;12:740395. doi:10.3389/fimmu.2021.740395 ### APA ``` Kammers, K., Chen, A., Monaco, D. R., Hudelson, S. E., Grant-McAuley, W., Moore, R. D., Alter, G., Deeks, S. G., Morrison, C. S., Eller, L. A., Blankson, J. N., Laeyendecker, O., Ruczinski, I., Eshleman, S. H., & Larman, H. B. (2021). HIV antibody profiles in HIV controllers and persons with treatment-induced viral suppression. *Frontiers in Immunology*, 12, 740395. https://doi.org/10.3389/fimmu.2021.740395 ``` ### BibTeX ``` @article{Kammers2021HIVControllers, author = {Kammers, Kai and Chen, Athena and Monaco, Daniel R. and Hudelson, Sarah E. and Grant-McAuley, Wendy and Moore, Richard D. and Alter, Galit and Deeks, Steven G. and Morrison, Charles S. and Eller, Leigh A. and Blankson, Joel N. and Laeyendecker, Oliver and Ruczinski, Ingo and Eshleman, Susan H. and Larman, H. Benjamin}, title = {HIV Antibody Profiles in HIV Controllers and Persons With Treatment-Induced Viral Suppression}, journal = {Frontiers in Immunology}, volume = {12}, pages = {740395}, year = {2021}, doi = {10.3389/fimmu.2021.740395} } ``` Kammers and colleagues used VirScan phage-display antibody profiling against 3,384 HIV peptides covering the full HIV proteome to compare reactivity patterns across HIV controllers, treatment-suppressed non-controllers, and viremic non-controllers. Sixty-two peptides were preferentially targeted in controllers versus ART-suppressed non-controllers, clustering into seven epitope groups across *env*, *gag*, *integrase*, and *vpu*. Reactivity to a gag p17 cluster was inversely correlated with viral load set point in an independent longitudinal cohort — pointing past canonical bNAb targets toward a wider antibody repertoire that may track with natural control. [ Read publication at Frontiers in Immunology ](https://doi.org/10.3389/fimmu.2021.740395) In this publication: - **62 differentially reactive peptides** distinguished HIV controllers from ART-suppressed non-controllers (FDR 5%); 61 of these clustered into 7 homologous epitope groups across *env* (34), *gag* (22), *integrase* (4), and *vpu* (2). - **Discovery + Validation cohorts:** 13 elite controllers, 27 viremic controllers, 12 viremic non-controllers, and 21 ART-suppressed non-controllers (Discovery, N=73), with elevated reactivity confirmed in an independent Validation Cohort of 29 elite controllers and 37 ART-suppressed non-controllers (N=66). - **gag p17 cluster reactivity inversely correlated with viral load set point** in an independent longitudinal cohort of non-controllers — surfacing a peptide-resolution biomarker for cure-trial and ATI study design. - **ART vs natural suppression are immunologically distinct:** ART-suppressed non-controllers had markedly lower HIV-peptide reactivity than controllers or viremic non-controllers, implicating ongoing low-level antigen exposure — not viral load alone — as the driver of high antibody reactivity in controllers. People living with HIV who keep their virus under control without medication — called "HIV controllers" — have long puzzled clinicians because most patients require antiretroviral treatment (ART) to suppress the virus. This study asked whether the antibody response itself differs between people who control HIV naturally and those who suppress it with medication, by applying VirScan — a phage-display library that presents 3,384 short peptides spanning the entire HIV proteome — to plasma from a Discovery Cohort of 13 elite controllers, 27 viremic controllers, 12 viremic non-controllers, and 21 ART-suppressed non-controllers, then re-tested key signals in an independent Validation Cohort and a separate longitudinal cohort of non-controllers. Sixty-two peptides showed significantly higher antibody reactivity in HIV controllers than in non-controllers suppressed on ART (FDR 5%). Sixty-one of those clustered into seven groups of homologous epitopes spread across *env* (34 peptides, including six in the V3 loop / CD4 binding loop of gp120), *gag* (22 peptides — 18 in p17, four in p24), *integrase* (four), and *vpu* (two). The Validation Cohort confirmed elevated aggregate reactivity to these peptides in elite controllers. Notably, reactivity to the gag p17 cluster was inversely correlated with viral load set point in the independent longitudinal cohort — meaning the more antibody reactivity to p17 epitopes a person had, the lower their typical viral load tended to be in the absence of treatment. The pattern across the three groups was telling. Controllers and viremic non-controllers (people not on ART) shared elevated antibody reactivity, but ART-suppressed non-controllers had markedly lower reactivity to most HIV peptides. The authors conclude that ongoing low-level antigen exposure — not viral load alone — appears to drive the high antibody reactivity in controllers, and that specific antibody specificities may contribute to viral control rather than simply reflecting it. For HIV cure and vaccine investigators, the work delivers a peptide-resolution biomarker (gag p17 cluster reactivity) and a cohort-portable assay framework that supports retrospective biobank reanalysis as cleanly as prospective study design. 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