Sheila M. Keating, Christopher D. Pilcher, Vivek Jain, Mila Lebedeva, Dylan Hampton, Mohamed Abdel-Mohsen, Xutao Deng, Gary Murphy, Alex Welte, Shelley N. Facente, Frederick Hecht, Steven G. Deeks, Satish K. Pillai, Michael P. Busch

HIV antibodies are generated and maintained by ongoing systemic expression of HIV antigen. We investigated whether HIV antibody responses as measured by high-throughput quantitative and qualitative assays could be used to indirectly measure persistent HIV replication in individuals on antiretroviral therapy (ART). HIV antibody measurements were made over time on and off suppressive ART and were compared to measures of HIV reservoir size and expression of anti-viral restriction factors. Among untreated individuals including both "elite" controllers (viral load ≤ 40) and non-controllers, antibody parameters were stable over time and correlated with the individual viral load (VL). Viral suppression with ART leads to progressive decline in antibodies after treatment induction that persisted for 5-7 years. Higher levels of HIV antibodies on suppressive therapy were associated with later initiation of ART after infection, with higher DNA and cell-associated RNA levels, and with lower expression of multiple anti-HIV host restriction factors. These findings suggest that declining antibody levels on ART reflect lower levels of antigen production and/or viral replication in the persistent HIV reservoir. Relatively inexpensive and quantitative HIV antibody assays may be useful indirect markers enabling efficient monitoring of the viral reservoir and suppression during cure interventions.