Human immunodeficiency virus (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 receiving antiretroviral therapy (ART).

HIV antibody responses were measured over time in the presence or absence of suppressive ART and were compared to the HIV reservoir size and expression of antiviral restriction factors.

Among untreated individuals, including both elite controllers (ie, persons with a viral load of ≤40 copies/mL) and noncontrollers, antibody parameters were stable over time and correlated with the individual viral load. Viral suppression with ART led to a progressive decline in antibody responses after treatment induction that persisted for 5–7 years. Higher levels of HIV antibodies during 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 during ART reflect lower levels of antigen production and/or viral replication in the persistent HIV reservoir. Results of relatively inexpensive and quantitative HIV antibody assays may be useful indirect markers that enable efficient monitoring of the viral reservoir and suppression during functional-cure interventions.