Two distinct mechanisms leading to loss of virological control in the rare group of antiretroviral therapy-naïve, transiently aviraemic children living with HIV

HIV-specific CD8+ T-cells play a central role in immune control of adult HIV, but their contribution in paediatric infection is less well-characterised. Previously, we identified a group of ART-naïve children with persistently undetectable plasma viraemia, termed ‘elite controllers’, and a second group who achieved aviraemia only transiently. To investigate the mechanisms of failure to maintain aviraemia, we characterized in three transient aviraemics (TAs), each of whom expressed the disease-protective HLA-B*81:01, longitudinal HIV-specific T-cell activity and viral sequences. In two TAs, a CD8+ T-cell response targeting the immunodominant epitope TPQDLNTML (‘Gag-TL9’) was associated with viral control, followed by viral rebound and the emergence of escape variants with lower replicative capacity. Both TAs mounted variant-specific responses, but only at low functional avidity, resulting in immunological progression. By contrast, in TA-3, intermittent viraemic episodes followed aviraemia without virus escape or a diminished CD4+ T-cell count. High quality and magnitude of the CD8+ T-cell response was associated with aviraemia. We therefore identify two distinct mechanisms of loss of viral control. In one scenario, CD8+ T-cell responses initially cornered low replicative capacity escape variants, but with insufficient avidity to prevent viraemia and disease progression. In the other, loss of viral control was associated neither with virus escape nor progression, but with a decrease in the quality of the CD8+ T-cell response, followed by recovery of viral control in association with improved antiviral response. These data suggest the potential for a consistently strong and polyfunctional antiviral response to achieve long-term viral control without escape. IMPORTANCE Very early initiation of antiretroviral therapy (ART) in paediatric HIV infection offers a unique opportunity to limit the size and diversity of the viral reservoir. However, only exceptionally is ART alone sufficient to achieve remission. Additional interventions are therefore required that likely include contributions from host immunity. The HIV-specific T-cell response plays a central role in immune control of adult HIV, often mediated through protective alleles such as HLA-B*57/58:01/81:01. However, due to the tolerogenic and type 2 biased immune response in early life, HLA-I-mediated immune suppression of viraemia is seldom observed in children. We describe a rare group of HLA-B*81:01-positive, ART-naïve children who achieved aviraemia, albeit only transiently, and investigate the role of the CD8+ T-cell response in the establishment and loss of viral control. We identify a mechanism by which the HIV-specific response can achieve viraemic control without viral escape, that can be explored in strategies to achieve remission.