Background
HIV-1 Exceptional Elite Controllers (EEC) maintain undetectable viremia and halt disease progression more than 20 years after infection in the absence of treatment and may be considered as functionally cured. However, loss of control in these individuals is unknown. In this study we performed a detailed, longitudinal characterisation of the HIV-1 reservoir, viral evolution and immune (B- and T-cell) response in an EEC that unexpectedly lost viral control 32 years after diagnosis.
Methods
The participant was HIV-1-diagnosed in 1985 and was clinically followed since 1990. A comprehensive virological and immunological study was performed on longitudinal available samples (n=16) between 19 and 37 years after diagnosis (Figure 1). We assessed reservoir integrity by IPDA and single genome amplification; evolution and dynamics of viral quasispecies; infectivity and fusogenicity of isolated Env clones; autologous neutralizing capacity and HIV-1-specific cellular immune response.
Results
This EEC (HLA: B39:01/B44:02 and heterozygous CCR5Δ32) had undetectable viral load (VL) for 31 years since diagnosis, except for four transient episodes ≤150 copies/mL. In December 2016, the EEC lost viral control and started ART in October 2021. During the control period, the DNA reservoir was dominated by defective virus (>95%) mainly in the 5’LTR, and by a homogeneous viral quasispecies consisting predominantly of sequences highly similar to the most recent common ancestor (MRCA). For all Env clones analysed (n=9), genetic distance to MRCA was positively correlated with functionality, defined by both infectivity and fusogenicity. Autologous neutralisation against this dominant ancestral Env was observed in all samples analysed (before and after loss of control), as well as an HIV-1-specific Gag immune response. Despite this, extensive sampling during the control period identified evident fluctuations in reservoir size and integrity, viral populations and signs of quasispecies evolution (estimated by env divergence and sequence diversity). These fluctuations were also reflected in the immune response analysed.
Conclusions
This large longitudinal characterisation of a case of loss of control after 32 years, suggests that persistent virological control is not necessarily associated with a steady-state scenario, but may be highly dynamic and involve both virological and immunological changes that will define the outcome of exceptional control.