Background: Increasing evidence suggests that virus-specific CD8⁺ T-cell responses are important in the control of HIV-1 replication. Early treatment of persons with acute HIV-1 infection followed by supervised treatment interruptions (STI) has shown promise for augmenting HIV-1-specific immunity and enhancing immune control of infection. However, subsequent loss of control allows for the assessment of correlates of protective immunity.

Methods: Virus-specific CD8⁺ T-cell responses were measured longitudinally using an IFN-g Elispot assay and a panel of overlapping B-clade peptides spanning all expressed HIV-1 proteins. Full-length sequencing of HIV was performed from both PBMC and plasma samples derived from time points throughout infection.

Results: An acute STI-treated individual effectively controlled infection for over 290 days after repetitive cycles of STI and then experienced a dramatic increase in plasma viral load. Breakthrough of plasma viremia occurred at a time when 25 distinct CD8 T-cell epitopes in Gag, RT, Integrase, Env, Nef, Vpr, Vif, and Rev were targeted. This sudden increase in viremia was associated with a decline in over half of the targeted CD8⁺ T-cell responses. Viral sequencing in this subject revealed super-infection with a second B-clade virus coincident with loss of immune control. Declining CD8⁺ T-cell responses were coupled with sequence changes relative to the initial virus which resulted in impaired recognition. Interestingly, an immunodominant CD8⁺ T-cell epitope in Gag was shared between both viruses indicating that maintained responses against this epitope were not sufficient to prevent emergence of the second virus. However, new CD8⁺ T-cell responses were detected against the second virus indicating that the generation of new responses, in the setting of chronic persistent viral infection, is possible. In addition, neutralizing antibodies to the super-infecting strain were lacking at the time of super-infection but arose later, potentially contributing to viral evolution and neutralization-escape.

Conclusions: These data in a single individual show that HIV-1 super-infection can occur in the setting of a strong and broadly directed virus-specific CD8 T-cell response. The lack of cross protective immunity against a closely related HIV-1 strain, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development.