Background: While the majority of HIV-1-infected individuals ultimately progress to disease, a minority of individuals spontaneously controls viral replication to low or undetectable levels in the absence of treatment (viral controllers), often for prolonged periods (HIV-1 long-term non-progressors [LTNP]). Understanding the correlates of immune protection in these individuals will provide important insights regarding HIV-1 pathogenesis and vaccine design.

Methods: We investigated 80 HIV-1-infected persons who spontaneously control plasma viremia below 2000 RNA copies/mL in the absence of therapy, and 24 untreated HIV-1 progressors as controls. Fresh PBMC were screened for T-cell responses using overlapping peptides spanning the entire expressed HIV-1 genome in IFN-g ELISpot and intracellular cytokine staining assays. Maturation status of the immunodominant responses was investigated in a subset of study subjects using CCR7 and CD45RA monoclonal antibodies. HLA typing, chemokine receptor and GBV-C RNA status analysis were performed on all study subjects.

Results:  In spite of very similar viral loads, HIV controllers displayed a wide range of HIV-1 specific T-cell responses both in breadth (20 epitopic regions, range 2 to 48) and magnitude (4000 to 34,000 SFC/million PBMC). No statistically significant differences in breadth and magnitude of HIV-1-specific responses were observed between controllers and progressors. However, the number of individuals with terminally differentiated HIV-1-specific T-cell responses was higher in controllers compared to progressors. Multiple novel CTL epitopes were characterized. Those with factors known to be associated with enhanced immune control included 60% who expressed HLA B27 or B57, 22% with chemokine receptor mutations, 48% with concomitant GBV-C infection. For 25%, no factors associated with enhanced control were identified.

Conclusions:  Robust CD8 T-cell responses can be detected in both HIV-1 controllers and progressors. Our data suggest that HIV-1-specific CD8 T cells of mature phenotype may be more easily detectable HIV controllers. A high proportion of individuals expressed HLA class I alleles associated with slow disease progression, indicating that control of viral replication may be at least partially CD8⁺ T-cell mediated, but others had weak to undetectable responses. These data indicate that viral controllers are a heterogeneous group, and that multiple factors may influence long-term containment of viremia.

Keywords: HIV; LTNP; T cell response