316 Evaluation of Correlates of Protection in HIV-1 Controllers M. M. Addo*1, A. Rathod1, X. G. Yu1, R. Draenert1, M. N. Johnston1, C. Corcoran1, S. Davis1, A. Piechocka-Trocha1, M. Altfeld1, E. S. Rosenberg1, B. D. Walker1, and the HIV-Controller Study Group2 1Partners AIDS Res Ctr, Massachusetts Gen Hosp, Boston, MA and 2Multicenter
Background: World-wide 40 million individuals are infected with HIV-1, and 14,000 new infections occur everyday. While the majority of individuals progress to disease, a small percentage of individuals control viral replication in the absence of treatment ("Viral Controllers"). Understanding the correlates of protection in these individuals will provide important insights to HIV-1 pathogenesis and will be crucial for vaccine design and drug development.
Method: We investigated a cohort of 50 HIV-1 infected individuals who spontaneously control plasma viremia below 1000 RNA copies/ml in the absence of antiretroviral therapy. Fresh PBMC were screened for T-cell responses using overlapping peptides spanning the entire expressed HIV-1 genome in an IFN-g ELISpot assay and by flow-based intracellular cytokine staining. In addition HLA typing, chemokine receptor analysis (CCR5delta32, CCR264I) and GBV-C RNA status analysis were performed on all study subjects.
Results: All HIV-1 proteins served as targets for HIV-1 specific CD8 T-cells in the study cohort. Individuals studied had high and broadly directed HIV-1 specific CD8 T-cell responses, recognizing up to 48 different epitopic regions per individual (median 19, range 2-48) with magnitudes ranging from 4,000 to 34,000 SFC/million PBMC. Fifty-four percent (54%) of study subjects expressed at least 1 HLA allele associated with slow disease progression (HLA-B57, -B27, -B51, -A25 with 34%, 15%, 5%, and 5% of individuals, respectively). Heterozygosity for the CCR5D32bp mutation was found in 20% of individuals; 28% had the CCR264I mutation; 47% of the study subjects were found to be positive for GBV-C RNA.
Conclusions: Many immunological, genetic, and other factors may contribute to improved viral control in HIV-1 controllers. Strong and broadly directed CD8 T-cell responses and robust CD4 T-cell responses can be detected. 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 in these individuals. The exact relative contribution of these factors to improved viral control remain to be defined.
