Abstract
BackgroundCD8+ T cell responses are known to be important to the control of HIV-1 infection. While responses to reverse transcriptase and most structural and accessory proteins have been extensively studied, CD8 T cell responses specifically directed to the HIV-1 enzymes Protease and Integrase have not been well characterized, and few epitopes have been described in detail.MethodsWe assessed comprehensively the CD8 T cell responses to synthetic peptides spanning Protease and Integrase in 56 HIV-1 infected subjects with acute, chronic, or controlled infection using IFN-γ-Elispot assays and intracellular cytokine staining. Fine-characterization of novel CTL epitopes was performed on peptide-specific CTL lines in Elispot and 51Chromium-release assays.ResultsThirteen (23%) and 38 (68%) of the 56 subjects had detectable responses to Protease and Integrase, respectively, and together these targeted most regions within both proteins. Sequence variability analysis confirmed that responses cluster largely around conserved regions of Integrase, but responses against a large, highly conserved region of the N-terminal DNA-binding domain of Integrase were not readily detected. CD8 T cell responses targeted regions of Protease that contain known Protease inhibitor mutation residues, but strong Protease-specific CD8 T cell responses were rare. Fine-mapping of targeted epitopes allowed the identification of three novel, HLA class I-restricted, frequently-targeted optimal epitopes. There were no significant correlations between CD8 T cell responses to Protease and Integrase and clinical disease category in the study subjects, nor was there a correlation with viral load.ConclusionsThese findings confirm that CD8 T cell responses directed against HIV-1 include potentially important functional regions of Protease and Integrase, and that pharmacologic targeting of these enzymes will place them under both drug and immune selection pressure.
Highlights
In HIV-1 infection, virus-specific CD8 T cell responses are readily detected in peripheral blood and lymph nodes, but HIV-1 replication typically persists in the face of an exuberant CD8 response [1,2,3]
Partial control of viremia during acute infection correlates with the appearance of HIV-specific CD8 T cells [6,7], and some reports have suggested that there is an inverse correlation between the CD8 response and HIV-1 viral load, this remains controversial [8,9,10,11]
All but one of the 28 subjects enrolled in the acute cohort began effective antiretroviral treatment at the time of enrollment, 12 subjects were subsequently enrolled in a supervised treatment interruption trial [25], and had CD8 responses measured while off therapy
Summary
In HIV-1 infection, virus-specific CD8 T cell responses are readily detected in peripheral blood and lymph nodes, but HIV-1 replication typically persists in the face of an exuberant CD8 response [1,2,3]. Partial control of viremia during acute infection correlates with the appearance of HIV-specific CD8 T cells [6,7], and some reports have suggested that there is an inverse correlation between the CD8 response and HIV-1 viral load, this remains controversial [8,9,10,11]. The specific relationship between CD8 T cells and viral control in HIV-1 infection remains unclear, CD8 responses appear to be a critical component of an effective HIV-1-specific immune response [16,17]. While responses to reverse transcriptase and most structural and accessory proteins have been extensively studied, CD8 T cell responses directed to the HIV-1 enzymes Protease and Integrase have not been well characterized, and few epitopes have been described in detail
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