Antigen presentation of incoming viral particles has been we

Antigen presentation of incoming viral particles has been well studied for diverse viruses in antigen-presenting cells (APCs), mostly in dendritic cells and macrophages in the context of the exogenous antigens’ pathway to prime the CD8+ T cells. However, CD4+ T cells are not known as efficient APCs, and thus the presentation of viral antigens from incoming particles through HLA-I that does not rely on de novo protein production is not completely expected and is not well characterized in CD4+ T cells. Furthermore, activated CD4+ T cells and resting CD4+ T cells possess different enzymatic activities regarding the antigen-processing pathway (J.B., unpublished data), and due to their activation status, resting CD4+ T cells are not expected to efficiently present antigen from incoming particles. Therefore, our study confirms that resting CD4+ T cells are able to present antigens from incoming particles through HLA-I and provides some mechanistic insight regarding this antigen-presentation pathway. Additional studies will be required to understand why CD8+ T cells from HIV controllers are more efficient in recognizing non-activated infected cells and to determine factors that modulate this recognition. It will be important also to determine whether this is unique to the protective g-quadruplex HLA-B∗27 and B∗57 or can be seen in the context of other alleles. Nevertheless, these data indicate that non-productively infected cells can be targeted by CD8+ T cells, suggesting a path forward to reducing the viral reservoir. Furthermore, our study could have implications for T cell-based prophylactic vaccines as an adjunct to antibody-mediated vaccines, as the presence of these cells at the time of infection may limit the establishment of the reservoir.
STAR★Methods
Acknowledgments The authors thank Thomas Murooka and Thorsten Mempel for the HIV proviral constructs, the Ragon Cell Processing Lab, the clinical staff at the Massachusetts General Hospital, and all of the study participants, as well as the Ragon Microscopy Core (particularly Thomas J. Diefenbach) and the Ragon Flow Cytometry Core (particularly Michael Waring). The authors thank also Thomas Obadia from Institut Pasteur (Paris) for help with the biostatistics analysis. This study was supported in part by grants from the Bill and Melinda Gates Foundation (OPP1066973 and OPP1146433), the NIAID (R37AI067073 and R01AI118544), and the Harvard University Center for AIDS Research (CFAR; P30 AI060354), which is supported by the following institutes and centers co-funded by and participating with the NIH: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR.
Background Suppression of HIV-1 replication by antiretroviral therapy (ART) has sharply reduced HIV-related mortality and rendered HIV infection manageable for those with access to treatment [1]. Approximately 21.7 million people living with HIV-1 are receiving ART [2]. The UNAIDS 90-90-90 target encourages all countries to optimize the continuum of care until 73% of people living with HIV are virally suppressed [3]. Based on the results of the START study [4] the WHO recommended ART for all HIV-positive persons, independent of the CD4 T-cell count [5]. Since monitoring of plasma viral load (VL) is necessary to detect treatment failure, there is growing demand for access to VL measurement on a global scale [[6], [7], [8]]. Automated real-time PCR-based technologies, which display an increased dynamic range and are less prone to contamination, have replaced endpoint-based methods for VL measurement [9]. As the lower limits of detection (LOD) and quantification (LLOQ) of these platforms dropped [10], transient low-level viremia (viral blips of 50 to 500 copies/mL) and persistent low-level viremia have been more frequently detected in patients on ART. Although the clinical relevance of low-level viremia is still debated, some studies implicate it in predicting treatment failure and early occurrence of drug resistance [9,[11], [12], [13], [14], [15], [16], [17]]. Therefore, standardization and development of assays with a reliable readout near the LLOQ and thresholds that define treatment failure is important for clinical decision making.