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Dendritic cells (DC) are known to modulate antiviral immune responses; however, the knowledge about the role of different DC subsets in antiviral T cell priming in human tissues remains uncompleted. In the context of HIV infection, we determined the phenotype and location of plasmacytoid and CD141+ myeloid DCs (pDCs and mDCs) in lymph nodes of people living with HIV (PLWH). We found an interaction between pDCs and CD141+ mDCs with CD8+ T cells, being associated with participants' viral levels in blood and tissue. Moreover, we demonstrated a higher and more polyfunctional superantigen- and HIV-specific CD8+ T cell response after the coculture with Toll-like receptor (TLR)-primed pDCs and CD141+ mDCs. Last, we showed the potential of programmed cell death-1 (PD-1) blocking using pembrolizumab to further increase antigen-specific CD8+ T cell response along with TLR agonists. Therefore, these results showed a cooperation between pDCs, CD141+ mDCs and CD8+ T cells in lymph nodes of PLWH, which is associated with higher HIV control, highlighting the importance of DC subsets crosstalk to achieve a more potent anti-HIV response and support the use of DC-based immunotherapies for HIV control.

Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS. However, current latency reversing agents are inefficient, and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood. To identify natural activators of latent HIV-1, we screened a comprehensive peptide/protein library derived from human hemofiltrate, representing the entire blood peptidome, using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses. Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4 (RBP4), the carrier of retinol (Vitamin A). We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines. Functional analyses indicate that this reactivation involves activation of the canonical NF-¦ÊB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production. High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1. Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads. As a potent natural HIV-1 latency-reversing agent, RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure. Subject terms: Preclinical research, Infectious diseases

Persistence of the HIV-1 reservoir is the major barrier to a cure. Little is known about the dynamics of the proviral integration site landscape and inducibility of the viral reservoir in early-treated individuals. Here, we perform a longitudinal analysis of the viral reservoir in individuals who started treatment during acute infection and compare these findings to chronically-treated individuals. Even in early-treated individuals, clonal expansion contributes to reservoir persistence. Integration site analysis reveals similar distributions after one year of antiretroviral therapy (ART), irrespective of treatment initiation timing. Notably, proviruses integrated in heterochromatin regions are already detected in early-treated individuals after one year on ART and are progressively enriched after five years on ART, suggesting post-integration selection mechanisms. Using a lipid nanoparticle containing Tat mRNA (Tat-LNP) in combination with phorbol myristate acetate (PMA), we detect for the first time the inducible reservoir in individuals treated during acute infection with small reservoir sizes. Furthermore, we show that, in both the acute and chronic cohorts, the inducible reservoir shifts towards a more differentiated T cell compartment over time. Collectively, these findings indicate that clonal expansion and integration site selection contribute to reservoir persistence early after ART initiation in individuals treated shortly after seroconversion. Author summaryDespite ART, HIV persists in a small pool of infected cells. This reservoir is the main barrier to curing HIV. We studied how this reservoir changes over time in people who started treatment very early after infection and compared them to people who started later. We found that, even with early treatment, the infected cells persist and expand over time. After 5 years on ART, in people who started treatment early, HIV becomes enriched in regions of the genome that are less transcriptionally active, suggesting that selective pressures shape which infected cells persist. We also applied a new combination of latency reversal agents, allowing us for the first time to detect the inducible reservoir even in people with very small reservoir sizes. Finally, we observed that the inducible reservoir shifts towards more differentiated types of immune cells over time on ART. Together, our findings provide new insights into how HIV persists despite early treatment.