Utilizing immunotherapy towards achieving a functional cure for HIV-1.

PURPOSE OF REVIEW: Advancements in antiretroviral therapy (ART) have positively impacted the life expectancy and possibility of living a normal life for people with HIV-1. However, lifelong daily medication is necessary to prevent disease progression. To this end, immunotherapeutic strategies are being tested with the aim of developing a functional cure in which the immune system effectively controls HIV-1 in the absence of ART. RECENT FINDINGS: The most promising advances in achieving sustained HIV-1 remission or cure include broadly neutralizing antibodies (bNAbs) that are administered alone or in combination with other agents. Newer and more innovative approaches redirecting T cells or natural killer cells to kill HIV-1 infected cells have also shown promising results. Finally, multiple ongoing trials focus on combining bNAbs with other immune-directed therapies to enhance both innate and adaptive immunity. SUMMARY: While immunotherapies as an alternative to conventional ART have generally proven to be well tolerated, these therapeutic approaches have largely been unsuccessful in inducing ART-free control of HIV-1. However, promising results from recent trials involving bNAbs that have reported durable HIV-1 control among a subset of participants, provide reason for cautious optimism that we with further optimization of these treatment strategies may be able to achieve functional cure for HIV-1.

COVID-19 inactivated and non-replicating viral vector vaccines induce regulatory training phenotype in human monocytes under epigenetic control.

Background: Trained immunity is the enhanced innate immune response resulting from exposure to pathogens or vaccines against an unrelated pathogen stimulus. Certain vaccines induce a memory like response in monocytes and NK cells, leading to modulation in cytokine production, metabolic changes, and modifications in histone patterns. Here, we hypothesized that vaccination against SARS-CoV-2 could induce the training of monocytes in addition to stimulating the adaptive immune response. Methods: Therefore, we aimed to investigate the immunophenotyping, cytokine and metabolic profile of monocytes from individuals who were completely immunized with two doses of inactivated COVID-19 vaccine or non-replicating viral vector vaccine. Subsequently, we investigated the epigenetic mechanisms underlying monocyte immune training. As a model of inflammatorychallenge, to understand if the monocytes were trained by vaccination and how they were trained, cells were stimulated in vitro with the endotoxin LPS, an unrelated stimulus that would provoke the effects of training. Results: When challenged in vitro, monocytes from vaccinated individuals produced less TNF-α and those who received inactivated vaccine produced less IL-6, whereas vaccination with non-replicating viral vector vaccine induced more IL-10. Inactivated vaccine increased classical monocyte frequency, and both groups showed higher CD163 expression, a hallmark of trained immunity. We observed increased expression of genes involved in glycolysis and reduced IRG1 expression in vaccinated subjects, a gene associated with the tolerance phenotype in monocytes. We observed that both vaccines reduced the chromatin accessibility of genes associated with the inflammatory response, the inactivated COVID-19 vaccine trained monocytes to a regulatory phenotype mediated by histone modifications in the IL6 and IL10 genes, while the non-replicating viral vector COVID-19 vaccine trained monocytes to a regulatory phenotype, mediated by histone modifications in the IL6, IL10, TNF, and CCL2 genes. Conclusions: Our findings support the recognized importance of adopting vaccination against SARS CoV-2, which has been shown to be effective in enhancing the adaptive immune response against the virus and reducing mortality and morbidity rates. Here, we provide evidence that vaccination also modulates the innate immune response by controlling the detrimental inflammatory response to unrelated pathogen stimulation.