Letizia Santinelli

Background: The efficacy, safety, and virological control of long-acting cabotegravir/rilpivirine (CAB/RPV LA) have been described, but limited data are available regarding its impact on biochemical markers, HIV reservoir, and immune response. This study aimed to evaluate these aspects in people living with HIV (PLWH) switching from oral ART to CAB/RPV LA.Methods: A total of 162 peripheral blood samples were collected from 81 PLWH switching to CAB/RPV LA at baseline (T0) and after 48 weeks (T1). A matched group of HIV-negative individuals (HC) was also included. Total HIV-DNA was quantified by real-time PCR. Expression of CD38 and HLA-DR expression in CD4+ and CD8+ T cell subsets, as well as CD57 expression on natural killer (NK), CD4+ and CD8+ T cells, was assessed by multiparametric flow cytometry.Findings: After 48 weeks of CAB/RPV LA, PLWH showed a reduction in HIV-DNA levels (p < 0.05), decreased creatinine and increased estimated glomerular filtration rate (eGFR) (p < 0.0001). Despite persistent higher immune activation compared to HC, a partial reduction in CD38 expression was observed in central memory and effector memory CD4+ T cells at T1 compared to T0 (p < 0.05). Markers of immune senescence also improved, with a decrease in the frequency of CD57+ CD8+ T cells and CD57+ NK cells following LA treatment (p < 0.05), although levels remained higher than in HC. Virological suppression was maintained in all participants, but two individuals were switched back to oral therapy as a preventive measure due to HIV-RNA blips, associated with the emergence of resistance mutation and a dramatic increased body mass index, respectively.Interpretation: CAB/RPV LA is an effective therapeutic strategy for maintaining virological suppression and reducing HIV-DNA levels, suggesting a potential effect on the viral reservoir. Furthermore, this new treatment appears to improve renal function and reduce immune activation and senescence.

To investigate relevant biomarkers that might aid in the diagnosis and monitoring of long COVID (LC), an analysis of IFN-α, IFN-β, ISG15, and ISG56 transcripts was performed by Real-Time PCR among people of working age who had been infected with SARS-CoV-2 one year prior to the study [LC and non-long COVID (NLC)]. Despite no differences in the transcript levels of IFN-α, IFN-β, ISG15, and ISG56 between LC and NLC, higher IFN-β mRNA levels were observed among LC compared to NLC individuals who were hospitalized for more than 10 days during acute SARS-CoV-2 infection. Moreover, previously SARS-CoV-2 infected participants that did not require respiratory support and developed LC exhibited higher levels of IFN-α and IFN-β compared to NLC with the same clinical characteristics. These results highlight that SARS-CoV-2 infection leads to changes in peripheral innate immune pathways, which could have implications for the development of LC.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recognized by pattern recognition receptors (PRRs), which play a vital role in triggering innate immune responses such as the production of type I and III interferons (IFNs). While modest PRR activation helps to defend against SARS-CoV-2, excessive or sustained activation can cause harmful inflammation and contribute to severe Coronavirus Disease 2019 (COVID-19). Altered expression of Toll-like receptors (TLRs), which are among the most important members of the PRR family members, particularly TLRs 2, 3, 4, 7, 8 and 9, has been strongly linked to COVID-19 severity. Furthermore, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), collectively known as RLRs (RIG-I-like receptors), act as sensors that detect SARS-CoV-2 RNA. The expression of these receptors, as well as that of different DNA sensors, varies in patients infected with SARS-CoV-2. Changes in PRR expression, particularly that of TLRs, cyclic GMP-AMP synthase (cGAS), and the stimulator of interferon genes (STING), have also been shown to play a role in the development and persistence of long COVID (LC). However, SARS-CoV-2 has evolved strategies to evade PRR recognition and subsequent signaling pathway activation, contributing to the IFN response dysregulation observed in SARS-CoV-2-infected patients. Nevertheless, PRR agonists and antagonists remain promising therapeutic targets for SARS-CoV-2 infection. This review aims to describe the PRRs involved in recognizing SARS-CoV-2, explore their expression during SARS-CoV-2 infection, and examine their role in determining the severity of both COVID-19 and long-term manifestations of the disease. It also describes the strategies developed by SARS-CoV-2 to evade PRR recognition and activation. Moreover, given the considerable interest in modulating PRR activity as a novel immunotherapy approach, this review will provide a description of PRR agonists and antagonists that have been investigated as antiviral strategies against SARS-CoV-2. This review aims to explore the complex interplay between PRRs and SARS-CoV-2 in depth, considering its implications for prognostic biomarkers, targeted therapeutic strategies and the mechanistic understanding of long LC. Additionally, it outlines future perspectives that could help to address knowledge gaps in PRR-mediated responses during SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recognized by pattern recognition receptors (PRRs), which play a vital role in triggering innate immune responses such as the production of type I and III interferons (IFNs). While modest PRR activation helps to defend against SARS-CoV-2, excessive activation can cause harmful inflammation and contribute to severe Coronavirus Disease 2019 (COVID-19). Altered expression of Toll-like receptors (TLRs), which are among the most important PRR family members, particularly TLRs 2, 3, 4, 7, 8 and 9, has been strongly linked to disease severity. Furthermore, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) — collectively known as RLRs (RIG-I-like receptors) — act as sensors that detect SARS-CoV-2 RNA. The expression of these receptors, as well as that of different DNA sensors, varies in patients infected with SARS-CoV-2. Changes in PRR expression, particularly that of TLRs, cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), have also been shown to play a role in the development and persistence of long COVID (LC). However, SARS-CoV-2 has evolved strategies to evade PRR recognition and subsequent signaling pathway activation, contributing to the IFN response dysregulation observed in SARS-CoV-2-infected patients. Nevertheless, PRR agonists and antagonists remain promising therapeutic targets for SARS-CoV-2 infection. This review aims to describe the PRRs involved in recognizing SARS-CoV-2, explore their expression during SARS-CoV-2 infection and examine their role in determining the severity of both acute and long-term manifestations of the disease. It also describes the strategies developed by SARS-CoV-2 to evade PRR recognition and activation. Finally, given the considerable interest in modulating PRR activity as a novel immunotherapy approach, this review will describe PRR agonists and antagonists that have been investigated as antiviral strategies against SARS-CoV-2.

Background/Objectives: Despite medical advances, stigma remains a major challenge for people living with HIV (PLWH). This study examined clinical, sociodemographic, and psychological predictors of HIV-related stigma, and explored whether affective temperament moderates the impact of depression on stigma. Methods: This cross-sectional observational study included 97 PLWH attending a tertiary infectious disease unit in Rome, Italy. Participants completed a battery of validated psychometric instruments assessing depressive symptoms, anxiety, manic symptoms, mixed affective states, general psychopathology, impulsivity, and affective temperament. HIV-related stigma was evaluated using the Berger HIV Stigma Scale, which measures personalized stigma, disclosure concerns, negative self-image, and concerns with public attitudes. Descriptive statistics were used to characterize the sample. Univariate linear regressions were conducted to explore associations between clinical, psychometric, and sociodemographic variables and each stigma subdimension, as well as the total stigma score. Variables significant at p < 0.05 were included in five multivariate linear regression models. Moderation analyses were subsequently performed to assess whether affective temperaments moderated the relationship between significant psychopathological predictors and stigma. Bonferroni correction was applied where appropriate. Results: Higher depressive symptom scores are significantly associated with greater internalized stigma (B = 0.902, p = 0.006) and total stigma (B = 2.603, p = 0.008). Furthermore, moderation analyses showed that anxious temperament significantly intensified the relationship between depressive symptoms and both negative self-image (interaction term B = 0.125, p = 0.001) and total stigma (B = 0.336, p = 0.002). Conclusions: Depressive symptoms and anxious temperament are associated with HIV-related stigma. Integrating psychological screening and targeted interventions for mood and temperament vulnerabilities may help reduce stigma burden in PLWH and improve psychosocial outcomes.

Doravirine (DOR) is a novel antiretroviral agent with a favorable resistance profile and high tolerability. However, evidence is limited on DOR among elderly people living with HIV (PLWH) and whether it might modulate chronic inflammation. We aimed to investigate the efficacy, safety, and tolerability of DOR as a switching strategy among elderly PLWH and its impact on chronic inflammation in a real-life setting. We recruited a cohort of ART-experienced PLWH undergoing a therapeutic switch to a DOR-based regimen under virologic control (defined as HIV-RNA CIs : 91.0%–98.7%) in the per-protocol analysis. After 48 weeks from the switch, we recorded significant reductions in serum fasting glycemia ( P 0.019), triglycerides ( P 0.024), and total cholesterol/HDL ratio ( P 0.017); no clinically significant differences were detected in the body weight and BMI, as long as in immune, hepatic, and renal profiles. A significant reduction in IL-6 ( P 0.019) and hs-CRP ( P 0.019) was observed. DOR is an effective and safe treatment choice for elderly PLWH. The intriguing modulatory effect of DOR-based regimens on chronic systemic inflammation deserves further investigation.