Raffaele Visintini

Therapeutic immunization with hiv-1 tat reduces immune activation and loss of regulatory t-cells and improves immune function in subjects on HAART

Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4+ T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4+ and CD8+ cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4+ T cells and B cells with reduction of CD8+ T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4+ and CD8+ T cells were accompanied by increases of CD4+ and CD8+ T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis. Trial registration ClinicalTrials.gov NCT00751595

Phase I therapeutic trial of the HIV-1 Tat protein and long term follow-up

A randomized, double blind, placebo-controlled phase I vaccine trial based on the native Tat protein was conducted in HIV-infected asymptomatic individuals. The vaccine was administered five times subcute with alum or intradermally without adjuvant at 7.5microg, 15microg or 30microg doses, respectively. The Tat vaccine was well tolerated both locally and systemically and induced and/or maintained Tat-specific T helper (Th)-1 T-cell responses and Th-2 responses in all subjects with a wide spectrum of functional anti-Tat antibodies, rarely seen in HIV-infected subjects. The data indicate the achievement of both the primary (safety) and secondary (immunogenicity) endpoints of the study.

The preventive phase I trial with the HIV-1 Tat-based vaccine.

The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials based on its role in the natural infection and AIDS pathogenesis, on the association of Tat-specific immune response with the asymptomatic stage as well as on its sequence conservation among HIV clades. A randomized, double blind, placebo-controlled phase I study (ISS P-001) was conducted in healthy adult volunteers without identifiable risk of HIV infection. Tat was administered 5 times monthly, subcute in alum or intradermic alone at 7.5 microg, 15 microg or 30 microg, respectively (ClinicalTrials.gov identifier: NCT00529698). Vaccination with Tat resulted to be safe and well tolerated (primary endpoint) both locally and systemically. In addition, Tat induced both Th1 and Th2 type specific immune responses in all subjects (secondary endpoint) with a wide spectrum of functional antibodies that are rarely seen in natural infection, providing key information for further clinical development of the Tat vaccine candidate.

Psychological stress in nurses' relationships with HIV-infected patients: The risk of burnout syndrome

To assess the role played by psychological stress and sociodemographic factors as predictors of burnout in nurses, we administered the AIDS Impact Scale (AIS) and the Maslach Burnout Inventory (MBI) to nurses in the AIDS field. The sample was composed of 410 nurses from 19 departments for the treatment of infectious diseases. In these subjects we observed a low level of burnout in the MBI, but a small proportion had a high level of burnout We did not find significant associations between sociodemographic variables and the MBI scales. We found significant correlations between the MBI and three AIS scales that specifically assessed the emotional involvement of nurses in their relationships with patients. The results suggest that an empathic involved relationship seems to be protective towards burnout rather than a frustrating involved relationship. Moreover nurses tolerate stress better if they receive supportive social rewards. We found that the impact of working with HIV-infected patients causes psychological stress (measured with the AIS), but it is a weak predictor of burnout (measured with the MBI). The results indicated the incompatibility between the relational/defensive model of the AIS and the environmental/work performance model of the MBI.

The therapeutic phase I trial of the recombinant native HIV-1 Tat protein.

The native HIV-1 Tat protein was chosen as a vaccine candidate based on its key role in the virus life cycle and on the correlation of Tat-specific immune responses with the asymptomatic stage and lower disease progression rates, but also due to its sequence conservation amongst the various HIV clades as well as the adjuvant effects on dendritic cells. Safety, immunogenicity and efficacy data in monkeys support the development of this vaccine concept.

Parallel conduction of the phase I preventive and therapeutic trials based on the Tat vaccine candidate

The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials in both uninfected (ClinicalTrials.gov identifier: NCT00529698) and infected volunteers (ClinicalTrials.gov identifier: NCT00505401). The rationale was based on the role of Tat in the natural infection and AIDS pathogenesis, on the association of Tat-specific immune responses with the asymptomatic stage and slow-progression rate as well as on its sequence conservation among HIV clades (http://www.hiv1tat-vaccines.info/). The parallel conduction in the same clinical centers of randomized, double blind, placebo-controlled phase I studies both in healthy, immunologically competent adults and in HIV-infected, clinically asymptomatic, individuals represents a unique occasion to compare the vaccine-induced immune response in both the preventive and therapeutic setting. In both studies, the same lot of the native Tat protein was administered 5 times, every four weeks, subcute (SC) with alum adjuvant or intradermic (ID), in the absence of adjuvant, at 7.5 microg, 15 microg or 30 microg doses, respectively. The primary and secondary endpoints of these studies were the safety and immunogenicity of the vaccine candidate, respectively. The study lasted 52 weeks and monitoring was conducted for on additional 3 years. The results of both studies indicated that the Tat vaccine is safe and well tolerated both locally and systemically and it is highly immunogenic at all the dosages and by both routes of administration. Vaccination with Tat induced a balanced immune response in uninfected and infected individuals. In particular, therapeutic immunization induced functional antibodies and partially reverted the marked Th1 polarization of anti-Tat immunity seen in natural infection, and elicited a more balanced Th1/Th2 immune response. Further, the number of CD4 T cells correlated positively with anti-Tat antibody titers. Based on these results, a phase II study is ongoing in infected drug-treated individuals (http://www.hiv1tat-vaccines.info/).

Prediction of adherence to antiretroviral therapy: can patients' gender play some role? An Italian pilot study.

Abstract Recent literature has shown that adherence to HAART is a multi-faceted phenomenon, which involves both behavioural and psychological features. Therefore, the results obtained so far, though promising, have not yet unambiguously identified the factors that could predict non-adherence. Since any support for strengthening the adherence should take into account the HIV+ patients’ perception of both their state of health and their relational style, this study tried to identify some psychological characteristics involved in the adherence phenomenon. A self-administered battery of tests including the Attachment Style Questionnaire (ASQ) and the Multidimensional Health Locus of Control Form-C (MHLC-C) was administered to an Italian sample. Results showed significant gender differences between non-adherent and adherent subjects. Specifically, the psychological profile of non-adherent males seemed focused less on relational aspects and perceived relevance of physicians and of ‘significant other people’, whilst that of non-adherent females seemed more ‘relationshiporiented’. This study means to encourage clinicians to plan specific, gender-focused support for enhancing adherence.

The usefulness of the Multidimensional Health Locus of Control Form C (MHLC-C) for HIV+ subjects : An Italian study

Abstract In the last few years, highly active antiretroviral therapy (HAART) has resulted in a remarkable decrease in HIV-related morbidity and mortality. This “new deal” encouraged clinical research in investigating patients’ manifest behaviours and their beliefs regarding their health status, which likely influence not only their treatment-linked behaviours but also their quality of life. Locus of control has been shown to be a construct that can predict and explain health-related behaviours. The Multidimensional Health Locus of Control Form C (MHLC-C) is a condition-specific locus of control scale that can be easily adapted for use with any medical or health-related condition. With the aim to enhance the knowledge about the HIV+ patients’ point of view of their complex health condition, this study preliminarily investigated the psychometrics properties of the MHLC-C Italian version and its generalizability across samples defined both by being adherent or not and by gender. Two more samples of chronic patients (Cardiac Surgery and Cancer) were enrolled to better characterize the HIV+ patients MHLC-C profile. The results showed the validity, reliability and generalizability of the 4-factor structure of MHLC-C. More interestingly, HIV+ subjects revealed a peculiar pattern of beliefs regarding their health condition that clinicians should take into account when managing patients’ complex bio-psychosocial condition.

Referral to group psychotherapy: A retrospective study on patients' personality features associated with clinicians' judgments.

Abstract This study was designed to explore selected personality features of patients that are associated with clinicians’ judgments about whom to refer to dynamic group psychotherapy versus individual therapy. Results suggested that an aspect of patients’ adult attachment style, namely level of confidence and level of hostility, may have influenced the clinicians’ judgments and decision making about treatment referrals.

Corticolimbic Connectivity Mediates the Relationship between Adverse Childhood Experiences and Symptom Severity in Borderline Personality Disorder

The interaction between biological and environmental factors (especially adverse childhood experiences, ACEs) plays a crucial role in the development and maintenance of borderline personality disorder (BPD). These factors act influencing BPD core features such as pervasive instability in affect regulation, impulse control, social cognition, and interpersonal relationships. In line with this perspective, abnormalities in social cognition and related neurobiological underpinnings could mediate the relationship between ACEs and psychopathological manifestations in adulthood. In a sample of 14 females, functional connectivity (FC) analyses were performed modeling the interaction between ACEs and corticolimbic dysregulation during emotional processing and its relationship with BPD symptom severity. ACEs were associated with a dampening of the negative FC between (1) the right amygdala (Amy) and right dorsolateral prefrontal cortex (DLPFC) and between (2) the left Amy and bilateral DLPFC, right precuneus, left cerebellum and left dorsomedial prefrontal cortex during emotional processing. The connectivity between right Amy and DLPFC mediates the relationship between childhood adversities and BPD symptomatology. Furthermore, the negative FC between Amy and DLPFC, postcentral gyrus, the vermis of cerebellum and precuneus was also associated with BPD symptom severity, with a weaker negative coupling between Amy and these regions being related to a worse BPD psychopathology. Our results confirm the role of ACEs in contributing to social cognition impairments in BPD and related symptomatology from a neurobiological perspective.