HIV-1 prophylactic vaccine comprised of topical DermaVir prime and protein boost elicits cellular immune responses and controls pathogenic R5 SHIV162P3

Topical DNA vaccination (DermaVir) facilitates antigen presentation to naive T cells. DermaVir immunization in mice, using HIV-1 Env and Gag, elicited cellular immune responses. Boosting with HIV-1 gp120 Env and p41 Gag augmented Th1 cytokine levels. Intramuscular DNA administration was less efficient in priming antigen-specific cytokine production and memory T cells. In rhesus macaques, DermaVir immunization induced Gag- and Env-specific Th1 and Th2 cytokines and generation of memory T cells. Boosting of DermaVir-primed serum antibody levels was noted following gp140(SHIV89.6P)/p27(SIV) immunization. Rectal challenge with pathogenic R5-tropic SHIV162P3 resulted in control of plasma viremia (4/5 animals) that was reflected in jejunum, colon and mesenteric lymph nodes. An inverse correlation was found between Gag- and Env-specific central memory T cell responses on the day of challenge and plasma viremia at set point. Overall, the topical DermaVir/protein vaccination yields central memory T cell responses and facilitates control of pathogenic SHIV infection.     

Clinical outcome of neurological patients with COVID-19: the impact of healthcare organization improvement between waves

Neurological Sciences - The aim of this study is to evaluate the differences in clinical presentations and the impact of healthcare organization on outcomes of neurological COVID-19 patients...     

Neurological involvement associated with COVID-19 disease: a study on psychosocial factors

Neurological Sciences - Several people affected by COVID-19 experienced neurological manifestations, altered sleep quality, mood disorders, and disability following hospitalization for a long time....     

Differential chemokine expression profiles in human peripheral blood T lymphocytes: dependence on T-cell coreceptor and calcineurin signaling

The chemokine superfamily consists of small (8-10 kDa) molecules that function to attract, selectively, different subsets of leukocytes. Binding of chemokines to their appropriate G-protein-coupled receptors is necessary for primary immune responses and for homing of leukocytes to lymphoid tissues. Here, we have characterized the signaling pathways in primary T lymphocytes that regulate chemokine gene induction using an RNase protection assay. Dependence on stimulation through the coreceptor CD28 and sensitivity to the calcineurin inhibitors cyclosporine and tacrolimus were studied using purified human peripheral blood lymphocytes. Lymphotactin (Ltn), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta were all rapidly induced and sensitive to cyclosporine treatment. At later time points, the expression of MIP-1alpha and MIP-1beta, but not of Ltn, was restored despite the inhibition of calcineurin activity. By contrast, the induction of interleukin-8 was delayed and was found to be cyclosporine insensitive. Calcineurin activity of IP-10 mRNA induction was contingent on the specific T-cell stimulation conditions, suggesting that IP-10 expression is modulated by calcineurin-dependent and -independent signaling pathways. Differential chemokine expression profiles result from the engagement of T-cell coreceptors and the requirement for, and the dependence on, calcineurin phosphatase activity.     

Neuroanatomical Correlates of Transcranial Magnetic Stimulation in Presymptomatic <Emphasis Type="Italic">Granulin</Emphasis> Mutation Carriers

Frontotemporal dementia (FTD) is characterized by behavioural and language impairment, accompanied by atrophic changes in fronto-temporo-insular cortices. In the presymptomatic phases of genetic FTD, subtle or no volumetric changes have been reported. Transcranial magnetic stimulation (TMS) represents an approach to explore cortical connectivity, and some TMS measures have been demonstrated to be impaired in Granulin (GRN) mutation carriers. We aimed at exploring cross-sectional changes in cortical thickness (CT) and surface area (SA) in the presymptomatic phases of GRN-related FTD, and their relationship with TMS parameters. Nineteen presymptomatic GRN mutation carriers and seventeen age and sex-matched non-carriers underwent 3T MRI scanning and a paired-pulse TMS protocol. The surface-based pipeline of FreeSurfer was applied in order to obtain cortical volumes (CVs), CT and SA measures. Then, between groups differences and correlation with TMS parameters were assessed. GRN carriers showed increased CT and decreased SA of the right parietal lobe, without significant volume changes. TMS parameters of intracortical inhibition and facilitation, which were significantly impaired in presymptomatic GRN mutation carriers, correlated with reduced SA and CV of the right insula. Our results suggest that splitting CV into its two main components could improve the sensitivity when exploring structural brain changes in presymptomatic or early phases of neurodegenerative conditions. TMS parameters might reflect damage within cortical regions reported to be affected early in the conversion to the symptomatic phase of the disease.     

Replicating Adenovirus-Simian Immunodeficiency Virus (SIV) Vectors Efficiently Prime SIV-Specific Systemic and Mucosal Immune Responses by Targeting Myeloid Dendritic Cells and Persisting in Rectal Macrophages,Regardless of Immunization Route

Although priming with replicating adenovirus type 5 host range mutant (Ad5hr)-human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) recombinants, followed by HIV/SIV envelope boosting, has proven highly immunogenic, resulting in protection from SIV/simian-human immunodeficiency virus (SHIV) challenges, Ad5hr recombinant distribution, replication, and persistence have not been examined comprehensively in nonhuman primates. We utilized Ad5hr-green fluorescent protein and Ad5hr-SIV recombinants to track biodistribution and immunogenicity following mucosal priming of rhesus macaques by the intranasal/intratracheal, sublingual, vaginal, or rectal route. Ad recombinants administered by all routes initially targeted macrophages in bronchoalveolar lavage (BAL) fluid and rectal tissue, later extending to myeloid dendritic cells in BAL fluid with persistent expression in rectal mucosa 25 weeks after the last Ad immunization. Comparable SIV-specific immunity, including cellular responses, serum binding antibody, and mucosal secretory IgA, was elicited among all groups. The ability of the vector to replicate in multiple mucosal sites irrespective of delivery route, together with the targeting of macrophages and professional antigen-presenting cells, which provide potent immunogenicity at localized sites of virus entry, warrants continued use of replicating Ad vectors.     

Preclinical evaluation of cellular immune responses elicited by a polyvalent DNA prime/protein boost HIV-1 vaccine

While DNA vaccines have been shown to prime cellular immune responses, levels are often low in nonhuman primates or humans. Hence, efforts have been directed toward boosting responses by combining DNA with different vaccination modalities. To this end, a polyvalent DNA prime/protein boost vaccine, consisting of codon optimized HIV-1 env (A, B, C, E) and gag (C) and homologous gp120 proteins in QS-21, was evaluated in rhesus macaques and BALB/c mice. Humoral and cellular responses, detected following DNA immunization, were increased following protein boost in macaques and mice. In dissecting cellular immune responses in mice, protein-enhanced responses were found to be mediated by CD4+ and CD8+ T cells with a Th1 cytokine bias. Our study reveals that, in addition to augmenting humoral responses, protein boosting of DNA-primed animals augments cellular immune responses mediated by CD8+ CTL, CD4+ T-helper cells and Th1 cytokines; thus, offering much promise in controlling HIV-1 in vaccinees.     

Durable protection of rhesus macaques immunized with a replicating adenovirus-SIV multigene prime/protein boost vaccine regimen against a second SIVmac251 rectal challenge: role of SIV-specific CD8+ T cell responses

Previously, priming with replication-competent adenovirus-SIV multigenic vaccines and boosting with envelope subunits strongly protected 39% of rhesus macaques against rectal SIV(mac251) challenge. To evaluate protection durability, eleven of the protected and two SIV-infected unimmunized macaques that controlled viremia were re-challenged rectally with SIV(mac251). Strong protection was observed in 8/11 vaccinees, including two exhibiting <50 SIV RNA copies. Decreased viremia compared to na?ve controls was observed in the other three. The SIV-infected unimmunized macaques modestly controlled viremia but exhibited CD4 counts < or =200, unlike the protected macaques. Durable protection was associated with significantly increased SIV-specific ELISPOT responses and lymphoproliferative responses to p27 at re-challenge. After CD8 depletion, 2 of 8 re-challenged, protected vaccinees maintained <50 SIV RNA copies; SIV RNA emerged in 6. Re-appearance of CD8 cells and restoration of SIV-specific cellular immunity coincided with viremia suppression. Overall, cellular immunity induced by vaccination and/or low-level, inapparent viremia post-first SIV(mac251) challenge, was associated with durable protection against re-challenge.