Cirurgia paraendodôntica: revisão de literatura / Parendodontic surgery: a literature review

O tratamento endodôntico envolve procedimentos como abertura coronária, modelagem, limpeza, desinfecção e selamento tridimensional. Apesar de apresentar um índice de insucesso de cerca de 4%, retratamentos podem ser realizados por cirurgiões-dentistas habilitados. Quando o retratamento não é indicado, a cirurgia parendodôntica, que inclui curetagem, apicectomia e retro obturação do sistema de canais, surge como uma alternativa eficaz para manter o dente em função e estética na cavidade bucal, antes de considerar a extração. O presente trabalho busca revisar a literatura respeito da cirurgia parendodôntica. Os trabalhos foram selecionados nas plataformas Scielo, PubMed, Google Acadêmico e BVS, publicados nos últimos 5 anos em português e inglês. Pôde-se concluir que a cirurgia parendodôntica é uma alternativa efetiva em casos de insucesso do tratamento endodôntico, devendo ser considerada e indicada de maneira apropriada.

Endodontic treatment, commonly performed in dentistry, involves procedures such as coronal opening, modeling, cleaning, disinfection, and three-dimensional sealing. Despite having a failure rate of around 4%, portraits can be carried out by qualified dental surgeons. When retreatment is not indicated, endodontic surgery, including curettage, apicoectomy and retrofilling of the canal system, appears as an effective alternative to maintain dental function and oral aesthetics in the mouth, before considering extraction. The present work seeks to review the literature regarding paraendodontic surgery. The works were selected on the Scielo, PubMed, Google Scholar and VHL platforms, published in the last 5 years in Portuguese and English. It was concluded that endodontic surgery is an effective alternative in cases of unsuccessful endodontic treatment and should be considered and indicated appropriately.

Vaccine induced mucosal and systemic memory NK/ILCs elicit decreased risk of SIV/SHIV acquisition.

SIV and HIV-based envelope V1-deleted (ΔV1) vaccines, delivered systemically by the DNA/ALVAC/gp120 platform, decrease the risk of mucosal SIV or SHIV acquisition more effectively than V1-replete vaccines. Here we investigated the induction of mucosal and systemic memory-like NK cells as well as antigen-reactive ILC response by DNA/ALVAC/gp120-based vaccination and their role against SIV/SHIV infection. ΔV1 HIV vaccination elicited a higher level of mucosal TNF-α+ and CD107+ memory-like NK cells than V1-replete vaccination, suggesting immunogen dependence. Mucosal memory-like NK cells, systemic granzyme B+ memory NK cells, and vaccine-induced mucosal envelope antigen-reactive IL-17+ NKp44+ ILCs, IL-17+ ILC3s, and IL-13+ ILC2 subsets were linked to a lower risk of virus acquisition. Additionally, mucosal memory-like NK cells and mucosal env-reactive IFN-γ+ ILC1s and env- reactive IL-13+ ILC2 subsets correlated with viral load control. We further observed a positive correlation between post-vaccination systemic and mucosal memory-like NK cells, suggesting vaccination enhances the presence of these cells in both compartments. Mucosal and systemic memory-like NK cells positively correlated with V2-specific ADCC responses, a reproducible correlate of reduced risk of SIV/HIV infection. In contrast, an increased risk was associated with the level of mucosal PMA/Ionomycin-induced IFN-γ+ and CD107+ NKG2A-NKp44- ILCs. Plasma proteomic analyses demonstrated that suppression of mucosal memory-like NK cells was linked to the level of CCL-19, LT-α, TNFSF-12, and IL-15, suppression of systemic env-reactive granzyme B+ memory-like NK cells was associated with the level of OLR1, CCL-3, and OSM, and suppression of IL-17+ ILCs immunity was correlated with the level of IL-6 and CXCL-9. In contrast, FLT3 ligand was associated with promotion of protective mucosal env-reactive IL-17+ responses. These findings emphasize the importance of mucosal memory-like NK cell and envelope- reactive ILC responses for protection against mucosal SIV/SHIV acquisition.

Tuberculosis Diagnosis: Current, Ongoing, and Future Approaches.

Tuberculosis (TB) remains an impactful infectious disease, leading to millions of deaths every year. Mycobacterium tuberculosis causes the formation of granulomas, which will determine, through the host-pathogen relationship, if the infection will remain latent or evolve into active disease. Early TB diagnosis is life-saving, especially among immunocompromised individuals, and leads to proper treatment, preventing transmission. This review addresses different approaches to diagnosing TB, from traditional methods such as sputum smear microscopy to more advanced molecular techniques. Integrating these techniques, such as polymerase chain reaction (PCR) and loop-mediated isothermal amplification (LAMP), has significantly improved the sensitivity and specificity of M. tuberculosis identification. Additionally, exploring novel biomarkers and applying artificial intelligence in radiological imaging contribute to more accurate and rapid diagnosis. Furthermore, we discuss the challenges of existing diagnostic methods, including limitations in resource-limited settings and the emergence of drug-resistant strains. While the primary focus of this review is on TB diagnosis, we also briefly explore the challenges and strategies for diagnosing non-tuberculous mycobacteria (NTM). In conclusion, this review provides an overview of the current landscape of TB diagnostics, emphasizing the need for ongoing research and innovation. As the field evolves, it is crucial to ensure that these advancements are accessible and applicable in diverse healthcare settings to effectively combat tuberculosis worldwide.

Geraniol Potentiates the Effect of Fluconazole against Planktonic and Sessile Cells of Azole-Resistant Candida tropicalis: In Vitro and In Vivo Analyses.

Candida tropicalis is regarded as an opportunistic pathogen, causing diseases ranging from superficial infections to life-threatening disseminated infections. The ability of this yeast to form biofilms and develop resistance to antifungals represents a significant therapeutic challenge. Herein, the effect of geraniol (GER), alone and combined with fluconazole (FLZ), was evaluated in the planktonic and sessile cells of azole-resistant C. tropicalis. GER showed a time-dependent fungicidal effect on the planktonic cells, impairing the cell membrane integrity. Additionally, GER inhibited the rhodamine 6G efflux, and the molecular docking analyzes supported the binding affinity of GER to the C. tropicalis Cdr1 protein. GER exhibited a synergism with FLZ against the planktonic and sessile cells, inhibiting the adhesion of the yeast cells and the viability of the 48-h biofilms formed on abiotic surfaces. C. tropicalis biofilms treated with GER, alone or combined with FLZ, displayed morphological and ultrastructural alterations, including a decrease in the stacking layers and the presence of wilted cells. Moreover, neither GER alone nor combined with FLZ caused toxicity, and both treatments prolonged the survival of the Galleria mellonella larvae infected with azole-resistant C. tropicalis. These findings indicate that the combination of GER and FLZ may be a promising strategy to control azole-resistant C. tropicalis infections.

Inhaled nitric oxide in moderate-to-severe COVID-19 acute respiratory distress syndrome: a retrospective cohort study.

OBJECTIVE: In this study, we present the findings from a cohort of patients with COVID-19 with acute respiratory distress syndrome who underwent standard therapy, including prone positioning, with or without adjunctive inhalation of nitric oxide. Our investigation sought to determine whether inhaled nitric oxide administration yielded clinical enhancement in this population. Remarkably, nitric oxide administration elevated the PaO2/FiO2 ratio, which is indicative of improved oxygenation. Despite this improvement, discernible mortality benefits did not emerge in association with the inhaled nitric oxide treatment. To evaluate the responsiveness of COVID-19 acute respiratory distress syndrome patients to inhaled nitric oxide as part of their standard therapy. METHODS: This retrospective cohort study included critically ill adult patients with confirmed COVID-19 treated between March 2020 and May 2021. Eligible patients with moderate-to-severe acute respiratory distress syndrome due to COVID-19 were subsequently categorized into two groups based on inhaled nitric oxide use throughout their stay in the intensive care unit. The primary endpoints were overall mortality and improvement in oxygenation parameters 6 hours after inhaled nitric oxide use. RESULTS: A total of 481 patients admitted to the intensive care unit due to COVID-19 acute respiratory distress syndrome were screened, 105 of which were included. Among the 105 patients, inhaled nitric oxide therapy was used in 33 patients, will 72 did not undergo inhaled nitric oxide therapy. No significant difference in mortality was observed between the groups (67% for the treatment and 82% for the no-treatment groups respectively, p=0.173). Among the patients who used inhaled nitric oxide, 17 (51%) were considered responsive to therapy. There was no significant difference in the length of stay in the intensive care unit (p=0.324) or total hospitalization time (p=0.344). CONCLUSION: Inhaled nitric oxide rescue therapy improved oxygenation in patients with COVID-19 with moderate-to-severe acute respiratory distress syndrome but did not affect mortality.

Clinical outcomes and direct cost analysis of rotator cuff repair surgery.

OBJECTIVE: The purpose of this study was to evaluate the clinical and functional outcomes in patients who underwent surgical treatment for rotator cuff tears using open and arthroscopic techniques, and to evaluate the direct costs involved. METHODS: Retrospective cohort study with analysis of the data of patients who were referred to two private hospitals in Sao Paulo, Brazil for surgical repair of the rotator cuff from January 2018 to September 2019. Clinical outcomes were assessed using functional scores (SPADI and QuickDASH) and a quality of life questionnaire (EuroQoL). Procedure costs were calculated relative to each hospital's costliest procedure. RESULTS: Data from 362 patients were analyzed. The mean patient age was 57 years (SD= 10.46), with a slight male predominance (53.9%). Arthroscopic procedures were more common than open procedures (95.6% versus 4.4%). Significant clinical improvement was reported in 84.8% of the patients. The factors associated with increased surgery costs were arthroscopic technique (increase of 29.2%), age (increase of 0.6% per year), and length of stay (increase of 18.9% per day of hospitalization). CONCLUSION: Rotator cuff repair surgery is a highly effective procedure, associated with favorable clinical outcomes and improvement in life quality, and low rates of complications. Arthroscopic surgery tends to be costlier than open surgery.

Complete Rescue of HTLV-1p12KO Infectivity by Depletion of Monocytes Together with NK and CD8+ T Cells.

The transient depletion of monocytes alone prior to exposure of macaques to HTLV-1 enhances both HTLV-1WT (wild type) and HTLV-1p12KO (Orf-1 knockout) infectivity, but seroconversion to either virus is not sustained over time, suggesting a progressive decrease in virus expression. These results raise the hypotheses that either HTLV-1 persistence depends on a monocyte reservoir or monocyte depletion provides a transient immune evasion benefit. To test these hypotheses, we simultaneously depleted NK cells, CD8+ T cells, and monocytes (triple depletion) prior to exposure to HTLV-1WT or HTLV-1p12KO. Remarkably, triple depletion resulted in exacerbation of infection by both viruses and complete rescue of HTLV-1p12KO infectivity. Following triple depletion, we observed rapid and sustained seroconversion, high titers of antibodies against HTLV-1 p24Gag, and frequent detection of viral DNA in the blood and tissues of all animals when compared with depletion of only CD8+ and NK cells, or monocytes alone. The infection of macaques with HTLV-1WT or HTLV-1p12KO was associated with higher plasma levels of IL-10 after 21 weeks, while IL-6, IFN-γ, IL-18, and IL-1ß were only elevated in animals infected with HTLV-1WT. The repeat depletion of monocytes, NK, and CD8+ cells seven months following the first exposure to HTLV-1 did not further exacerbate viral replication. These results underscore the contribution of monocytes in orchestrating anti-viral immunity. Indeed, the absence of orf-1 expression was fully compensated by the simultaneous depletion of CD8+ T cells, NK cells, and monocytes, underlining the primary role of orf-1 in hijacking host immunity.

Exploring the clinical relevance of "Angico Gum": an effective biopolymer for topical protection of oesophageal mucosa in gastroesophageal reflux disease patients.

OBJECTIVES: Angico gum (AG) (Anadenanthera colubrina var. Cebil [Griseb.] Altschul) is utilized by some Brazilian communities to alleviate symptoms from gastroesophageal reflux disease. Here, we aimed to investigate the "in vitro" topical protective capacity of AG on human esophageal mucosa. METHODS: Biopsies of the distal esophageal mucosa were collected from 35 patients with heartburn (24 non-erosive and 11 with erosive oesophagitis (EE)) and mounted in Üssing chambers. AG was applied topically, followed by exposure with acid solution (pH 2.0 or pH 1.0), where transepithelial electrical resistance (TER) and The transepithelial permeability for fluorescein was assessed. The incubation of the AG labeled with FITC in the esophageal mucosa was localized by fluorescence microscopy. KEY FINDINGS: Pretreatment with AG prevented the drop in TER induced by acid solution, as well as significantly decreases the fluorescein permeability in non-erosive patients. The protective effect of AG was sustained for up to 120 min both in biopsies of non-erosive and erosive esophagitis. Confocal microscope images showed mucosal luminal adherence of FITC-labeled AG. CONCLUSION: AG had a prolonged topical protective effect against acid solution in mucosal biopsies of patients with non-erosive and erosive esophagitis.

Association of vitamin D and cognition in people with type 2 diabetes: a systematic review.

CONTEXT: There is a high prevalence of vitamin D deficiency and impaired cognitive function in people with type 2 diabetes mellitus (T2DM). OBJECTIVE: To critically and systematically review the literature on the association between vitamin D status and cognitive performance in people with type 2 diabetes. DATA SOURCES: This review was conducted according to PRISMA recommendations. MEDLINE, SCOPUS, the Cochrane Library, and Web of Science databases were searched using the terms "Diabetes Mellitus, Type 2", "Cognitive Function", and "Vitamin D". DATA EXTRACTION: Eight observational and 1 randomized study were included, containing data of 14 648 adult and elderly individuals (19-74 y). All extracted data were compiled, compared, and critically analyzed. DATA ANALYSIS: There is no strong evidence that lower serum concentrations of vitamin D and vitamin D-binding protein are associated with worsening cognitive function in individuals with T2DM. Vitamin D supplementation (12 wk) improved the scores of some executive functioning tests, although there was no difference between low doses (5000 IU/wk) and high doses (50 000 IU/wk). CONCLUSIONS: There is no high-quality evidence demonstrating an association between vitamin D status and cognitive function, or clinical benefits on cognition from vitamin D supplementation in individuals with T2DM. Future studies are needed. Systematic Review Registration: PROSPERO registration no. CRD42021261520.

Impact of COVID-19 pandemic on surgical activity in the Brazilian private healthcare system.

INTRODUCTION: Surgical volume was drastically reduced in many countries due to challenges imposed by the COVID-19 pandemic. OBJECTIVES: We sought to estimate the number of cancelled surgical and diagnostic procedures within the Brazilian private healthcare system between 2020 and 2021 over the course of the COVID-19 pandemic, and to project the procedural backlog generated for specific elective and time-sensitive surgeries, and diagnostic procedures. METHODS: Data were systematically extracted from the Brazilian national regulatory agency for the private healthcare system and included (i) quarterly and annual surgical and diagnostic volume, and (ii) the number of private health insurance beneficiaries between January 2016 and June 2021. Based on pre-pandemic data we estimated the expected number of surgical and diagnostic procedures that failed to be performed between 2020 and 2021. RESULTS: The average quarterly surgical and diagnostic procedures declined by 29.5% in 2020 and by 21.5% in 2021 compared to 2019. In 2020, such reduction reflected a lower number of diagnostic procedures under anesthesia (-35.1%), as well as elective (-14.7%), time-sensitive (-18.8%), and urgent (-4.6%) surgeries. In the first half of 2021, though the surgical and diagnostic procedures increased compared to 2020, they remained significantly below their historical average. The estimated backlogs were 134.385,64 for total surgical procedures, 2.634,64 for bariatric surgery and arthroplasty revision (elective surgeries), 2.845,61 for oncologic (time-sensitive) surgeries, and 304.193,99 for diagnostic procedures, requiring 1.7, 15.9, and 6.8 years, respectively, to make up for such backlogs. CONCLUSION: There was a major decline on the number of surgical and diagnostic procedures due to the COVID-19 pandemic. Despite a slight recovery of elective surgeries throughout the pandemic, many time-sensitive surgeries and diagnostic procedures were cancelled, with potential medium- to long-term consequences to patients and the system as a whole.

Development of a Melting-Curve-Based Multiplex Real-Time PCR Assay for the Simultaneous Detection of Viruses Causing Respiratory Infection.

The prompt and accurate identification of the etiological agents of viral respiratory infections is a critical measure in mitigating outbreaks. In this study, we developed and clinically evaluated a novel melting-curve-based multiplex real-time PCR (M-m-qPCR) assay targeting the RNA-dependent RNA polymerase (RdRp) and nucleocapsid phosphoprotein N of SARS-CoV-2, the Matrix protein 2 of the Influenza A virus, the RdRp domain of the L protein from the Human Respiratory Syncytial Virus, and the polyprotein from Rhinovirus B genes. The analytical performance of the M-m-qPCR underwent assessment using in silico analysis and a panel of reference and clinical strains, encompassing viral, bacterial, and fungal pathogens, exhibiting 100% specificity. Moreover, the assay showed a detection limit of 10 copies per reaction for all targeted pathogens using the positive controls. To validate its applicability, the assay was further tested in simulated nasal fluid spiked with the viruses mentioned above, followed by validation on nasopharyngeal swabs collected from 811 individuals. Among them, 13.4% (109/811) tested positive for SARS-CoV-2, and 1.1% (9/811) tested positive for Influenza A. Notably, these results showed 100% concordance with those obtained using a commercial kit. Therefore, the M-m-qPCR exhibits great potential for the routine screening of these respiratory viral pathogens.

In Vivo Treatment with Insulin-like Growth Factor 1 Reduces CCR5 Expression on Vaccine-Induced Activated CD4+ T-Cells.

At the heart of the DNA/ALVAC/gp120/alum vaccine's efficacy in the absence of neutralizing antibodies is a delicate balance of pro- and anti-inflammatory immune responses that effectively decreases the risk of SIVmac251 acquisition in macaques. Vaccine efficacy is linked to antibodies recognizing the V2 helical conformation, DC-10 tolerogenic dendritic cells eliciting the clearance of apoptotic cells via efferocytosis, and CCR5 downregulation on vaccine-induced gut homing CD4+ cells. RAS activation is also linked to vaccine efficacy, which prompted the testing of IGF-1, a potent inducer of RAS activation with vaccination. We found that IGF-1 changed the hierarchy of V1/V2 epitope recognition and decreased both ADCC specific for helical V2 and efferocytosis. Remarkably, IGF-1 also reduced the expression of CCR5 on vaccine-induced CD4+ gut-homing T-cells, compensating for its negative effect on ADCC and efferocytosis and resulting in equivalent vaccine efficacy (71% with IGF-1 and 69% without).

HTLV-1 p12 modulates the levels of prion protein (PrPC) in CD4+ T cells.

Introduction: Infection with human T cell lymphotropic virus type 1 (HTLV-1) is endemic in Brazil and is linked with pro-inflammatory conditions including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic neuroinflammatory incapacitating disease that culminates in loss of motor functions. The mechanisms underlying the onset and progression of HAM/TSP are incompletely understood. Previous studies have demonstrated that inflammation and infectious agents can affect the expression of cellular prion protein (PrPC) in immune cells. Methods: Here, we investigated whether HTLV-1 infection affected PrPC content in cell lines and primary CD4+cells in vitro using flow cytometry and western blot assays. Results: We found that HTLV-1 infection decreased the expression levels of PrPC and HTLV-1 Orf I encoded p12, an endoplasmic reticulum resident protein also known to affect post-transcriptionally cellular proteins such as MHC-class I and the IL-2 receptor. In addition, we observed a reduced percentage of CD4+ T cells from infected individuals expressing PrPC, which was reflected by IFN type II but not IL-17 expression. Discussion: These results suggested that PrPC downregulation, linked to both HTLV-1 p12 and IFN-γ expression in CD4+ cells, may play a role in the neuropathogenesis of HTLV-1 infection.

The Antibacterial and Wound Healing Properties of Natural Products: A Review on Plant Species with Therapeutic Potential against Staphylococcus aureus Wound Infections.

Wounds of an acute or chronic etiology affect millions of people worldwide, with increasing prevalence every year. Microbial infections are one of the main causes that impair the wound healing process, and Staphylococcus aureus, a commensal member of the skin microbiota, is one of the main causative agents of wound infections. Crucially, a high proportion of these infections are caused by methicillin-resistant Staphylococcus aureus, which, in addition to ß-lactams, has acquired resistance to almost all the antibacterial agents used to treat it, limiting therapeutic options. Studies on the antimicrobial and healing activities of extracts, essential oils, or metabolites obtained from native plants have been reported in many countries that have a diverse flora and traditions with the use of medicinal plants for the treatment of wound infections. Due to their great chemical diversity, plants have proven to be promising sources of bioactive molecules for the discovery and development of new drugs or strategies for the treatment of wounds. This review highlights the main herbal preparations that have antimicrobial and healing activities with potential for the treatment of wound infections caused by Staphylococcus aureus.

Synergistic Antifungal Interaction between Pseudomonas aeruginosa LV Strain Metabolites and Biogenic Silver Nanoparticles against Candida auris.

Candida auris has been found to be a persistent colonizer of human skin and a successful pathogen capable of causing potentially fatal infection, especially in immunocompromised individuals. This fungal species is usually resistant to most antifungal agents and has the ability to form biofilms on different surfaces, representing a significant therapeutic challenge. Herein, the effect of metabolites of Pseudomonas aeruginosa LV strain, alone and combined with biologically synthesized silver nanoparticles (bioAgNP), was evaluated in planktonic and sessile (biofilm) cells of C. auris. First, the minimal inhibitory and fungicidal concentration values of 3.12 and 6.25 µg/mL, respectively, were determined for F4a, a semi-purified bacterial fraction. Fluopsin C and indolin-3-one seem to be the active components of F4a. Like the semi-purified fraction, they showed a time- and dose-dependent fungicidal activity. F4a and bioAgNP caused severe changes in the morphology and ultrastructure of fungal cells. F4a and indolin-3-one combined with bioAgNP exhibited synergistic fungicidal activity against planktonic cells. F4a, alone or combined with bioAgNP, also caused a significant decrease in the number of viable cells within the biofilms. No cytotoxicity to mammalian cells was detected for bacterial metabolites combined with bioAgNP at synergistic concentrations that presented antifungal activity. These results indicate the potential of F4a combined with bioAgNP as a new strategy for controlling C. auris infections.

Cholera toxin B scaffolded, focused SIV V2 epitope elicits antibodies that influence the risk of SIVmac251 acquisition in macaques.

Introduction: An efficacious HIV vaccine will need to elicit a complex package of innate, humoral, and cellular immune responses. This complex package of responses to vaccine candidates has been studied and yielded important results, yet it has been a recurring challenge to determine the magnitude and protective effect of specific in vivo immune responses in isolation. We therefore designed a single, viral-spike-apical, epitope-focused V2 loop immunogen to reveal individual vaccine-elicited immune factors that contribute to protection against HIV/SIV. Method: We generated a novel vaccine by incorporating the V2 loop B-cell epitope in the cholera toxin B (CTB) scaffold and compared two new immunization regimens to a historically protective 'standard' vaccine regimen (SVR) consisting of 2xDNA prime boosted with 2xALVAC-SIV and 1xΔV1gp120. We immunized a cohort of macaques with 5xCTB-V2c vaccine+alum intramuscularly simultaneously with topical intrarectal vaccination of CTB-V2c vaccine without alum (5xCTB-V2/alum). In a second group, we tested a modified version of the SVR consisting of 2xDNA prime and boosted with 1xALVAC-SIV and 2xALVAC-SIV+CTB-V2/alum, (DA/CTB-V2c/alum). Results: In the absence of any other anti-viral antibodies, V2c epitope was highly immunogenic when incorporated in the CTB scaffold and generated highly functional anti-V2c antibodies in the vaccinated animals. 5xCTB-V2c/alum vaccination mediated non-neutralizing ADCC activity and efferocytosis, but produced low avidity, trogocytosis, and no neutralization of tier 1 virus. Furthermore, DA/CTB-V2c/alum vaccination also generated lower total ADCC activity, avidity, and neutralization compared to the SVR. These data suggest that the ΔV1gp120 boost in the SVR yielded more favorable immune responses than its CTB-V2c counterpart. Vaccination with the SVR generates CCR5- α4ß7+CD4+ Th1, Th2, and Th17 cells, which are less likely to be infected by SIV/HIV and likely contributed to the protection afforded in this regimen. The 5xCTB-V2c/alum regimen likewise elicited higher circulating CCR5- α4ß7+ CD4+ T cells and mucosal α4ß7+ CD4+ T cells compared to the DA/CTB-V2c/alum regimen, whereas the first cell type was associated with reduced risk of viral acquisition. Conclusion: Taken together, these data suggest that individual viral spike B-cell epitopes can be highly immunogenic and functional as isolated immunogens, although they might not be sufficient on their own to provide full protection against HIV/SIV infection.

Vaccine plus microbicide effective in preventing vaginal SIV transmission in macaques.

The human immunodeficiency virus epidemic continues in sub-Saharan Africa, and particularly affects adolescent girls and women who have limited access to antiretroviral therapy. Here we report that the risk of vaginal simian immunodeficiency virus (SIV)mac251 acquisition is reduced by more than 90% using a combination of a vaccine comprising V1-deleted (V2 enhanced) SIV envelope immunogens with topical treatment of the zinc-finger inhibitor SAMT-247. Following 14 weekly intravaginal exposures to the highly pathogenic SIVmac251, 80% of a cohort of 20 macaques vaccinated and treated with SAMT-247 remained uninfected. In an arm of 18 vaccinated-only animals without microbicide, 40% of macaques remained uninfected. The combined SAMT-247/vaccine regimen was significantly more effective than vaccination alone. By analysing immune correlates of protection, we show that, by increasing zinc availability, SAMT-247 increases natural killer cytotoxicity and monocyte efferocytosis, and decreases T-cell activation to augment vaccine-induced protection.

Effect of Passive Administration of Monoclonal Antibodies Recognizing Simian Immunodeficiency Virus (SIV) V2 in CH59-Like Coil/Helical or ß-Sheet Conformations on Time of SIVmac251 Acquisition.

The monoclonal antibodies (MAbs) NCI05 and NCI09, isolated from a vaccinated macaque that was protected from multiple simian immunodeficiency virus (SIV) challenges, both target an overlapping, conformationally dynamic epitope in SIV envelope variable region 2 (V2). Here, we show that NCI05 recognizes a CH59-like coil/helical epitope, whereas NCI09 recognizes a ß-hairpin linear epitope. In vitro, NCI05 and, to a lesser extent, NCI09 mediate the killing of SIV-infected cells in a CD4-dependent manner. Compared to NCI05, NCI09 mediates higher titers of antibody-dependent cellular cytotoxicity (ADCC) to gp120-coated cells, as well as higher levels of trogocytosis, a monocyte function that contributes to immune evasion. We also found that passive administration of NCI05 or NCI09 to macaques did not affect the risk of SIVmac251 acquisition compared to controls, demonstrating that these anti-V2 antibodies alone are not protective. However, NCI05 but not NCI09 mucosal levels strongly correlated with delayed SIVmac251 acquisition, and functional and structural data suggest that NCI05 targets a transient state of the viral spike apex that is partially opened, compared to its prefusion-closed conformation. IMPORTANCE Studies suggest that the protection against SIV/simian-human immunodeficiency virus (SHIV) acquisition afforded by the SIV/HIV V1 deletion-containing envelope immunogens, delivered by the DNA/ALVAC vaccine platform, requires multiple innate and adaptive host responses. Anti-inflammatory macrophages and tolerogenic dendritic cells (DC-10), together with CD14+ efferocytes, are consistently found to correlate with a vaccine-induced decrease in the risk of SIV/SHIV acquisition. Similarly, V2-specific antibody responses mediating ADCC, Th1 and Th2 cells expressing no or low levels of CCR5, and envelope-specific NKp44+ cells producing interleukin 17 (IL-17) also are reproducible correlates of decreased risk of virus acquisition. We focused on the function and the antiviral potential of two monoclonal antibodies (NCI05 and NCI09) isolated from vaccinated animals that differ in antiviral function in vitro and recognize V2 in a linear (NCI09) or coil/helical (NCI05) conformation. We demonstrate that NCI05, but not NCI09, delays SIVmac251 acquisition, highlighting the complexity of antibody responses to V2.

HIV vaccine candidate efficacy in female macaques mediated by cAMP-dependent efferocytosis and V2-specific ADCC.

The development of an effective vaccine to protect against HIV acquisition will be greatly bolstered by in-depth understanding of the innate and adaptive responses to vaccination. We report here that the efficacy of DNA/ALVAC/gp120/alum vaccines, based on V2-specific antibodies mediating apoptosis of infected cells (V2-ADCC), is complemented by efferocytosis, a cyclic AMP (cAMP)-dependent antiphlogistic engulfment of apoptotic cells by CD14+ monocytes. Central to vaccine efficacy is the engagement of the CCL2/CCR2 axis and tolerogenic dendritic cells producing IL-10 (DC-10). Epigenetic reprogramming in CD14+ cells of the cyclic AMP/CREB pathway and increased systemic levels of miRNA-139-5p, a negative regulator of expression of the cAMP-specific phosphodiesterase PDE4D, correlated with vaccine efficacy. These data posit that efferocytosis, through the prompt and effective removal of apoptotic infected cells, contributes to vaccine efficacy by decreasing inflammation and maintaining tissue homeostasis.