Viral vector delivered immunogen focuses HIV-1 antibody specificity and increases durability of the circulating antibody recall response.

The modestly efficacious HIV-1 vaccine regimen (RV144) conferred 31% vaccine efficacy at 3 years following the four-shot immunization series, coupled with rapid waning of putative immune correlates of decreased infection risk. New strategies to increase magnitude and durability of protective immunity are critically needed. The RV305 HIV-1 clinical trial evaluated the immunological impact of a follow-up boost of HIV-1-uninfected RV144 recipients after 6-8 years with RV144 immunogens (ALVAC-HIV alone, AIDSVAX B/E gp120 alone, or ALVAC-HIV + AIDSVAX B/E gp120). Previous reports demonstrated that this regimen elicited higher binding, antibody Fc function, and cellular responses than the primary RV144 regimen. However, the impact of the canarypox viral vector in driving antibody specificity, breadth, durability and function is unknown. We performed a follow-up analysis of humoral responses elicited in RV305 to determine the impact of the different booster immunogens on HIV-1 epitope specificity, antibody subclass, isotype, and Fc effector functions. Importantly, we observed that the ALVAC vaccine component directly contributed to improved breadth, function, and durability of vaccine-elicited antibody responses. Extended boosts in RV305 increased circulating antibody concentration and coverage of heterologous HIV-1 strains by V1V2-specific antibodies above estimated protective levels observed in RV144. Antibody Fc effector functions, specifically antibody-dependent cellular cytotoxicity and phagocytosis, were boosted to higher levels than was achieved in RV144. V1V2 Env IgG3, a correlate of lower HIV-1 risk, was not increased; plasma Env IgA (specifically IgA1), a correlate of increased HIV-1 risk, was elevated. The quality of the circulating polyclonal antibody response changed with each booster immunization. Remarkably, the ALVAC-HIV booster immunogen induced antibody responses post-second boost, indicating that the viral vector immunogen can be utilized to selectively enhance immune correlates of decreased HIV-1 risk. These results reveal a complex dynamic of HIV-1 immunity post-vaccination that may require careful balancing to achieve protective immunity in the vaccinated population. Trial registration: RV305 clinical trial (ClinicalTrials.gov number, NCT01435135). ClinicalTrials.gov Identifier: NCT00223080.

Precision symptom phenotyping identifies early clinical and proteomic predictors of distinct COVID-19 sequelae.

BACKGROUND: Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory profiles may improve clinical prognostication and trial endpoints. METHODS: 1,988 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative post-COVID symptom scores were included in this analysis. Among participants who reported moderate-to-severe symptoms on surveys collected 6-months post-SARS-CoV-2 infection, principal component analysis (PCA) followed by K-means clustering identified distinct clusters of symptoms. RESULTS: Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization compared to those with no/mild symptoms at 6-months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking, and elevated ICAM-1 concentrations to sensory symptoms. CONCLUSIONS: We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC.

Significant Increase in Early Reoperation After Latarjet-Bristow Procedure Versus Arthroscopic Bankart Repair for Anterior Shoulder Instability: A Propensity-Score Matched Analysis.

PURPOSE: To compare the 30-day outcomes, including length of stay, short-term complications, hospital readmission, all-cause reoperation, and death after arthroscopic Bankart (AB) and Latarjet. METHODS: Patients in the National Surgical Quality Improvement Program database who had undergone either AB or Latarjet-Bristow (LB) procedures for anterior shoulder instability from 2012 to 2018 were identified using Current Procedural Terminology codes. Nearest neighbor propensity score matching was used to address any potential demographic differences. The 30-day incidence of postoperative complications were compared, and univariate and multivariate logistic regressions were used to identify risk factors associated with the incidence of post-operative complications. RESULTS: A total of 7,519 patients were identified, with 6,990 (93.0%) undergoing AB and 529 (7.0%) LB. After propensity score matching, the baseline demographics were not significantly different (P > .05). There was no significant difference in rate of total adverse events between the AB and LB cohorts (P = .06). There was a significant difference in the rate of return to the operating room between LB (1.9%) when compared to AB (0%) (P < .001). Of reoperations, 40% were due to need for revision stabilization (0.8% of all LB cases) and 40% were for irrigation and debridement. There was also a significant difference in operative time (AB = 87 minutes, LB = 131 minutes; P < .0001). CONCLUSIONS: Overall 30-day complication rates were low for both groups, with similar rates among AB and LB patients. However, there was a statistically significant increased rate of short-term reoperation or revision stabilization in the LB cohort. LEVEL OF EVIDENCE: Level III, retrospective comparative prognostic trial.

Epidemiology of Hamstring Tears in National Collegiate Athletic Association Athletes: Findings From the National Collegiate Athletic Association Injury Surveillance Program Between 2014/2015 and 2018/2019.

OBJECTIVE: To describe the epidemiology of hamstring tears in National Collegiate Athletic Association (NCAA) sports. DESIGN: Descriptive epidemiology study. Athletic trainers from NCAA schools reported injuries to the NCAA Injury Surveillance Program. SETTING: A convenience sample of NCAA hamstring tear injuries during the 2014/2015 through 2018/2019 academic years. PATIENTS OR PARTICIPANTS: NCAA student-athletes. INDEPENDENT VARIABLES: Sport, sex, event type, season segment, injury history, and activity at the time of injury. MAIN OUTCOME MEASURES: Injury counts, rates, and proportions were used. RESULTS: Two thousand ninety-six hamstring tears from 8 474 400 athlete-exposures (AEs) were reported (2.47 per 10 000 AEs). Rates were highest in Men's Soccer (5.97 per 10 000 AEs) and Women's Soccer (3.13 per 10 000 AEs), among all Men's and Women's sports, respectively. Competition-related rates in Men's and Women's sports were highest in 2015 to 2016 then followed a decreasing pattern across the remainder of the study period. Among sex-comparable sports, rates were higher in men's (compared with women's) Baseball/Softball, Soccer, and Track and Field. The prevalence of recurrent injuries was comparable among men's (14.8%) and women's (11.5%) sports. Time loss hamstring tears were more prevalent in Men's sports than Women's sports [injury proportion ratio = 1.33; 95% confidence interval, (1.21, 1.47)]. CONCLUSIONS: Overall, hamstring tear rates were higher across all Men's sports compared with Women's sports. Rates across event type were comparable in several sports; and so, adjustments to practice are needed considering that practice environments are more modifiable than competitions. Indeed, improving hamstring tear prevention programs to reduce the burden of this injury in NCAA athletes remains critical.

Correction: RV144 HIV-1 vaccination impacts post-infection antibody responses.

[This corrects the article DOI: 10.1371/journal.ppat.1009101.].

Metabolic phenotypes reflect patient sex and injury status: A cross-sectional analysis of human synovial fluid.

OBJECTIVE: Osteoarthritis is a heterogeneous disease. The objective was to compare differences in underlying cellular mechanisms and endogenous repair pathways between synovial fluid (SF) from male and female participants with different injuries to improve the current understanding of the pathophysiology of downstream post-traumatic osteoarthritis (PTOA). DESIGN: SF from n = 33 knee arthroscopy patients between 18 and 70 years with no prior knee injuries was obtained pre-procedure and injury pathology assigned post-procedure. SF was extracted and analyzed via liquid chromatography-mass spectrometry metabolomic profiling to examine differences in metabolism between injury pathologies (ligament, meniscal, and combined ligament and meniscal) and patient sex. Samples were pooled and underwent secondary fragmentation to identify metabolites. RESULTS: Different knee injuries uniquely altered SF metabolites and downstream pathways including amino acid, lipid, and inflammatory-associated metabolic pathways. Notably, sexual dimorphic metabolic phenotypes were examined between males and females and within injury pathology. Cervonyl carnitine and other identified metabolites differed in concentrations between sexes. CONCLUSIONS: These results suggest that different injuries and patient sex are associated with distinct metabolic phenotypes. Considering these phenotypic associations, a greater understanding of metabolic mechanisms associated with specific injuries, sex, and PTOA development may yield data regarding how endogenous repair pathways differ between male and female injury types. Ongoing metabolomic analysis of SF in injured male and female patients can be performed to monitor PTOA development and progression.

Transmission of SARS-CoV-2 among recruits in a US Army training environment: a brief report.

BACKGROUND: In 2020, preventive measures were implemented to mitigate the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among 600-700 recruits arriving weekly at a basic combat training (BCT) facility in the southern United States. Trainees were sorted into companies and platoons (cocoons) at arrival, tested, quarantined for 14 days with daily temperature and respiratory-symptom monitoring and retested before release into larger groups for training where symptomatic testing was conducted. Nonpharmaceutical measures, such as masking, and social distancing, were maintained throughout quarantine and BCT. We assessed for SARS-CoV-2 transmission in the quarantine milieu. METHODS: Nasopharyngeal (NP) swabs were collected at arrival and at the end of quarantine and blood specimens at both timepoints and at the end of BCT. Epidemiological characteristics were analyzed for transmission clusters identified from whole-genome sequencing of NP samples. RESULTS: Among 1403 trainees enrolled from 25 August to 7 October 2020, epidemiological analysis identified three transmission clusters (n = 20 SARS-CoV-2 genomes) during quarantine, which spanned five different cocoons. However, SARS-CoV-2 incidence decreased from 2.7% during quarantine to 1.5% at the end of BCT; prevalence at arrival was 3.3%. CONCLUSIONS: These findings suggest layered SARS-CoV-2 mitigation measures implemented during quarantine minimized the risk of further transmission in BCT.

Increased Age, Operative Time, American Society of Anesthesiologists Classification, Functional Dependency, and Comorbidity Burden Are Risk Factors for Adverse Events After Meniscectomy and Meniscus Repair: 10-Year Analysis of 64,223 Patients.

PURPOSE: To use the National Surgical Quality Improvement Program (NSQIP) database to identify risk factors for 30-day adverse events and hospital readmission following isolated and unilateral meniscectomy or meniscus repair. METHODS: A retrospective review of the NSQIP database from the years 2012 to 2021 identified all patients undergoing isolated, unilateral meniscectomy or meniscus repair. Multivariable analyses were performed for each procedure to identify patient characteristics associated with any adverse event (AAE) or unplanned hospital readmission within 30 days of surgery. RESULTS: From 2012 to 2021, 59,450 (93%) patients underwent meniscectomy, and 4,773 (7%) patients underwent meniscus repair. Overall adverse event rate was 0.95% after meniscectomy and 1.40% after repair. Risk factors for AAE after meniscectomy included increased age (odds ratio [OR] = 1.010; P = .009), increased operative time (OR = 1.003; P = 0.011), American Society of Anesthesiologists (ASA) class IV (OR = 2.048; P = .045), functional dependency (OR = 3.527; P = .001), and current smoking (OR = 1.308; P = .018). Risk factors for AAE after meniscus repair included age (OR = 1.024; P = .016), operative time (OR = 1.004; P = .038), and bleeding disorders (OR = 7.000; P = .014). ASA class III increased risk of hospital readmission after both procedures (OR = 1.906; P = .008; OR = 4.101; P = .038), and medical comorbidities of heart failure (OR = 3.924; P = .016), hypertension (OR = 1.412; P = .011), and chronic obstructive pulmonary disease (OR = 2.350; P < .001) increased readmission risk after meniscectomy only. CONCLUSIONS: Per analysis of the ACS-NSQIP database, surgical treatment of meniscal tears in the knee has been performed frequently over the past 10 years, with meniscectomies comprising over 90% of cases. Increased age and operative time were associated with a modest risk of adverse events after both meniscectomy and meniscus repair. Increased comorbidity burden, evidenced by ASA class, dependent functional status, current smoking, and systemic medical conditions, such as heart failure, hypertension, chronic obstructive pulmonary disease, and bleeding disorders, greatly increased rates of unfavorable outcomes within 30 days of meniscus surgery. LEVEL OF EVIDENCE: Level III, retrospective prognostic comparative investigation.

Virological and Serological Assessment of US Army Trainees Isolated for Coronavirus Disease 2019.

BACKGROUND: Laboratory screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key mitigation measure to avoid the spread of infection among recruits starting basic combat training in a congregate setting. Because viral nucleic acid can be detected persistently after recovery, we evaluated other laboratory markers to distinguish recruits who could proceed with training from those who were infected. METHODS: Recruits isolated for coronavirus disease 2019 (COVID-19) were serially tested for SARS-CoV-2 subgenomic ribonucleic acid (sgRNA), and viral load (VL) by reverse-transcriptase polymerase chain reaction (RT-PCR), and for anti- SARS-CoV-2. Cluster and quadratic discriminant analyses of results were performed. RESULTS: Among 229 recruits isolated for COVID-19, those with a RT-PCR cycle threshold >30.49 (sensitivity 95%, specificity 96%) or having sgRNA log10 RNA copies/mL <3.09 (sensitivity and specificity 96%) at entry into isolation were likely SARS-CoV-2 uninfected. Viral load >4.58 log10 RNA copies/mL or anti-SARS-CoV-2 signal-to-cutoff ratio <1.38 (VL: sensitivity and specificity 93%; anti-SARS-CoV-2: sensitivity 83%, specificity 79%) had comparatively lower sensitivity and specificity when used alone for discrimination of infected from uninfected. CONCLUSIONS: Orthogonal laboratory assays used in combination with RT-PCR may have utility in determining SARS-CoV-2 infection status for decisions regarding isolation.

Clinical outcomes of cemented vs. uncemented reverse total shoulder arthroplasty for proximal humerus fractures: a systematic review.

BACKGROUND: Reverse total shoulder arthroplasty is an established treatment method for comminuted proximal humerus fractures. Both cemented and uncemented techniques exist, with uncemented reverse total shoulder offering many theoretical advantages, including improved biologic fixation, absence of cement related complications, and ease of revision if necessary. There are few studies comparing the outcomes of the two techniques. METHODS: The study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A search for studies assessing clinical outcomes of reverse total shoulder arthroplasty for proximal humerus fractures was performed of PubMed, Embase, Web of Science, and Cochrane Library. Main outcomes included Constant Score (CS), American Shoulder and Elbow Surgeons (ASES) score, and complication rate. Inclusion criteria were as follows: indication for arthroplasty was fracture; minimum one year follow up; article in English. Exclusion criteria were as follows: review articles; biomechanical or cadaver studies. Quality analysis was performed using the Cochrane Risk of Bias tool (RoB 2) and the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool. RESULTS: A total of 682 studies were identified through the initial search, with 36 studies meeting all inclusion criteria. There were 24 studies investigating cemented technique, 10 studies examining uncemented technique, and two studies involving both techniques. There was no difference in mean follow up between patients receiving a cemented vs. uncemented rTSA (32.3 months vs. 30.6 months, p = 0.06). Patients who received a cemented rTSA had a significantly higher Constant-Murley score than those who received an uncemented rTSA (59.4 vs 55.9, p < .001). There was no difference between the two groups when comparing ASES Scores (77.5 vs 78.6, p = 0.54) and overall complication rates (11.1% vs 11.8%, p = 0.23). CONCLUSION: Both cemented and uncemented rTSA are both valid options for treating acute proximal humerus fractures. Cemented rTSA may portend slightly improved clinical outcomes with similar overall complication rates compared to uncemented rTSA for proximal humerus fractures.

RV144 HIV-1 vaccination impacts post-infection antibody responses.

The RV144 vaccine efficacy clinical trial showed a reduction in HIV-1 infections by 31%. Vaccine efficacy was associated with stronger binding antibody responses to the HIV Envelope (Env) V1V2 region, with decreased efficacy as responses wane. High levels of Ab-dependent cellular cytotoxicity (ADCC) together with low plasma levels of Env-specific IgA also correlated with decreased infection risk. We investigated whether B cell priming from RV144 vaccination impacted functional antibody responses to HIV-1 following infection. Antibody responses were assessed in 37 vaccine and 63 placebo recipients at 6, 12, and 36 months following HIV diagnosis. The magnitude, specificity, dynamics, subclass recognition and distribution of the binding antibody response following infection were different in RV144 vaccine recipients compared to placebo recipients. Vaccine recipients demonstrated increased IgG1 binding specifically to V1V2, as well as increased IgG2 and IgG4 but decreased IgG3 to HIV-1 Env. No difference in IgA binding to HIV-1 Env was detected between the vaccine and placebo recipients following infection. RV144 vaccination limited the development of broadly neutralizing antibodies post-infection, but enhanced Fc-mediated effector functions indicating B cell priming by RV144 vaccination impacted downstream antibody function. However, these functional responses were not associated with clinical markers of disease progression. These data reveal that RV144 vaccination primed B cells towards specific binding and functional antibody responses following HIV-1 infection.

Factors associated with testing for HIV and other sexually transmitted infections in men who have sex with men and transgender women in Bangkok, Thailand.

BACKGROUND: Routine screening for HIV and other sexually transmitted infections (STIs) facilitates early diagnosis and treatment, thereby preventing morbidity and onward transmission. We estimated the prevalence of prior HIV/STI testing among men who have sex with men (MSM) and transgender women (TGW) in Bangkok, Thailand, and identified factors associated with prior testing. METHODS: Cross-sectional analyses were performed using data collected at enrollment into an HIV incidence cohort. From April to October 2017, MSM and TGW were enrolled if they were aged 18-35 years, reported anal intercourse with a male or TGW partner, and reported behavioral vulnerability to HIV. Participants answered questions about demographics, sexual behaviors, and lifetime HIV/STI testing history. Multivariable robust Poisson regression was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for factors potentially associated with prior testing. RESULTS: Among 1,014 participants, 348 (34.3%) were TGW and the median age was 21.6 (interquartile range 20.0-24.8) years. Prior testing for HIV was reported by 421 (41.5%) and for other STIs by 268 (26.4%). HIV testing was more common among participants aged ≥ 22 years (RR 1.37 [95% CI 1.13-1.67]), with college education as compared to secondary or less (RR 1.37 [95% CI 1.08-1.72]), and who met male sexual partners online (RR 1.52 [95% CI 1.24-1.85]), but lower among participants attracted to both men and women as compared to men only (RR 0.64 [95% CI 0.51-0.81]) and who met male sexual partners in bars (RR 0.83 [95% CI 0.72-0.97]). Similar associations were observed with prior testing for other STIs, including increased testing among participants with college education (RR 1.52 [95% CI 1.11-2.09]) and who met male sexual partners online (RR 1.73 [95% CI 1.30-2.31]), but lower among participants attracted to both men and women (RR 0.70 [95% CI 0.51-0.96]) and who met male sexual partners in bars (RR 0.67 [95% CI 0.54-0.83]). CONCLUSIONS: Despite behavioral vulnerability, prior testing for HIV and other STIs was uncommon. Online engagement strategies may be effectively reaching Thai MSM and TGW who meet sexual partners online, but new interventions are needed to encourage testing among younger, less educated, and bisexual MSM and TGW.

Sarcopaenia, obesity, sarcopaenic obesity and outcomes following hepatic resection for colorectal liver metastases: a systematic review and meta-analysis.

BACKGROUND: Obesity is a risk factor for the development of colorectal cancer. Limited evidence exists about outcomes for obese patients undergoing hepatic resection for colorectal liver metastases (CRLM). Sarcopaenia is characterised by a decline in muscle function and muscle mass. It is associated with poorer outcomes for patients on chemotherapy, but there are limited data for sarcopaenic patients undergoing hepatic resection for CRLM. METHODS: Pubmed, Embase, Cochrane Central, Web of Science, SCOPUS, and CINAHL databases were searched for articles which were selected in accordance with PRISMA guidelines. Primary outcomes were overall survival (OS) and disease-free survival (DFS). A random effects meta-analysis was conducted. RESULTS: Thirteen studies were included incorporating 2936 patients. No significant difference was found between obese and non-obese patients in OS (HR 0.81, CI 0.47-1.39, p = 0.44) or DFS (HR 1.0, CI 0.99-1.01, p = 0.98). Sarcopaenia was associated with worse OS (HR 1.65, CI 1.10-2.48, p = 0.01), and increased major post operative complications (OR 1.91, CI 1.16-3.14, p = 0.01). Only one study examined outcomes for sarcopaenic obese patients. CONCLUSION: Limited evidence exists describing the impact of obesity and sarcopenia on outcomes following hepatic resection for CRLM. Obese patients do not have worse oncological outcomes, whereas sarcopaenia is associated with poorer long-term survival.

Boosting with AIDSVAX B/E Enhances Env Constant Region 1 and 2 Antibody-Dependent Cellular Cytotoxicity Breadth and Potency.

Induction of protective antibodies is a critical goal of HIV-1 vaccine development. One strategy is to induce nonneutralizing antibodies (NNAbs) that kill virus-infected cells, as these antibody specificities have been implicated in slowing HIV-1 disease progression and in protection. HIV-1 Env constant region 1 and 2 (C1C2) monoclonal antibodies (MAbs) frequently mediate potent antibody-dependent cellular cytotoxicity (ADCC), making them an important vaccine target. Here, we explore the effect of delayed and repetitive boosting of RV144 vaccine recipients with AIDSVAX B/E on the C1C2-specific MAb repertoire. It was found that boosting increased clonal lineage-specific ADCC breadth and potency. A ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-specific MAb showed that it bound a highly conserved Env gp120 epitope. Thus, boosting to affinity mature these types of IgG C1C2-specific antibody responses may be one method by which to make an improved HIV vaccine with higher efficacy than that seen in the RV144 trial.IMPORTANCE Over one million people become infected with HIV-1 each year, making the development of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human HIV-1 vaccine regimen is the only HIV-1 clinical trial to date to demonstrate vaccine efficacy. An area of focus has been on identifying ways by which to improve upon RV144 vaccine efficacy. The RV305 HIV-1 vaccine regimen was a follow-up boost of RV144 vaccine recipients that occurred 6 to 8 years after the conclusion of RV144. Our study focused on the effect of delayed boosting in humans on the vaccine-induced Env constant region 1 and 2 (C1C2)-specific antibody repertoire. It was found that boosting with an HIV-1 Env vaccine increased C1C2-specific antibody-dependent cellular cytotoxicity potency and breadth.

VPR-254: an inhibitor of ROR-gamma T with potential utility for the treatment of inflammatory bowel disease.

INTRODUCTION: Retinoic Acid Related Orphan Nuclear Receptor gamma T (RORγT) is a lineage specifying transcription factor for IL-17 expressing cells, which may contribute to the pathogenesis of Inflammatory Bowel Disease (IBD). VPR-254 is a selective in vitro inhibitor of RORγT. AIMS: The main goals of our study were twofold: (1) To determine if ex vivo treatment with VPR-254 reduced relevant cytokine (IL-17 and IL-21) secretion from colonic strips of mice with colitis; (2) To determine if treatment of mice with VPR-254 attenuated parameters of colitis, using three murine IBD models. METHODS: VPR-254 was evaluated ex vivo in a colonic strip assay, using tissue from mice with Dextran sulfate sodium (DSS)-induced colitis. In vivo, VPR-254 was evaluated for efficacy in DSS, Trintirobenzenesulfonic acid (TNBS) and Anti-CD40 antibody-induced murine models of colitis. RESULTS: VPR-254 reduced the production of key pro-inflammatory cytokines (e.g., IL-17) in ex vivo and in vivo models of colitis. This small molecule inhibitor of RORγT also improved various morphometric and histological parameters associated with three diverse murine models of IBD. CONCLUSION: Our results support the concept that an inhibitor of ROR-gamma T may have potential utility for the treatment of IBD.

Prospective Study of Acute HIV-1 Infection in Adults in East Africa and Thailand.

BACKGROUND: Acute human immunodeficiency virus type 1 (HIV-1) infection is a major contributor to transmission of HIV-1. An understanding of acute HIV-1 infection may be important in the development of treatment strategies to eradicate HIV-1 or achieve a functional cure. METHODS: We performed twice-weekly qualitative plasma HIV-1 RNA nucleic acid testing in 2276 volunteers who were at high risk for HIV-1 infection. For participants in whom acute HIV-1 infection was detected, clinical observations, quantitative measurements of plasma HIV-1 RNA levels (to assess viremia) and HIV antibodies, and results of immunophenotyping of lymphocytes were obtained twice weekly. RESULTS: Fifty of 112 volunteers with acute HIV-1 infection had two or more blood samples collected before HIV-1 antibodies were detected. The median peak viremia (6.7 log10 copies per milliliter) occurred 13 days after the first sample showed reactivity on nucleic acid testing. Reactivity on an enzyme immunoassay occurred at a median of 14 days. The nadir of viremia (4.3 log10 copies per milliliter) occurred at a median of 31 days and was nearly equivalent to the viral-load set point, the steady-state viremia that persists durably after resolution of acute viremia (median plasma HIV-1 RNA level, 4.4 log10 copies per milliliter). The peak viremia and downslope were correlated with the viral-load set point. Clinical manifestations of acute HIV-1 infection were most common just before and at the time of peak viremia. A median of one symptom of acute HIV-1 infection was recorded at a median of two study visits, and a median of one sign of acute HIV-1 infection was recorded at a median of three visits. CONCLUSIONS: The viral-load set point occurred at a median of 31 days after the first detection of plasma viremia and correlated with peak viremia. Few symptoms and signs were observed during acute HIV-1 infection, and they were most common before peak viremia. (Funded by the Department of Defense and the National Institute of Allergy and Infectious Diseases.).

Central Nervous System Inflammation and Infection during Early, Nonaccelerated Simian-Human Immunodeficiency Virus Infection in Rhesus Macaques.

Studies utilizing highly pathogenic simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) have largely focused on the immunopathology of the central nervous system (CNS) during end-stage neurological AIDS and SIV encephalitis. However, this may not model pathophysiology in earlier stages of infection. In this nonaccelerated SHIV model, plasma SHIV RNA levels and peripheral blood and colonic CD4+ T cell counts mirrored early human immunodeficiency virus (HIV) infection in humans. At 12 weeks postinfection, cerebrospinal fluid (CSF) detection of SHIV RNA and elevations in IP-10 and MCP-1 reflected a discrete neurovirologic process. Immunohistochemical staining revealed a diffuse, low-level CD3+ CD4- cellular infiltrate in the brain parenchyma without a concomitant increase in CD68/CD163+ monocytes, macrophages, and activated microglial cells. Rare SHIV-infected cells in the brain parenchyma and meninges were identified by RNAScope in situ hybridization. In the meninges, there was also a trend toward increased CD4+ infiltration in SHIV-infected animals but no differences in CD68/CD163+ cells between SHIV-infected and uninfected control animals. These data suggest that in a model that closely recapitulates human disease, CNS inflammation and SHIV in CSF are predominantly mediated by T cell-mediated processes during early infection in both brain parenchyma and meninges. Because SHIV expresses an HIV rather than SIV envelope, this model could inform studies to understand potential HIV cure strategies targeting the HIV envelope.IMPORTANCE Animal models of the neurologic effects of HIV are needed because brain pathology is difficult to assess in humans. Many current models focus on the effects of late-stage disease utilizing SIV. In the era of antiretroviral therapy, manifestations of late-stage HIV are less common. Furthermore, new interventions, such as monoclonal antibodies and therapeutic vaccinations, target HIV envelope. We therefore describe a new model of central nervous system involvement in rhesus macaques infected with SHIV expressing HIV envelope in earlier, less aggressive stages of disease. Here, we demonstrate that SHIV mimics the early clinical course in humans and that early neurologic inflammation is characterized by predominantly T cell-mediated inflammation accompanied by SHIV infection in the brain and meninges. This model can be utilized to assess the effect of novel therapies targeted to HIV envelope on reducing brain inflammation before end-stage disease.

Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial.

The canary pox vector and gp120 vaccine (ALVAC-HIV and AIDSVAX B/E gp120) in the RV144 HIV-1 vaccine trial conferred an estimated 31% vaccine efficacy. Although the vaccine Env AE.A244 gp120 is antigenic for the unmutated common ancestor of V1V2 broadly neutralizing antibody (bnAbs), no plasma bnAb activity was induced. The RV305 (NCT01435135) HIV-1 clinical trial was a placebo-controlled randomized double-blinded study that assessed the safety and efficacy of vaccine boosting on B cell repertoires. HIV-1-uninfected RV144 vaccine recipients were reimmunized 6-8 years later with AIDSVAX B/E gp120 alone, ALVAC-HIV alone, or a combination of ALVAC-HIV and AIDSVAX B/E gp120 in the RV305 trial. Env-specific post-RV144 and RV305 boost memory B cell VH mutation frequencies increased from 2.9% post-RV144 to 6.7% post-RV305. The vaccine was well tolerated with no adverse events reports. While post-boost plasma did not have bnAb activity, the vaccine boosts expanded a pool of envelope CD4 binding site (bs)-reactive memory B cells with long third heavy chain complementarity determining regions (HCDR3) whose germline precursors and affinity matured B cell clonal lineage members neutralized the HIV-1 CRF01 AE tier 2 (difficult to neutralize) primary isolate, CNE8. Electron microscopy of two of these antibodies bound with near-native gp140 trimers showed that they recognized an open conformation of the Env trimer. Although late boosting of RV144 vaccinees expanded a novel pool of neutralizing B cell clonal lineages, we hypothesize that boosts with stably closed trimers would be necessary to elicit antibodies with greater breadth of tier 2 HIV-1 strains. TRIAL REGISTRATION: ClinicalTrials.gov NCT01435135.

Rare HIV-1 transmitted/founder lineages identified by deep viral sequencing contribute to rapid shifts in dominant quasispecies during acute and early infection.

In order to inform the rational design of HIV-1 preventive and cure interventions it is critical to understand the events occurring during acute HIV-1 infection (AHI). Using viral deep sequencing on six participants from the early capture acute infection RV217 cohort, we have studied HIV-1 evolution in plasma collected twice weekly during the first weeks following the advent of viremia. The analysis of infections established by multiple transmitted/founder (T/F) viruses revealed novel viral profiles that included: a) the low-level persistence of minor T/F variants, b) the rapid replacement of the major T/F by a minor T/F, and c) an initial expansion of the minor T/F followed by a quick collapse of the same minor T/F to low frequency. In most participants, cytotoxic T-lymphocyte (CTL) escape was first detected at the end of peak viremia downslope, proceeded at higher rates than previously measured in HIV-1 infection, and usually occurred through the exploration of multiple mutational pathways within an epitope. The rapid emergence of CTL escape variants suggests a strong and early CTL response. Minor T/F viral strains can contribute to rapid and varied profiles of HIV-1 quasispecies evolution during AHI. Overall, our results demonstrate that early, deep, and frequent sampling is needed to investigate viral/host interaction during AHI, which could help identify prerequisites for prevention and cure of HIV-1 infection.

Correction: Rare HIV-1 transmitted/founder lineages identified by deep viral sequencing contribute to rapid shifts in dominant quasispecies during acute and early infection.

[This corrects the article DOI: 10.1371/journal.ppat.1006510.].