Oral Preexposure Prophylaxis Uptake and Discontinuation in the HIV Vaccine Trials Network 704/HIV Prevention Trials Network 085 Study: Implications for Biomedical Human Immunodeficiency Virus Prevention Trials.

Background: HIV Vaccine Trials Network (HVTN) 704/085, a placebo-controlled clinical trial assessing the efficacy of VRC01 broadly neutralizing antibody infusion for HIV prevention, offered oral preexposure prophylaxis (PrEP) as the standard of prevention at no cost to participants. Methods: We characterized features of- identified factors associated with- PrEP initiation and discontinuation, and the effects of PrEP initiation on HIV incidence. Results: Of 2221 participants, 31.8% initiated oral PrEP during study follow-up, with the highest proportion of PrEP initiations in Brazil (83.2%) and the United States (US) (54.2%). Prior PrEP use was associated with PrEP initiation (hazard ratio [HR], 2.22 [95% confidence interval {CI}, 1.25-3.95]). Participants from Switzerland (HR, 0.5 [95% CI, .3-1.0]) and Peru (HR, 0.08 [95% CI, .06-.1]) had lower likelihood of PrEP initiation compared to the US, while participants from Brazil had higher likelihood (HR, 2.6 [95% CI, 2.0-3.3]). In the US, PrEP initiation was lower in areas with higher unmet need for PrEP (HR, 0.9 per 5 units [95% CI, 0.8-1.0]). PrEP initiators had 58% less risk of acquiring HIV than PrEP noninitiators. Among PrEP initiators, 34.4% discontinued PrEP during study follow-up. Brazil had 63% less likelihood of PrEP discontinuation than the US (HR, 0.37 [95% CI, .22-.60]). Conclusions: When included as standard of prevention in HVTN 704/085, oral PrEP utilization patterns mirrored those observed in real-life settings. Variable effects of oral PrEP on HIV outcomes in clinical trials may be expected based on regional differences in oral PrEP use.

Safety and pharmacokinetics of VRC07-523LS administered via different routes and doses (HVTN 127/HPTN 087): A Phase I randomized clinical trial.

BACKGROUND: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV. METHODS AND FINDINGS: Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions were reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 µg/mL (25.2, 33.4), 58.5 µg/mL (49.4, 69.3), and 257.2 µg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 µg/mL (8.8, 13.3) and 22.8 µg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 µg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 µg/mL (2.5, 4.6), 6.5 µg/mL (5.6, 7.5), and 27.2 µg/mL (23.9, 31.0) with IV dosing; 0.97 µg/mL (0.65, 1.4) and 3.1 µg/mL (2.2, 4.3) with SC dosing, and 2.6 µg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days). CONCLUSIONS: VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens. TRIAL REGISTRATION: ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).

Prevention efficacy of the broadly neutralizing antibody VRC01 depends on HIV-1 envelope sequence features.

In the Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081), prevention efficacy (PE) of the monoclonal broadly neutralizing antibody (bnAb) VRC01 (vs. placebo) against HIV-1 acquisition diagnosis varied according to the HIV-1 Envelope (Env) neutralization sensitivity to VRC01, as measured by 80% inhibitory concentration (IC80). Here, we performed a genotypic sieve analysis, a complementary approach to gaining insight into correlates of protection that assesses how PE varies with HIV-1 sequence features. We analyzed HIV-1 Env amino acid (AA) sequences from the earliest available HIV-1 RNA-positive plasma samples from AMP participants diagnosed with HIV-1 and identified Env sequence features that associated with PE. The strongest Env AA sequence correlate in both trials was VRC01 epitope distance that quantifies the divergence of the VRC01 epitope in an acquired HIV-1 isolate from the VRC01 epitope of reference HIV-1 strains that were most sensitive to VRC01-mediated neutralization. In HVTN 704/HPTN 085, the Env sequence-based predicted probability that VRC01 IC80 against the acquired isolate exceeded 1 µg/mL also significantly associated with PE. In HVTN 703/HPTN 081, a physicochemical-weighted Hamming distance across 50 VRC01 binding-associated Env AA positions of the acquired isolate from the most VRC01-sensitive HIV-1 strain significantly associated with PE. These results suggest that incorporating mutation scoring by BLOSUM62 and weighting by the strength of interactions at AA positions in the epitope:VRC01 interface can optimize performance of an Env sequence-based biomarker of VRC01 prevention efficacy. Future work could determine whether these results extend to other bnAbs and bnAb combinations.

A Randomised Clinical Trial of the Safety and Pharmacokinetics of VRC07-523LS Administered via Different Routes and Doses (HVTN 127/HPTN 087).

Background: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the only bnAb HIV prevention efficacy studies to date, the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. Greater efficacy is required before passively administered bnAbs become a viable option for HIV prevention; furthermore subcutaneous (SC) or intramuscular (IM) administration may be preferred. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. Methods: Participants were recruited between 02 February 2018 and 09 October 2018. 124 healthy participants without HIV were randomized to receive five VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), SC (T4: 2.5 mg/kg, T5: 5 mg/kg) or IM (T6: 2.5 mg/kg or P6: placebo) routes at four-month intervals. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA after the first dose through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum pharmacokinetics. Neutralization activity was measured in a TZM-bl assay and anti-drug antibodies (ADA) were assayed using a tiered bridging assay testing strategy. Results: Injections were well-tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusions were generally well-tolerated, with infusion reactions reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals) following the first administration were 29.0 µg/mL (25.2, 33.4), 58.5 µg/mL (49.4, 69.3), and 257.2 µg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 µg/mL (8.8, 13.3) and 22.8 µg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 µg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM concentrations immediately prior to the second administration were 3.4 µg/mL (2.5, 4.6), 6.5 µg/mL (5.6, 7.5), and 27.2 µg/mL (23.9, 31.0) with IV dosing; 0.97 µg/mL (0.65, 1.4) and 3.1 µg/mL (2.2, 4.3) with SC dosing, and 2.6 µg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titres, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titre ADA at a lone timepoint. VRC07-523LS has an estimated mean half-life of 42 days (95% CI: 40.5, 43.5), approximately twice as long as VRC01. Conclusions: VRC07-523LS was safe and well-tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens.

High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials.

The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load (p = 0.03), which is particularly strong above a threshold of IIP = 1.6 (r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300-1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected.

Hyperexcitability in the Olfactory Bulb and Impaired Fine Odor Discrimination in the Fmr1 KO Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is the single most common monogenetic cause of autism spectrum disorders (ASDs) in humans. FXS is caused by loss of expression of the fragile X mental retardation protein (FMRP), an mRNA-binding protein encoded on the X chromosome involved in suppressing protein translation. Sensory processing deficits have been a major focus of studies of FXS in both humans and rodent models of FXS, but olfactory deficits remain poorly understood. Here, we conducted experiments in wild-type (WT) and Fmr1 knock-out (KO; Fmr1-/y ) mice (males) that lack expression of the gene encoding FMRP to assess olfactory circuit and behavioral abnormalities. In patch-clamp recordings conducted in slices of the olfactory bulb, output mitral cells (MCs) in Fmr1 KO mice displayed greatly enhanced excitation under baseline conditions, as evidenced by a much higher rate of occurrence of spontaneous network-level events known as long-lasting depolarizations (LLDs). The higher probability of spontaneous LLDs (sLLDs), which appeared to be because of a decrease in GABAergic synaptic inhibition in glomeruli leading to more feedforward excitation, caused a reduction in the reliability of stimulation-evoked responses in MCs. In addition, in a go/no-go operant discrimination paradigm, we found that Fmr1 KO mice displayed impaired discrimination of odors in difficult tasks that involved odor mixtures but not altered discrimination of monomolecular odors. We suggest that the Fmr1 KO-induced reduction in MC response reliability is one plausible mechanism for the impaired fine odor discrimination.SIGNIFICANCE STATEMENT Fragile X syndrome (FXS) in humans is associated with a range of debilitating deficits including aberrant sensory processing. One sensory system that has received comparatively little attention in studies in animal models of FXS is olfaction. Here, we report the first comprehensive physiological analysis of circuit defects in the olfactory bulb in the commonly-used Fmr1 knock-out (KO) mouse model of FXS. Our studies indicate that Fmr1 KO alters the local excitation/inhibition balance in the bulb, similar to what Fmr1 KO does in other brain circuits, but through a novel mechanism that involves enhanced feedforward excitation. Furthermore, Fmr1 KO mice display behavioral impairments in fine odor discrimination, an effect that may be explained by changes in neural response reliability.

Hyperexcitability in the olfactory bulb and impaired fine odor discrimination in the Fmr1 KO mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is the single most common monogenetic cause of autism spectrum disorders in humans. FXS is caused by loss of expression of the Fragile X mental retardation protein (FMRP), an mRNA-binding protein encoded on the X chromosome involved in suppressing protein translation. Sensory processing deficits have been a major focus of studies of FXS in both humans and rodent models of FXS, but olfactory deficits remain poorly understood. Here we conducted experiments in wild-type and Fmr1 KO ( Fmr1 -/y ) mice (males) that lack expression of the gene encoding FMRP to assess olfactory circuit and behavioral abnormalities. In patch-clamp recordings conducted in slices of the olfactory bulb, output mitral cells (MCs) in Fmr1 KO mice displayed greatly enhanced excitation, as evidenced by a much higher rate of occurrence of spontaneous network-level events known as long-lasting depolarizations (LLDs). The higher probability of LLDs did not appear to reflect changes in inhibitory connections onto MCs but rather enhanced spontaneous excitation of external tufted cells (eTCs) that provide feedforward excitation onto MCs within glomeruli. In addition, in a go/no-go operant discrimination paradigm, we found that Fmr1 KO mice displayed impaired discrimination of odors in difficult tasks that involved odor mixtures but not altered discrimination of monomolecular odors. We suggest that the higher excitability of MCs in Fmr1 KO mice may impair fine odor discrimination by broadening odor tuning curves of MCs and/or altering synchronized oscillations through changes in transient inhibition. Significance Statement: Fragile X syndrome (FXS) in humans is associated with a range of debilitating deficits including aberrant sensory processing. One sensory system that has received comparatively little attention in studies in animal models of FXS is olfaction. Here, we report the first comprehensive physiological analysis of circuit defects in the olfactory bulb in the commonly-used Fmr1 knockout (KO) mouse model of FXS. Our studies indicate that Fmr1 KO alters the local excitation/inhibition balance in the bulb - similar to what Fmr1 KO does in other brain circuits - but through a novel mechanism that involves enhanced feedforward excitatory drive. Furthermore, Fmr1 KO mice display behavioral impairments in fine odor discrimination, an effect that may be explained by enhanced neural excitability.

Infusion Reactions After Receiving the Broadly Neutralizing Antibody VRC01 or Placebo to Reduce HIV-1 Acquisition: Results From the Phase 2b Antibody-Mediated Prevention Randomized Trials.

BACKGROUND: The antibody-mediated prevention (AMP) studies (HVTN 703/HPTN 081 and HVTN 704/HPTN 085) are harmonized phase 2b trials to assess HIV prevention efficacy and safety of intravenous infusion of anti-gp120 broadly neutralizing antibody VRC01. Antibodies for other indications can elicit infusion-related reactions (IRRs), often requiring premedication and limiting their application. We report on AMP study IRRs. METHODS: From 2016 to 2018, 2699 HIV-uninfected, at-risk men and transgender adults in the Americas and Switzerland (704/085) and 1924 at-risk heterosexual women in sub-Saharan Africa (703/081) were randomized 1:1:1 to VRC01 10 mg/kg, 30 mg/kg, or placebo. Participants received infusions every 8 weeks (n = 10/participant) over 72 weeks, with 104 weeks of follow-up. Safety assessments were conducted before and after infusion and at noninfusion visits. A total of 40,674 infusions were administered. RESULTS: Forty-seven participants (1.7%) experienced 49 IRRs in 704/085; 93 (4.8%) experienced 111 IRRs in 703/081 (P < 0.001). IRRs occurred more frequently in VRC01 than placebo recipients in 703/081 (P < 0.001). IRRs were associated with atopic history (P = 0.046) and with younger age (P = 0.023) in 703/081. Four clinical phenotypes of IRRs were observed: urticaria, dyspnea, dyspnea with rash, and "other." Urticaria was most prevalent, occurring in 25 (0.9%) participants in 704/085 and 41 (2.1%) participants in 703/081. Most IRRs occurred with the initial infusion and incidence diminished through the last infusion. All reactions were managed successfully without sequelae. CONCLUSIONS: IRRs in the AMP studies were uncommon, typically mild or moderate, successfully managed at the research clinic, and resolved without sequelae. Analysis is ongoing to explore potential IRR mechanisms.

Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition.

BACKGROUND: Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear. METHODS: We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC80) of acquired isolates was measured with the TZM-bl assay. RESULTS: Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], -11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, -45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC80 <1 µg per milliliter) per 100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients (estimated prevention efficacy, 75.4%; 95% CI, 45.5 to 88.9). The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates. CONCLUSIONS: VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective. (Supported by the National Institute of Allergy and Infectious Diseases; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 ClinicalTrials.gov numbers, NCT02716675 and NCT02568215.).

Feasibility and Successful Enrollment in a Proof-of-Concept HIV Prevention Trial of VRC01, a Broadly Neutralizing HIV-1 Monoclonal Antibody.

BACKGROUND: The Antibody-Mediated Prevention trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081) are the first efficacy trials to evaluate whether VRC01, a broadly neutralizing monoclonal antibody targeting the CD4-binding site of the HIV envelope protein, prevents sexual transmission of HIV-1. HVTN 704/HPTN 085 enrolled 2701 cisgender men and transgender (TG) individuals who have sex with men at 26 sites in Brazil, Peru, Switzerland, and the United States. METHODS: Participants were recruited and retained through early, extensive community engagement. Eligible participants were randomized 1:1:1 to 10 mg/kg or 30 mg/kg of VRC01 or saline placebo. Visits occurred monthly, with intravenous (IV) infusions every 8 weeks over 2 years, for a total of 10 infusions. Participants were followed for 104 weeks after first infusion. RESULTS: The median HVTN 704/HPTN 085 participant age was 28 years; 99% were assigned male sex; 90% identified as cisgender men, 5% as TG women and the remaining as other genders. Thirty-two percent were White, 15% Black, and 57% Hispanic/Latinx. Twenty-eight percent had a sexually transmitted infection at enrollment. More than 23,000 infusions were administered with no serious IV administration complications. Overall, retention and adherence to the study schedule exceeded 90%, and the dropout rate was below 10% annually (7.3 per 100 person-years) through week 80, the last visit for the primary end point. CONCLUSIONS: HVTN 704/HPTN 085 exceeded accrual and retention expectations. With exceptional safety of IV administration and operational feasibility, it paves the way for future large-scale monoclonal antibody trials for HIV prevention and/or treatment.

Food purchasing behaviour of shoppers from different South African socio-economic communities: results from grocery receipts, intercept surveys and in-supermarkets audits.

OBJECTIVE: To identify factors associated with food purchasing decisions and expenditure of South African supermarket shoppers across income levels. DESIGN: Intercept surveys were conducted, grocery receipts collated and expenditure coded into categories, with each category calculated as percentage of the total expenditure. In-supermarket food quality audit and shelf space measurements of foods such as fruits and vegetables (F&V) (healthy foods), snacks and sugar-sweetened beverages (SSB) (unhealthy foods) were also assessed. Shoppers and supermarkets were classified by high-, middle- and low-income socio-economic areas (SEA) of residential area and location, respectively. Shoppers were also classified as "out-shoppers" (persons shopping outside their residential SEA) and "in-shoppers" (persons shopping in their residential SEA). Data were analysed using descriptive analysis and ANOVA. SETTING: Supermarkets located in different SEA in urban Cape Town. PARTICIPANTS: Three hundred ninety-five shoppers from eleven purposively selected supermarkets. RESULTS: Shelf space ratio of total healthy foods v. unhealthy foods in all the supermarkets was low, with supermarkets located in high SEA having the lowest ratio but better quality of fresh F&V. The share expenditure on SSB and snacks was higher than F&V in all SEA. Food secure shoppers spent more on food, but food items purchased frequently did not differ from the food insecure shoppers. Socio-economic status and food security were associated with greater expenditure on food items in supermarkets but not with overall healthier food purchases. CONCLUSION: Urban supermarket shoppers in South Africa spent substantially more on unhealthy food items, which were also allocated greater shelf space, compared with healthier foods.

Broadly Neutralizing Antibodies for HIV Prevention.

In the last decade, over a dozen potent broadly neutralizing antibodies (bnAbs) to several HIV envelope protein epitopes have been identified, and their in vitro neutralization profiles have been defined. Many have demonstrated prevention efficacy in preclinical trials and favorable safety and pharmacokinetic profiles in early human clinical trials. The first human prevention efficacy trials using 10 sequential, every-two-month administrations of a single anti-HIV bnAb are anticipated to conclude in 2020. Combinations of complementary bnAbs and multi-specific bnAbs exhibit improved breadth and potency over most individual antibodies and are entering advanced clinical development. Genetic engineering of the Fc regions has markedly improved bnAb half-life, increased mucosal tissue concentrations of antibodies (especially in the genital tract), and enhanced immunomodulatory and Fc effector functionality, all of which improve antibodies' preventative and therapeutic potential. Human-derived monoclonal antibodies are likely to enter the realm of primary care prevention and therapy for viral infections in the near future.

Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk.

HVTN 505 is a preventative vaccine efficacy trial testing DNA followed by recombinant adenovirus serotype 5 (rAd5) in circumcised, Ad5-seronegative men and transgendered persons who have sex with men in the United States. Identified immune correlates of lower HIV-1 risk and a virus sieve analysis revealed that, despite lacking overall efficacy, vaccine-elicited responses exerted pressure on infecting HIV-1 viruses. To interrogate the mechanism of the antibody correlate of HIV-1 risk, we examined antigen-specific antibody recruitment of Fcγ receptors (FcγRs), antibody-dependent cellular phagocytosis (ADCP), and the role of anti-envelope (anti-Env) IgG3. In a prespecified immune correlates analysis, antibody-dependent monocyte phagocytosis and antibody binding to FcγRIIa correlated with decreased HIV-1 risk. Follow-up analyses revealed that anti-Env IgG3 breadth correlated with reduced HIV-1 risk, anti-Env IgA negatively modified infection risk by Fc effector functions, and that vaccine recipients with a specific FcγRIIa single-nucleotide polymorphism locus had a stronger correlation with decreased HIV-1 risk when ADCP, Env-FcγRIIa, and IgG3 binding were high. Additionally, FcγRIIa engagement correlated with decreased viral load setpoint in vaccine recipients who acquired HIV-1. These data support a role for vaccine-elicited anti-HIV-1 Env IgG3, antibody engagement of FcRs, and phagocytosis as potential mechanisms for HIV-1 prevention.

Terminalia Larval Host Fruit Reduces the Response of Bactrocera dorsalis (Diptera: Tephritidae) Adults to the Male Lure Methyl Eugenol.

Methyl eugenol (ME) is a powerful semiochemical attractant to males of the oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae), and is the keystone of detection, control, and eradication programs against this polyphagous and highly invasive tephritid pest. Despite its status as a model lure against B. dorsalis, variation among individuals in their attraction is known, independent of the generally increasing attraction with age and decreases with previous exposure. Here we report that adult male B. dorsalis that fed on Terminalia catappa L. (Myrtales: Combretaceae) (tropical almond) fruit as larvae have a significantly lower behavioral response to ME compared with wild males from Psidium guajava L. (Myrtales: Myrtaceae) or colony-reared males raised on artificial larval diet. F1 males from the tropical almond stock reared on artificial larval diet did not show reduced attraction to ME, suggesting that the lowered response of parental males (sires) results from the host fruit itself, perhaps its relatively high amount of ME. Experiments with ME added to artificial diet lend some support to this interpretation. In addition to the results above, we report on quantities of ME in three different host fruits (T. catappa, P. guajava, and Carica papaya L. (Brassicales: Caricaceae)) of B. dorsalis. This study indicates the need for further research on the effect of host fruit on adult response to lures in economically important tephritids.

Sieve analysis of breakthrough HIV-1 sequences in HVTN 505 identifies vaccine pressure targeting the CD4 binding site of Env-gp120.

Although the HVTN 505 DNA/recombinant adenovirus type 5 vector HIV-1 vaccine trial showed no overall efficacy, analysis of breakthrough HIV-1 sequences in participants can help determine whether vaccine-induced immune responses impacted viruses that caused infection. We analyzed 480 HIV-1 genomes sampled from 27 vaccine and 20 placebo recipients and found that intra-host HIV-1 diversity was significantly lower in vaccine recipients (P ≤ 0.04, Q-values ≤ 0.09) in Gag, Pol, Vif and envelope glycoprotein gp120 (Env-gp120). Furthermore, Env-gp120 sequences from vaccine recipients were significantly more distant from the subtype B vaccine insert than sequences from placebo recipients (P = 0.01, Q-value = 0.12). These vaccine effects were associated with signatures mapping to CD4 binding site and CD4-induced monoclonal antibody footprints. These results suggest either (i) no vaccine efficacy to block acquisition of any viral genotype but vaccine-accelerated Env evolution post-acquisition; or (ii) vaccine efficacy against HIV-1s with Env sequences closest to the vaccine insert combined with increased acquisition due to other factors, potentially including the vaccine vector.

Transient Peripheral Immune Activation follows Elective Sigmoidoscopy or Circumcision in a Cohort Study of MSM at Risk of HIV Infection.

BACKGROUND: Rectal and genital sampling in HIV prevention trials permits assessments at the site of HIV entry. Yet the safety and acceptability of circumcision and sigmoidoscopy (and associated abstinence recommendations) are unknown in uncircumcised men who have sex with men (MSM) at high risk of HIV infection. METHODS: Twenty-nine HIV-seronegative high-risk Peruvian MSM agreed to elective sigmoidoscopy biopsy collections (weeks 2 and 27) and circumcision (week 4) in a 28-week cohort study designed to mimic an HIV vaccine study mucosal collection protocol. We monitored adherence to abstinence recommendations, procedure-related complications, HIV infections, peripheral immune activation, and retention. RESULTS: Twenty-three (79.3%) underwent a first sigmoidoscopy, 21 (72.4%) were circumcised, and 16 (55.2%) completed a second sigmoidoscopy during the study period. All who underwent procedures completed the associated follow-up safety visits. Those completing the procedures reported they were well tolerated, and complication rates were similar to those reported in the literature. Immune activation was detected during the healing period (1 week post-sigmoidoscopy, 6 weeks post-circumcision), including increases in CCR5+CD4+T cells and α4ß7+CD4+T cells. Most participants adhered to post-circumcision abstinence recommendations whereas reduced adherence occurred post-sigmoidoscopy. CONCLUSION: Rectosigmoid mucosal and genital tissue collections were safe in high-risk MSM. Although the clinical implications of the post-procedure increase in peripheral immune activation markers are unknown, they reinforce the need to provide ongoing risk reduction counseling and support for post-procedure abstinence recommendations. Future HIV vaccine studies should also consider the effects of mucosal and tissue collections on peripheral blood endpoints in trial design and analysis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02630082.

Engaging Transgender People in NIH-Funded HIV/AIDS Clinical Trials Research.

In 2009, the National Institutes of Health recognized the need to expand knowledge of lesbian, gay, bisexual, and transgender (LGBT) health and commissioned the Institute of Medicine to report on the health of these populations in the United States. The resulting Institute of Medicine publication called for more knowledge of the health of LGBT populations, as well as improved methodologies to reach them, more LGBT-focused research, and enhanced training programs and cultural competency of physicians and researchers. Several of the National Institutes of Health-funded HIV/AIDS clinical trials networks, including the Adolescent Medicine Trials Network for HIV/AIDS Interventions, HIV Prevention Trials Network, HIV Vaccine Trials Network, and Microbicide Trials Network, have focused attention on engaging transgender (TG) individuals in research. They have identified issues that transcend the nature of research (ie, treatment or prevention, adult or adolescent) and have adopted various approaches to effectively engage the TG community. Each network has recognized the importance of developing partnerships to build trust with and seek input from TG individuals on research plans and policies. They have established standing advisory groups and convened consultations for this purpose. To ensure that trial data are reflective of the participants they are seeking to enroll, they have reviewed and revised data collection forms to incorporate the 2-step method of collecting sex at birth and gender identity as 2 independent variables, and some have also revised research protocol templates and policies for concept development to ensure that they are appropriate for the inclusion of TG participants. The networks have also initiated trainings to enhance cultural sensitivity and developed a range of materials and resources for network and clinical research site staff. They continue to identify TG-specific research needs in an effort to be more responsive to and improve the health of TG individuals, particularly related to HIV/AIDS.

Psychosocial Mediators of the Fitness-Depression Relationship Within Adolescents.

BACKGROUND: A lot of evidence showed that boys and girls are at high risk of developing major or minor depression in adolescence. Increases in physical fitness have been associated with lower levels of depressive symptoms, yet the mechanisms that underlie (or mediate) this relationship have not been thoroughly examined. METHODS: 528 boys (mean age = 12.33 years) and 507 girls (mean age = 12.32 years) drawn from a suburban school district participated. Self-report measures were used to assess the mediators (body satisfaction and social physique anxiety) and the outcome (depression); the Progressive Aerobic Cardiovascular Endurance Run (PACER) in conjunction with age, Body Mass Index (BMI), and sex were used to determine an objective estimate of cardiorespiratory fitness. Path analyses were used to test the proposed models. RESULTS: The effects of fitness on depressive symptoms were mediated through body satisfaction and social physique anxiety; 25% to 35% of the depression variance was explained. CONCLUSION: Boys' and girls' depression scores were based on the extent that their fitness levels improved their body satisfaction and lowered their social physique anxiety; body satisfaction was particularly important for girls. Thus, early adolescents' psychological well-being may be enhanced through improvements in aerobic functioning.

Positive Allosteric Modulation of Kv Channels by Sevoflurane: Insights into the Structural Basis of Inhaled Anesthetic Action.

Inhalational general anesthesia results from the poorly understood interactions of haloethers with multiple protein targets, which prominently includes ion channels in the nervous system. Previously, we reported that the commonly used inhaled anesthetic sevoflurane potentiates the activity of voltage-gated K+ (Kv) channels, specifically, several mammalian Kv1 channels and the Drosophila K-Shaw2 channel. Also, previous work suggested that the S4-S5 linker of K-Shaw2 plays a role in the inhibition of this Kv channel by n-alcohols and inhaled anesthetics. Here, we hypothesized that the S4-S5 linker is also a determinant of the potentiation of Kv1.2 and K-Shaw2 by sevoflurane. Following functional expression of these Kv channels in Xenopus oocytes, we found that converse mutations in Kv1.2 (G329T) and K-Shaw2 (T330G) dramatically enhance and inhibit the potentiation of the corresponding conductances by sevoflurane, respectively. Additionally, Kv1.2-G329T impairs voltage-dependent gating, which suggests that Kv1.2 modulation by sevoflurane is tied to gating in a state-dependent manner. Toward creating a minimal Kv1.2 structural model displaying the putative sevoflurane binding sites, we also found that the positive modulations of Kv1.2 and Kv1.2-G329T by sevoflurane and other general anesthetics are T1-independent. In contrast, the positive sevoflurane modulation of K-Shaw2 is T1-dependent. In silico docking and molecular dynamics-based free-energy calculations suggest that sevoflurane occupies distinct sites near the S4-S5 linker, the pore domain and around the external selectivity filter. We conclude that the positive allosteric modulation of the Kv channels by sevoflurane involves separable processes and multiple sites within regions intimately involved in channel gating.