Earth at risk: An urgent call to end the age of destruction and forge a just and sustainable future.

Human development has ushered in an era of converging crises: climate change, ecological destruction, disease, pollution, and socioeconomic inequality. This review synthesizes the breadth of these interwoven emergencies and underscores the urgent need for comprehensive, integrated action. Propelled by imperialism, extractive capitalism, and a surging population, we are speeding past Earth's material limits, destroying critical ecosystems, and triggering irreversible changes in biophysical systems that underpin the Holocene climatic stability which fostered human civilization. The consequences of these actions are disproportionately borne by vulnerable populations, further entrenching global inequities. Marine and terrestrial biomes face critical tipping points, while escalating challenges to food and water access foreshadow a bleak outlook for global security. Against this backdrop of Earth at risk, we call for a global response centered on urgent decarbonization, fostering reciprocity with nature, and implementing regenerative practices in natural resource management. We call for the elimination of detrimental subsidies, promotion of equitable human development, and transformative financial support for lower income nations. A critical paradigm shift must occur that replaces exploitative, wealth-oriented capitalism with an economic model that prioritizes sustainability, resilience, and justice. We advocate a global cultural shift that elevates kinship with nature and communal well-being, underpinned by the recognition of Earth's finite resources and the interconnectedness of its inhabitants. The imperative is clear: to navigate away from this precipice, we must collectively harness political will, economic resources, and societal values to steer toward a future where human progress does not come at the cost of ecological integrity and social equity.

Contraception and intersection with HIV services in 11 high HIV burden sub-Saharan African countries: Results from the population-based HIV Impact Assessment cross-sectional studies conducted from 2015 to 2018.

OBJECTIVE: The United Nations' Sustainable Development Goal 3.7.1 addresses the importance of family planning. The objective of this paper is to provide information on family planning to policymakers to help increase access to contraceptive methods to women in sub-Saharan Africa. METHODS: We analyzed data from the Population-based HIV Impact Assessment studies conducted in 11 sub-Saharan African countries from 2015 to 2018 to assess the relationship between HIV services and family planning. Analyses were restricted to women aged 15-49 years who reported being sexually active within the past 12 months and had data on contraceptive use. RESULTS: Approximately 46.4% of participants reported using any form of contraception; 93.6% of whom used modern contraceptives. Women with a positive HIV status were more likely to use contraceptives (P < 0.0001) than HIV-negative women. Unmet need was higher among women who were confirmed to be HIV-negative in Namibia, Uganda, and Zambia than confirmed to be positive. Women aged 15-19 years used contraception less than 40% of the time. CONCLUSION: This analysis highlights crucial gaps in progress among HIV-negative and young women (aged 15-19 years). To provide access to modern contraception for all women, programs and governments need to focus on women who desire but do not have access to these family planning resources.

Autoimmune conditions in the World Trade Center general responder cohort: A nested case-control and standardized incidence ratio analysis.

BACKGROUND: The World Trade Center (WTC) general responder cohort (GRC) was exposed to environmental toxins possibly associated with increased risk of developing autoimmune conditions. OBJECTIVES: Two study designs were used to assess incidence and risks of autoimmune conditions in the GRC. METHODS: Three clinically trained professionals established the status of possible GRC cases of autoimmune disorders adhering to diagnostic criteria, supplemented, as needed, by specialists' review of consenting responders' medical records. Nested case-control analyses using conditional logistic regression estimated the risk associated with high WTC exposure (being in the 9/11/2001 dust cloud or ≥median days' response worked) compared with low WTC exposure (all other GRC members'). Four controls were matched to each case on age at case diagnosis (±2 years), sex, race/ethnicity, and year of program enrollment. Sex-specific and sensitivity analyses were performed. GRC age- and sex-adjusted standardized incidence ratios (SIRs) were compared with the Rochester Epidemiology Project (REP). Complete REP inpatient and outpatient medical records were reviewed by specialists. Conditions meeting standardized criteria on ≥2 visits were classified as REP confirmed cases. RESULTS: Six hundred and twenty-eight responders were diagnosed with autoimmune conditions between 2002 and 2017. In the nested case-control analyses, high WTC exposure was not associated with autoimmune domains and conditions (rheumatologic domain odds ratio [OR] = 1.03, 95% confidence interval [CI] = 0.77, 1.37; rheumatoid arthritis OR = 1.12, 95% CI = 0.70, 1.77). GRC members had lower SIR than REP. Women's risks were generally greater than men's. CONCLUSIONS: The study found no statistically significant increased risk of autoimmune conditions with WTC exposures.

Graphene-Ta2O5 heterostructure enabled high performance, deep-ultraviolet to mid-infrared photodetection.

Ultrafast, high sensitive, low cost photodetectors operating at room temperature sensitive from the deep-ultraviolet to mid-infrared region remain a significant challenge in optoelectronics. Achievements in traditional semiconductors using cryogenic operation and complicated growth processes prevent the cost-effective and practical application of broadband detectors. Alternative methods towards high-performance photodetectors, hybrid graphene-semiconductor colloidal quantum dots have been intensively explored. However, the operation of these photodetectors has been limited by the spectral bandwidth and response time. Here, we have demonstrated hybrid photodetectors operating from the deep-ultraviolet to the mid-infrared region with high sensitivity and ultrafast response by coupling graphene with a p-type semiconductor photosensitizer, nitrogen-doped Ta2O5 thin film. Photons with energy higher than the energy of the defect centers release holes from neutral acceptors. The holes are transferred into graphene, leaving behind ionized acceptors. Due to the advantage of two-dimensional heterostructure including homogeneous thickness, extending in a two-dimensional plane, large contact area between the N-Ta2O5 thin film and graphene, and the high mobility of carriers in graphene, holes are transferred rapidly to graphene and recirculated during the long lifetime of ionized acceptors. The photodetectors achieve a high photo-responsivity (up to 3.0 × 106 A W-1), ultrafast rise time (faster than 20 ns), and a specific detectivity (up to ∼2.2 × 1012 Jones). The work provides a method for achieving high-performance optoelectronics operating in the deep-ultraviolet to mid-infrared region.

Mental health mediators of subjective cognitive concerns among World Trade Center responders.

Decline in cognitive functioning among rescue and recovery workers who responded in the aftermath of the September 11, 2001, World Trade Center (WTC) attacks is of emerging interest. Responders are vulnerable to cognitive decline from exposure to airborne toxins present at the WTC site, as well as from WTC-related mental and physical health conditions. To better understand the relationship between occupational WTC exposure, mental health, physical health and subjective cognitive functioning, we examined the mediating role of health status in the association between exposure and subjective cognitive concerns in a multi-site, longitudinal investigation of the WTC General Responder cohort (n = 16,380 responders; n = 58,575 visits) for the period 2002-2015. Through latent class analyses, we identified a four-level marker of cognitive concerns based on information from a Self-Administered Mental Health Questionnaire. Using generalized linear mixed models with random intercepts, we observed that a higher intensity WTC exposure composite was associated with greater cognitive concerns, and that this association was operating almost entirely through mental health comorbidities, not physical health comorbidities. In fully adjusted models, the inclusion of probable depression, anxiety, PTSD and use of psychotropic medications attenuated the association between highest WTC exposure and greatest cognitive concerns. Physical health did not appear to be on the pathway between WTC exposure and cognitive concerns. Understanding the underlying sources of cognitive concerns may help identify vulnerable members of the General Responder cohort and potentially aid clinical decision-making, such as treatment choice and enhanced screening options. Earlier diagnosis and symptom treatment may help preserve functional independence.

Anaerobic-aerobic biofilm-based digestion of chemical contaminants of emerging concern (CEC) and pathogen indicator organisms in synthetic wastewater.

The efficacy of biofilm based anaerobic-aerobic treatment to reduce caffeine, carbamazepine, and three estrogens (Estrone (E1), 17ß-estradiol (E2), and 17α-ethynylestradiol (EE2)), as well as E. coli (CN-13) and F+ specific coliphage (MS2), from synthetic wastewater was investigated. Results showed no observable reduction of carbamazepine by either anaerobic or aerobic biofilms over a dosing period of 51-days followed by an additional 23 days of observation. Caffeine, by contrast, was reduced by 11.09% in the upflow anaerobic packed bed biofilm reactor (UAnPBBR) and by 91.90% in the aerobic trickling filter biofilm reactor (TF). Estrone (E1) and 17ß-estradiol (E2) showed minimal reduction in the UAnPBBR but 99.67% reduction in the TF, while EE2 was reduced 1.62% in the AnPBBR and 20.36% in the TF. On average, a 3-log reduction of E. coli (CN-13) and a 1-log reduction of F+ specific coliphage (MS2) concentration was observed across the overall reactor system.

An intravaginal ring that releases three antiviral agents and a contraceptive blocks SHIV-RT infection, reduces HSV-2 shedding, and suppresses hormonal cycling in rhesus macaques.

Women globally need access to multipurpose prevention technologies (MPTs) that prevent human immunodeficiency virus (HIV), sexually transmitted infections that increase HIV acquisition/transmission risk, and unintended pregnancy. Seeking an MPT with activity against HIV, herpes simplex virus-2 (HSV-2), and human papillomavirus (HPV), we developed a prototype intravaginal ring (IVR), the MZCL IVR, which released the antiviral agents MIV-150, zinc acetate, and carrageenan (MZC for short) and the contraceptive levonorgestrel (LNG). Previously, we showed that an MZC gel has potent activity against immunodeficiency viruses, HSV-2, and HPV and that the MZCL (MZC with LNG) IVR releases all four components in macaques in vivo at levels associated with efficacy. Vaginal fluid from treated macaques has in vitro activity against HIV, HSV-2, and HPV. Herein, we assessed the ability of the MZCL IVR to protect macaques against repeated co-challenge with HSV-2 and SHIV-RT (simian immunodeficiency virus [SIV] containing the reverse transcriptase gene from HIV) and prevent hormonal cycling. We evaluated in vivo drug release in co-challenged macaques by measuring drug levels in blood and vaginal fluid and residual drug levels in used IVRs. The MZCL IVR significantly prevented SHIV-RT infection, reduced HSV-2 vaginal shedding, and prevented cycling. No non-nucleoside HIV reverse transcriptase inhibitor (NNRTI)-resistant SHIV was detected in macaques that became infected after continuous exposure to MZC from the IVR. Macaques wearing the MZCL IVR also had carrageenan levels in vaginal fluid expected to protect from HPV (extrapolated from mice) and LNG levels in blood associated with contraceptive efficacy. The MZCL IVR is a promising MPT candidate that warrants further development.

Bio-oil extraction of Jatropha curcas with ionic liquid co-solvent: Fate of biomass protein.

The fate of oil-seed biomass protein has been tracked through all steps of a multi-phase extraction process using an ionic liquid based co-solvent system previously demonstrated to extract bio-oil and phorbol esters and to recover fermentable sugars from Jatropha oil seed. These analyses, however, did not address the fate of biomass protein. This work demonstrated that the majority of protein (∼86%) tracked with the biomass with the balance lost to co-solvent (∼12%) and methanol (∼2%) washes. A significant portion of the ionic liquid remained with the treated biomass and required aggressive methanol washes to recover. A system analysis showed a net-positive energy balance and thus the potential of this system to produce both bio-oil and protein-rich toxin-free biomass. While these results further support Jatropha as an oil seed crop, the additional costs of solvent recovery will need to be addressed if commercialization is to be realized.

MZC Gel Inhibits SHIV-RT and HSV-2 in Macaque Vaginal Mucosa and SHIV-RT in Rectal Mucosa.

The Population Council's microbicide gel MZC (also known as PC-1005) containing MIV-150 and zinc acetate dihydrate (ZA) in carrageenan (CG) has shown promise as a broad-spectrum microbicide against HIV, herpes simplex virus (HSV), and human papillomavirus. Previous data show antiviral activity against these viruses in cell-based assays, prevention of vaginal and rectal simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) infection, and reduction of vaginal HSV shedding in rhesus macaques and also excellent antiviral activity against HSV and human papillomavirus in murine models. Recently, we demonstrated that MZC is safe and effective against SHIV-RT in macaque vaginal explants. Here we established models of ex vivo SHIV-RT/HSV-2 coinfection of vaginal mucosa and SHIV-RT infection of rectal mucosa in macaques (challenge of rectal mucosa with HSV-2 did not result in reproducible tissue infection), evaluated antiviral activity of MZC, and compared quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay readouts for monitoring SHIV-RT infection. MZC (at nontoxic dilutions) significantly inhibited SHIV-RT in vaginal and rectal mucosas and HSV-2 in vaginal mucosa when present during viral challenge. Analysis of SHIV-RT infection and MZC activity by 1-step simian immunodeficiency virus gag quantitative RT-PCR and p27 enzyme-linked immunosorbent assay demonstrated similar virus growth dynamics and MZC activity by both methods and higher sensitivity of quantitative RT-PCR. Our data provide more evidence that MZC is a promising dual compartment multipurpose prevention technology candidate.

TOMOGRAPHIC RELATIONSHIPS BETWEEN RETINAL NEOVASCULARIZATION AND THE POSTERIOR VITREOUS IN PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: To describe anatomical relationships of retinal neovascular complexes (NVCs) and the posterior vitreous in proliferative diabetic retinopathy using spectral domain optical coherence tomography. METHODS: Cross-sectional study. Neovascular complexes were imaged using spectral domain optical coherence tomography in 51 eyes of 37 patients. The relationship of NVCs to the posterior vitreous cortex and posterior vitreous spaces, such as the premacular bursa, prevascular vitreous fissures, and perimacular cisterns, was analyzed. RESULTS: In the 77 NVCs evaluated, 61 (79%) had grown along the outer surface of the posterior hyaloid face, and vitreoschisis was present in 37 (48%). The "wolf's jaw" configuration was present in 9% and resulted from NVC arising from the arcades and proliferating along the posterior hyaloid face. By contrast, NVCs that invaded the bursa originated from smaller venous tributaries more distant from the arcades. The premacular bursa and prevascular vitreous fissure/perimacular cistern were invaded infrequently, respectively, in 15% and 38% (P = 0.137). CONCLUSION: Tomographic analysis of diabetic NVCs showed that most NVCs arise and grow along the posterior hyaloid face and that vitreoschisis is more prevalent than what has been found in ultrasound studies. The wolf's jaw configuration does not seem to result from the invasion of the bursa, as previously suggested.

Kinetic Measurements for Enzyme Immobilization.

Enzyme kinetics is the study of the chemical reactions that are catalyzed by enzymes, with a focus on their reaction rates. The study of an enzyme's kinetics considers the various stages of activity, reveals the catalytic mechanism of this enzyme, correlates its value to assay conditions, and describes how a drug or a poison might inhibit the enzyme. Victor Henri initially reported that enzyme reactions were initiated by a bond between the enzyme and the substrate. By 1910, Michaelis and Menten were advancing their work by studying the kinetics of an enzyme saccharase which catalyzes the hydrolysis of sucrose into glucose and fructose. They published their analysis and ever since the Michaelis-Menten equation has been used as the standard to describe the kinetics of many enzymes. Unfortunately, soluble enzymes must generally be immobilized to be reused for long times in industrial reactors. In addition, other critical enzyme properties have to be improved like stability, activity, inhibition by reaction products, and selectivity towards nonnatural substrates. Immobilization is by far the chosen process to achieve these goals.Although the Michaelis-Menten approach has been regularly adapted to the analysis of immobilized enzyme activity, its applicability to the immobilized state is limited by the barriers the immobilization matrix places upon the measurement of compounds that are used to model enzyme kinetics. That being said, the estimated value of the Michaelis-Menten coefficients (e.g., V max, K M) can be used to evaluate effects of immobilization on enzyme activity in the immobilized state when applied in a controlled manner. In this review enzyme activity and kinetics are discussed in the context of the immobilized state, and a few novel protocols are presented that address some of the unique constraints imposed by the immobilization barrier.

A Novel Microbicide/Contraceptive Intravaginal Ring Protects Macaque Genital Mucosa against SHIV-RT Infection Ex Vivo.

Women need multipurpose prevention products (MPTs) that protect against sexually transmitted infections (STIs) and provide contraception. The Population Council has developed a prototype intravaginal ring (IVR) releasing the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 (M), zinc acetate (ZA), carrageenan (CG) and levonorgestrel (LNG) (MZCL IVR) to protect against HIV, HSV-2, HPV and unintended pregnancy. Our objective was to evaluate the anti-SHIV-RT activity of MZCL IVR in genital mucosa. First, macaque vaginal tissues were challenged with SHIV-RT in the presence of (i) MIV-150 ± LNG or (ii) vaginal fluids (VF); available from studies completed earlier) collected at various time points post insertion of MZCL and MZC IVRs. Then, (iii) MZCL IVRs (vs. LNG IVRs) were inserted in non-Depo Provera-treated macaques for 24h and VF, genital biopsies, and blood were collected and tissues were challenged with SHIV-RT. Infection was monitored with one step SIV gag qRT-PCR or p27 ELISA. MIV-150 (LCMS/MS, RIA), LNG (RIA) and CG (ELISA) were measured in different compartments. Log-normal generalized mixed linear models were used for analysis. LNG did not affect the anti-SHIV-RT activity of MIV-150 in vitro. MIV-150 in VF from MZC/MZCL IVR-treated macaques inhibited SHIV-RT in vaginal mucosa in a dose-dependent manner (p<0.05). MIV-150 in vaginal tissue from MZCL IVR-treated animals inhibited ex vivo infection relative to baseline (96%; p<0.0001) and post LNG IVR group (90%, p<0.001). No MIV-150 dose-dependent protection was observed, likely because of high MIV-150 concentrations in all vaginal tissue samples. In cervical tissue, MIV-150 inhibited infection vs. baseline (99%; p<0.05). No cervical tissue was available for MIV-150 measurement. Exposure to LNG IVR did not change tissue infection level. These observations support further development of MZCL IVR as a multipurpose prevention technology to improve women's sexual and reproductive health.

In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa.

Our recent phase 1 trial demonstrated that PC-1005 gel containing 50 µM MIV-150, 14 mM zinc acetate dihydrate, and carrageenan (CG) applied daily vaginally for 14 days is safe and well tolerated. Importantly, cervicovaginal lavage fluid samples (CVLs) collected 4 or 24 h after the last gel application inhibited HIV-1 and human papillomavirus (HPV) in cell-based assays in a dose-dependent manner (MIV-150 for HIV-1 and CG for HPV). Herein we aimed to determine the anti-HIV and anti-herpes simplex virus 2 (anti-HSV-2) activity of PC-1005 in human cervical explants after in vitro exposure to the gel and to CVLs from participants in the phase 1 trial. Single HIV-1BaL infection and HIV-1BaL-HSV-2 coinfection explant models were utilized. Coinfection with HSV-2 enhanced tissue HIV-1BaL infection. In vitro exposure to PC-1005 protected cervical mucosa against HIV-1BaL (up to a 1:300 dilution) in single-challenge and cochallenge models. CG gel (PC-525) provided some barrier effect against HIV-1BaL at the 1:100 dilution in a single-challenge model but not in the cochallenge model. Both PC-1005 and PC-525 at the 1:100 dilution inhibited HSV-2 infection, pointing to a CG-mediated protection. MIV-150 and CG in CVLs inhibited HIV (single-challenge or cochallenge models) and HSV-2 infections in explants in a dose-dependent manner (P < 0.05). Stronger inhibition of HIV-1 infection by CVLs collected 4 h after the last gel administration was observed compared to infection detected in the presence of baseline CVLs. The anti-HIV and anti-HSV-2 activity of PC-1005 gel in vitro and CVLs in human ectocervical explants supports the further development of PC-1005 gel as a broad-spectrum on-demand microbicide.

Development of a high-throughput ß-Gal-based neutralization assay for quantitation of herpes simplex virus-neutralizing antibodies in human samples.

Measurement of neutralizing antibodies against herpes simplex virus (HSV) is important for evaluation of candidate vaccines. The established plaque-reduction neutralization assay is time consuming, labor intensive, and difficult to validate and transfer. Here, we describe the characterization of a HSV-neutralization assay based on the expression of a reporter gene, ß-galactosidase (ß-Gal). Using previously constructed HSV-ß-Gal recombinant viruses, HSV-2/Gal and HSV-1/tk12, we developed a colorimetric ß-Gal-based neutralization assay that is sensitive and highly reproducible, and performed in less than 48h. HSV-1 and HSV-2 neutralizing titers measured by the ß-Gal-based neutralization assay were equivalent to those obtained by a plaque reduction neutralization assay. Intra- and inter-assay precision studies demonstrated that the ß-Gal-based assay was repeatable and yielded low and acceptable variation. In addition, comparison of HSV-2 neutralizing antibody (NAb) titers measured in two independent laboratories by two unique ß-Gal-based assays showed a highly significant correlation (r=0.9499, p<0.0001) between the two assays. The new assay will serve as an important tool both for preclinical and clinical trials of new HSV vaccines.

Life cycle assessment comparison of activated sludge, trickling filter, and high-rate anaerobic-aerobic digestion (HRAAD).

This paper conducts a comparative assessment of the environmental impacts of three methods of treating primary clarifier effluent in wastewater treatment plants (WWTPs) through life cycle assessment methodology. The three technologies, activated sludge (AS), high rate anaerobic-aerobic digestion (HRAAD), and trickling filter (TF), were assessed for treatment of wastewater possessing average values of biochemical oxygen demand and total suspended solids of 90 mg L(-1) and 70 mg L(-1), respectively. The operational requirements to process the municipal wastewater to effluent that meets USEPA regulations have been calculated. The data for the AS system were collected from the East Honolulu WWTP (Hawaii, USA) while data for the HRAAD system were collected from a demonstration-scale system at the same plant. The data for the TF system were estimated from published literature. Two different assessment methods have been used in this study: IMPACT 2002+ and TRACI 2. The results show that TF had the smallest environmental impacts and that AS had the largest, while HRAAD was in between the two but with much reduced impacts compared with AS. Additionally, the study shows that lower sludge production is the greatest advantage of HRAAD for reducing environmental impacts compared with AS.

Multipurpose Prevention Approaches with Antiretroviral-Based Formulations.

We compared the preclinical safety and efficacy of tenofovir (TFV) 1% gel with that of MZC gel [containing 50 µM MIV-150, 14 mM Zn(O2CCH3)2(H2O)2, and 3% carrageenan] through a series of in vitro, ex vivo, and in vivo assays. The two gels showed good antiviral therapeutic indexes (50% cytotoxic concentration/50% effective concentration ratios; range, >25 to 800). MZC showed greater anti-simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) activity than TFV 1% gel in rhesus macaque vaginal explants. MZC protected mice from vaginal herpes simplex virus 2 (HSV-2) challenge (P < 0.0001), but the TFV 1% gel did not.

Volume-Rendering Optical Coherence Tomography Angiography of Macular Telangiectasia Type 2.

PURPOSE: To evaluate the vascular structure of eyes with macular telangiectasia type 2 (MacTel2) using volume-rendered optical coherence tomography angiography (OCTA). DESIGN: Retrospective cross-sectional study. PARTICIPANTS: A total of 14 consecutive patients (20 eyes) with MacTel2 who had a signal strength score ≥55 and could maintain fixation during the scan process. METHODS: The eyes were scanned using optical coherence tomography with split-spectrum amplitude decorrelation techniques to derive flow information. Data were extracted and used to create volume-rendered images of the retinal vasculature that could be rotated about 3 different axes for evaluation. MAIN OUTCOME MEASURES: Descriptive appraisal of the vascular abnormalities associated with MacTel2. RESULTS: Vessels posterior to the outer boundary of the deep retinal plexus were secondary to retinal thinning, vascular invasion, or a combination of both. These vessels had the same shape and distribution as the late staining seen during conventional fluorescein angiography. Lateral contraction in the temporal macula in 5 eyes created an appearance of vessels radiating from a central locus, which was the site of a right angle vein. Loss of macular tissue as part of the disease process led to a central amalgamation of the inner vascular plexus and the deep vascular plexus, which appeared to be in a state of decline. Subretinal neovascularization originated from the retinal circulation but involved not only the subretinal space but also could infiltrate the remaining, thinned, retina. CONCLUSIONS: Volume rendering of OCTA information preserves the 3-dimensional relationships among retinal vascular layers and provides opportunities to visualize retinal vascular abnormalities in unprecedented detail. The retinal vascular leakage and invasion in MacTel2 may arise as a consequence of loss of control with depletion of Müller cells and exposure of the remaining retinal vessels to the more hypoxic environment near the inner segments of the photoreceptors.

MIV-150/zinc acetate gel inhibits cell-associated simian-human immunodeficiency virus reverse transcriptase infection in a macaque vaginal explant model.

The transmission of both cell-free and cell-associated immunodeficiency viruses has been demonstrated directly in multiple animal species and possibly occurs in humans, as suggested by genotyping of the infecting human immunodeficiency virus (HIV) in acutely infected women and in semen from their partners. Therefore, a microbicide may need to block both mechanisms of HIV transmission to achieve maximum efficacy. To date, most of the preclinical evaluation of candidate microbicides has been performed using cell-free HIV. New models of mucosal transmission of cell-associated HIV are needed to evaluate candidate microbicide performance. The MIV-150/zinc acetate/carrageenan (MZC) gel protects Depo-Provera-treated macaques against cell-free simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) infection when applied vaginally up to 8 h before challenge. We recently demonstrated the potent activity of MZC gel against cell-free SHIV-RT in macaque vaginal explants. In the current study, we established a cell-associated SHIV-RT infection model of macaque vaginal tissues and tested the activity of MZC gel in this model. MZC gel protected tissues against cell-associated SHIV-RT infection when present at the time of viral exposure or when applied up to 4 days prior to viral challenge. These data support clinical testing of the MZC gel. Overall, our ex vivo model of cell-associated SHIV-RT infection in macaque vaginal mucosa complements the cell-free infection models, providing tools for prioritization of products that block both modes of HIV transmission.