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Purpose: Sexual assault is prevalent on UK University campuses, and prevention efforts are being increased. However, at present there is limited evidence about UK students' attitudes towards sexual assault prevention and what they think should be done to effectively address the issue. The purpose of this paper is to explore these views to provide a foundation for the development of a new intervention. Design/methodology/approach: A cross-sectional anonymous online survey was completed by 515 students (73 per cent women; M age: 21.56; 79 per cent heterosexual; and 82.9 per cent white). There were quantitative questions about experiences of sexual assault, attitudes towards sexual consent and victim blaming. Qualitative data were collected regarding participants' views on what universities should do to target sexual assault. Findings: In line with previous studies, the authors found evidence of commonplace and normalised sexual assault behaviours. Women had more positive attitudes towards explicit consent than men, and were less likely to blame victims of sexual assault who had been drinking. Consent behaviour was predicted by positive views towards consent and lower levels of blaming. Themes relating to "awareness," "attitudes," "environment" and "opposition" were identified in the qualitative data. Practical implications: Findings highlight the importance of engaging with students to develop effective prevention measures. Students are likely to find university-led prevention strategies acceptable, but this topic needs to be addressed in the context of the prevailing culture, which may provide an environment where certain behaviours are tolerated. New prevention programmes need to treat the issue as one that is relevant to all students and not just target men as perpetrators and women as victims. Such strategies need to do more than treat this as an isolated issue, to which the solution is re-education about the meaning of consent. Originality/value: There is at present a lack of research evidence about UK students' views on sexual assault prevention. This exploratory survey highlights areas for consideration when developing new interventions.

Background: Psychosis is a debilitating cluster of symptoms occurring in some Alzheimer's Disease (AD) patients, and is defined by the presence of delusions and/or hallucinations. Previous studies suggest that psychosis in AD patients is associated with increased tau burden and accelerated cognitive decline. We sought to assess differences in tau burden between cognitively impaired patients with psychosis(+P) and those without psychosis(‐P). Method: Twenty‐six ADNI participants with psychosis (+P; 11.5% CDR0, 42.3% CDR0.5, 30.7% CDR1, 11.5% CDR2, 4% CDR3, 77±7yr old, 50% women, 16±3yr education, 92% White) and 26 without psychosis were matched by CDR, age, sex, education, and race (‐P; 11.5% CDR0, 42.3% CDR0.5, 30.7% CDR1, 11.5% CDR2, 4% CDR3, 77±6yr old, 54% women, 15±3yr education, 92% White). The +P group was defined based on any endorsement of hallucinations or delusions on Neuropsychiatric Inventory. Flortaucipir PET data were processed according to ADNI methods. Difference in tau burden was assessed using a paired t‐test on the ROI and voxel‐level between +P and ‐P groups in Braak regions as well as the amygdala, hippocampus, and frontal, temporal, and parietal lobes A follow‐up voxelwise t‐test was performed within the +P group between those with and without concurrent symptoms at the time of their scan. Analyses were corrected for amyloid‐level and voxel‐wise analyses were evaluated at p<0.001 without multiple comparisons correction. Result: Descriptively, participant‐level scans demonstrated a variety of tau patterns, often with right laterality. Tau was elevated for +P participants compared to ‐P in the amygdala (0.6 [0.25, 0.96]; p = 0.003) and the hippocampus (0.3 [0.04, 0.55]; p = 0.03), while marginally elevated in the frontal cortex (0.09 [‐0.002, 0.189]; p = 0.06) [Figure1]. Voxel‐wise, elevated tau was localized to the amygdala, hippocampus, thalamus, and right frontal lobe [Figure2]. Additionally, with concurrent delusion symptomatology, elevated tau was localized to Braak III/IV regions [Figure3]. Conclusion: Tau burden in the amygdala may be a potential biomarker of psychosis across the AD continuum. Right‐sided laterality is consistent with psychosis‐related structural changes and psychosis‐related tau binding needs to be assessed further. Given that early psychosis in AD is associated with faster cognitive decline, these results could inform the development of prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Background: Noninvasive yet accurate PET quantification methods are crucial for safe yet meaningful PET studies. [11C]ER176 is a PET radioligand that images neuroinflammation via the 18‐kDa translocator protein (TSPO), which is upregulated in activated microglia and has previously been a PET target in Alzheimer's disease research. Currently, the gold‐standard method for quantifying ER176 PET is kinetic modeling of the dynamic PET data using the arterial input function (AIF), which is invasive and expensive. The current study explores a pseudo‐reference region (RR) technique to noninvasively quantify ER176 scans to facilitate clinical PET studies. Method: Dynamic 90‐min [11C]ER176 PET scans were acquired in 11 participants, 5 controls (5M/0F) and 6 patients (3 MCI‐3M/0F; 3 AD‐2M/1F). Arterial blood data were collected throughout the duration of the scan and were used along with the dynamic imaging data to determine regional total volume of distribution (VT) using the two‐tissue compartment model. Standardized Uptake Value Ratio (SUVR) was calculated by normalizing the radioactivity in each region by that of the reference region (cerebellar gray matter). We explored differences across methods (AIF‐derived VT vs. RR‐derived SUVR) and across groups (controls vs. patients). Result: Within each group, the outcome measures from AIF and RR methods were well correlated (Controls: R2 = 0.986, p < 0.001; Patients: R2 = 0.983, p < 0.001; Figure 1). Both methods showed greater TSPO expression in patients compared to controls, with mean differences in the medial temporal cortex of 14.99% between groups for VT and 10.65% between groups for SUVR, but lower variance for SUVR compared to VT (Figure 2). Both quantification methods showed similar regional patterns of percent differences between groups, corresponding to tau progression along Braak staging (Figure 3). Conclusion: Results suggest that using the cerebellum, which does not accumulate amyloid plaques or tau aggregates until end‐stage disease, as a reference region for [11C]ER176 may be a valid method for quantifying differences between AD patients and controls compared to gold‐standard methodology. Regional increases in neuroinflammation are more reliable for SUVR than VT in AD‐related regions. Ongoing work includes a larger sample size to further validate noninvasive PET quantification. [ABSTRACT FROM AUTHOR]

Background: 18F‐MK6240 binds hyperphosphorylated tau protein in neurofibrillary tangles, a hallmark of Alzheimer's disease(AD); however, the tracer may also bind to other similarly structured molecules, known as off‐target binding. Off‐target binding is inconsistent across individuals and can lead to biased quantitative assessment, making it difficult to accurately identify neurofibrillary tangle pathology. We examined variable off‐target binding by performing a correlation analysis with demographic factors, vascular risk, lifestyle factors, and co‐morbidities. Methods: Ninety‐five participants (65±3yrs; 67% women; 42/58% White/Black; 66% Hispanic; 12±4yrs education) in the Northern Manhattan Study of Metabolism and Mind(NOMEM) underwent 18F‐MK6240(90‐110min) and 18F‐Florbetaben(90‐110min) PET imaging and completed surveys, including age, sex, education, exercise levels, and medical history. Only visually‐determined amyloid‐negative participants were included to increase the likelihood that elevated tau PET signal was off‐target. Tau SUVR (cerebellar gray matter reference region) was calculated for composite Braak stages (I/II, III/IV, V/VI) and two known off‐target regions, the choroid plexus and the extra‐cerebral space around the brain. The extra‐cerebral mask was generated by dilating the gray/CSF boundary of the ANTs probability map and then subtracting the brain. Percent of variance explained (r2) from general linear models are reported between off‐target regions and factors of interest. Results: Descriptively, 18F‐MK6240 off‐target binding in choroid plexus was positively correlated with SUVR in Braak stage regions I/II (r2 = 0.37;p<0.001) and III/IV (r2 = 0.44;p<0.001) to a larger extent than V/VI (r2 = 0.21;p<0.001), while off‐target binding in the extra‐cerebral space was positively correlated with Braak stages I/II (r2 = 0.07;p<0.001) to a lesser extent than III/IV (r2 = 0.13;p<0.001) and V/VI (r2 = 0.18;p<0.001), suggesting that proximity of key AD regions to off‐target regions increases the likelihood of confounded signal. Off‐target binding in the choroid plexus was elevated amongst self‐identified Hispanic participants (r2 = 0.19;p<0.001). Extra‐cerebral off‐target binding was negatively associated with participant weight (r2 = 0.12;p<0.001). Conclusion: Extra‐cerebral off‐target binding of 18F‐MK6240 may confound signal in key AD regions in amyloid‐negative participants. Off‐target binding should be accounted for regionally and methods for capturing extra‐cerebral signal are critical. Understanding the role of factors related to tracer distribution, including weight, and sociodemographic factors will enhance the quantification of 18F‐MK6240 for the early detection of neurofibrillary tangle pathology. [ABSTRACT FROM AUTHOR]

Background: Noninvasive yet accurate PET quantification methods are crucial for safe yet meaningful PET studies. [11C]ER176 is a PET radioligand that images neuroinflammation via the 18‐kDa translocator protein (TSPO), which is upregulated in activated microglia and has previously been a PET target in Alzheimer's disease research. Currently, the gold‐standard method for quantifying ER176 PET is kinetic modeling of the dynamic PET data using the arterial input function (AIF), which is invasive and expensive. The current study explores a pseudo‐reference region (RR) technique to noninvasively quantify ER176 scans to facilitate clinical PET studies. Method: Dynamic 90‐min [11C]ER176 PET scans were acquired in 11 participants, 5 controls (5M/0F) and 6 patients (3 MCI‐3M/0F; 3 AD‐2M/1F). Arterial blood data were collected throughout the duration of the scan and were used along with the dynamic imaging data to determine regional total volume of distribution (VT) using the two‐tissue compartment model. Standardized Uptake Value Ratio (SUVR) was calculated by normalizing the radioactivity in each region by that of the reference region (cerebellar gray matter). We explored differences across methods (AIF‐derived VT vs. RR‐derived SUVR) and across groups (controls vs. patients). Result: Within each group, the outcome measures from AIF and RR methods were well correlated (Controls: R2 = 0.986, p < 0.001; Patients: R2 = 0.983, p < 0.001; Figure 1). Both methods showed greater TSPO expression in patients compared to controls, with mean differences in the medial temporal cortex of 14.99% between groups for VT and 10.65% between groups for SUVR, but lower variance for SUVR compared to VT (Figure 2). Both quantification methods showed similar regional patterns of percent differences between groups, corresponding to tau progression along Braak staging (Figure 3). Conclusion: Results suggest that using the cerebellum, which does not accumulate amyloid plaques or tau aggregates until end‐stage disease, as a reference region for [11C]ER176 may be a valid method for quantifying differences between AD patients and controls compared to gold‐standard methodology. Regional increases in neuroinflammation are more reliable for SUVR than VT in AD‐related regions. Ongoing work includes a larger sample size to further validate noninvasive PET quantification. [ABSTRACT FROM AUTHOR]

Background: Adults with Down syndrome (DS) overproduce the amyloid precursor protein and nearly all evidence clinical symptoms of Alzheimer's Disease (AD) dementia in later life. Sleep disordered breathing, and specifically, obstructive sleep apnea (OSA), is common in adults with DS. OSA has been associated with risk of AD in adults without DS, and sleep disturbances may have a bidirectional relationship with AD pathology. We hypothesized that greater tau burden is associated with subsequent sleep disordered breathing in a time‐lagged design. Methods: Eighty young adults with DS (37±8 yrs, 49% women, 94% cognitively‐stable/6% MCI‐DS) from the ABC‐DS study underwent tau PET ([18F]‐AV1451, Braak stage SUVRs) and were assessed 4±0.7 years after PET using WatchPAT home sleep testing. Sleep variables included oxygen desaturation index (ODI) and apnea‐hypopnea index (AHI). General linear models assessed tau burden on later sleep impairments. Models were run in the whole group and the cognitively‐stable group alone, with and without age adjustment. Analyses were run using overall sleep measures and those in REM and non‐REM (NREM) sleep separately. Results: In unadjusted models, greater tau in early, middle, and late Braak stages were associated with a higher ODI, while greater tau in middle Braak stages was associated with a higher AHI. In the cognitively‐stable group alone, greater tau in early and middle, but not late, Braak stages were associated with a higher ODI, while greater tau in middle Braak stages was associated with a higher AHI. Adjusting for age, greater tau in late Braak stages was associated with ODI in the whole group and the cognitively‐stable group alone. Associations for overall sleep measures were driven by NREM measures (Table 1). Conclusion: In adults with DS with a high prevalence of OSA, tau burden was associated with subsequent intermittent nocturnal hypoxemia as measured by the ODI during NREM sleep. These findings align with those in adults without DS, linking AD pathology, disturbed sleep, witnessed apneas, and nocturnal hypoxemia. Both longitudinal and randomized studies are required to clarify cause‐effect relationships, including the presence of mediating and/or moderating variables such as reduction in sleep depth or continuity. [ABSTRACT FROM AUTHOR]

Background: Moderate alcohol use may provide later life cognitive benefits compared to heavy alcohol use. However, results have been mixed, with reports of both increased and decreased gray and white matter volumes with moderate drinking. Additionally, alcohol use on brain health may differ by sex and race/ethnicity. Understanding the association between brain health and moderate drinking in a representative, community‐based study will provide insight into the reported cognitive benefits. We investigated the relationship between alcohol use and total brain volume (TBV) and white matter hyperintensities (WMH) in a diverse sample of middle‐aged non‐alcohol dependent community‐dwelling adults. Method: Participants (N = 350; Mage = 54±10 years; 33 Black Men, 38 Black Women, 66 Latinx Men, 166 Latinx Women, 7 White Men, 20 White Women) from the Offspring study of Racial and Ethnic Disparities in Alzheimer's Disease, a community‐based study in Northern Manhattan, underwent structural (TBV = 1051±106cm3) and vascular (WMH = 3±4cm3) MRI. Alcohol use was assessed by the Alcohol Use Disorder Identification Test–Concise (AUDIT‐C). Individuals likely to be alcohol dependent (AUDIT‐C≥9) were excluded (n = 16). We assessed alcohol use and TBV or WMH, adjusting for age, in the overall group, and stratified by sex/gender groups, racial/ethnic groups, and sex/gender by race/ethnicity groups. Result: Overall, greater TBV was associated with younger age (‐3.5cm3 [‐4.7, ‐2.3], p = 9E‐10) and greater alcohol use (5.1cm3 [‐6.8, 10.8], p = 0.085). No associations were found within men and women separately. Within race/ethnic groups, greater alcohol use was associated with greater TBV only among Latinx (7.6cm3 [0.1, 15.3], p = 0.055). Within sex/gender by race/ethnicity groups, greater alcohol use was associated with lower TBV among White men (‐36.8cm3 [‐45.0, ‐28.5], p = 1E‐3). There were no associations with WMH. Conclusion: Moderate alcohol use was not reliably associated with brain health, but the effect was on the order of 1‐2 years of aging, in a diverse sample of middle‐aged non‐alcohol dependent community‐dwelling adults. However, moderate alcohol use may have effects on brain volume within specific sex/gender and race/ethnicity groups with implications for later life cognitive impairment. Future work should explore region specific associations, alcohol use factors (i.e., context of use, alcohol type, duration of use), and its relationship to change over time. [ABSTRACT FROM AUTHOR]

Background: Adults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer's disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, but it is unknown when cerebrovascular disease emerges across the lifespan. Methods: Adults with DS from the multisite Alzheimer's Biomarker Consortium‐Down Syndrome study (ABC‐DS; n = 241; age = 25‐72, 44±10; 45% women; 77/11/12% Cognitively‐Stable/MCI‐DS/AD dementia) underwent harmonized MRI and received a cognitive diagnosis at a consensus conference. Cross‐sectional white matter hyperintensity volume (WMH; ischemic small vessel disease), enlarged perivascular space score (PVS; impaired toxin clearance), chronic infarcts (large vessel disease), and microbleeds (hemorrhagic small vessel disease/cerebral amyloid angiopathy) were fit against piece‐wise, left null regression models with age to estimate the age inflection point at which these cerebrovascular markers emerged. The residuals for each biomarker (i.e., more than expected for their age) were then regressed on diagnosis. Results: Total WMH volume (0.01‐31.7, 4±4.6 cm3), enlarged PVS score (0‐26, 8±5), infarcts (15% have at least one), and microbleeds (12% have at least one) were present in this lifespan sample of adults with DS. There was a significant inflection point in the fourth decade of life for total WMH (37±6, p = 7E‐3), enlarged PVS (31±6, p = 3E‐6), and infarcts (31±9, p = 2E‐3), but not microbleeds (36±21, p = 0.7). Regionally, there were significant inflection points for frontal (36±6, p = 3E‐3), parietal (36±7, p = 0.02), and occipital (42±6, p = 0.02), but not temporal WMH (33±14, p = 0.3). AD dementia was associated with higher residuals in parietal (0.5±0.2, p = 0.02) and occipital WMH (0.6±0.3, p = 0.02). Conclusion: In adults with DS, there is cerebrovascular pathology on MRI that emerges around the same age as what has been reported for amyloid PET positivity and tau PET accumulation in this population. More posterior small vessel disease for a given age may arise with a diagnosis of AD, suggesting a cerebrovascular process in AD pathogenesis. Longitudinal assessment in relation to AD biomarkers, including amyloid and tau PET, will provide additional insight. [ABSTRACT FROM AUTHOR]

Background: 18F‐Florbetaben (FBB) is a PET radioligand approved for determining binary amyloid status. According to the product label, FBB images may be acquired anytime 45‐130 minutes post injection. Protocols vary in the acquisition of FBB with respect to use of Early (50‐70 minutes‐post‐injection) or Late (90‐110 minutes‐post‐injection) frames. Identifying differences between Early and Late acquisitions of FBB data could aid in image interpretation and inform efforts towards harmonization across cohorts. We evaluated inter‐rater agreement of visual reads (VR) and differences in SUVR thresholds to characterize Early vs. Late frames. Method: Fifty‐three subjects were studied including 23 patients meeting clinical criteria for amnestic mild cognitive impairment or mild Alzheimer's disease and 30 cognitively normal controls. FBB images were acquired 50‐110 min post‐injection in 5‐min frames. Images were corrected for subject motion and separated into 50‐70 and 90‐110 min time windows. Three certified readers blind to cognitive status and time window provided a binary VR for each of the 106 data sets. Global standardized uptake value ratios (SUVRs) were calculated using a cerebellar gray matter reference. An ROC‐derived SUVR cut‐off value was determined for each window using a preliminary cohort (n=23) and evaluated in a larger cohort (n = 53). Result: Inter‐reader agreement was similar in 50‐70 min and 90‐110 min scans, (Fleiss Kappa= 0.597 and 0.598). SUVRs from 50‐70 min and 90‐110 min scans were highly correlated (r = 0.99, p<0.0001). SUVRs were greater in visually positive than in visually negative scans for both time windows (Fig. 1; p<0.0001). SUVRs were still increasing at 50‐70 min but became but plateaued at 90 min. ROC‐derived SUVR cut‐off values (Fig. 1; SUVR50‐70=1.342, SUVR90‐110=1.524) largely agreed with the majority consensus VR (49/53; 92.5%) across both time frames. Conclusion: Early and Late frame data were highly correlated, and both provided robust quantitative differences between visually positive and negative Ab groups. However, imaging at 90‐110 min provides more stable SUVRs and therefore is preferred for measuring longitudinal change in amyloid burden. [ABSTRACT FROM AUTHOR]

For organisms with complex life cycles, the transition between life stages can act as a significant demographic and selective bottleneck. Variation in developmental and growth rates among individuals present in one stage (e.g. larvae), due to initial differences in parental input and/or environmental conditions experienced, can propagate to future stages (e.g. juveniles), and such 'carry-over effects' can shape fitness and phenotypic distributions within a population. However, variation in the strength of carry-over effects between life stages and the intensity of selective mortality acting on intrinsic variation, and how these might be mediated by environmental variability in natural systems, is poorly known. Here, we evaluate variation in the strength to which larval growth histories can mediate juvenile performance (growth and survival), for a reef fish ( Forsterygion lapillum) common to rocky reefs of New Zealand. We used otoliths to reconstruct demographic histories of recently settled fish that were sampled across cohorts, sites and microhabitats. We quantified sources of variation in the strength of carry-over effects and selective mortality that operate on larval growth histories. We found overall that individuals that grew fast as larvae tended to experience proportional growth advantages as juveniles. However, the strength of growth advantages being maintained into the juvenile period varied among cohorts, sites and microhabitats. Specifically, a stronger growth advantage was found on some microhabitats (e.g. mixed stands of macroalgae) relative to others (e.g. monocultures of Carpophyllum maschalocarpum) for some cohorts and sites only. For other cohorts and sites, the degree of coupling between larval and juvenile growth rates was either indistinguishable between microhabitats or else not evident. Similarly, the intensity of growth-based selective mortality varied among cohorts, sites and microhabitats: for the cohort and site where carry-over effects differed between microhabitats, we also observed difference in the intensity to which fish with rapid larval growth rates were favoured. Overall, our results highlight how this spatial and temporal patchiness in extrinsic factors can interact with intrinsic variation of recruiting individuals to have a major influence on the resulting distribution of juveniles and their phenotypic traits. [ABSTRACT FROM AUTHOR]

Butyrate is an abundant metabolite produced by gut microbiota. While butyrate is a known histone deacetylase inhibitor that activates expression of many genes involved in immune system pathways, its effects on virus infections and on the antiviral type I interferon (IFN) response have not been adequately investigated. We found that butyrate increases cellular infection with viruses relevant to human and animal health, including influenza virus, reovirus, HIV-1, human metapneumovirus, and vesicular stomatitis virus. Mechanistically, butyrate suppresses levels of specific antiviral IFN stimulated gene (ISG) products, such as RIG-I and IFITM3, in human and mouse cells without inhibiting IFN-induced phosphorylation or nuclear translocation of the STAT1 and STAT2 transcription factors. Accordingly, we discovered that although butyrate globally increases baseline expression of more than 800 cellular genes, it strongly represses IFN-induced expression of 60% of ISGs and upregulates 3% of ISGs. Our findings reveal that there are differences in the IFN responsiveness of major subsets of ISGs depending on the presence of butyrate in the cell environment, and overall identify a new mechanism by which butyrate influences virus infection of cells. [ABSTRACT FROM AUTHOR]

Background: Psychosis in Alzheimer's disease (AD) is associated with worse outcomes, yet no established biomarkers exist for early diagnosis and intervention. We compared tau PET burden across older individuals with and without psychotic symptoms., Methods: [ 18 F]AV1451 tau PET binding was compared between 26 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with psychotic symptoms (delusions and/or hallucinations) and 26 ADNI subjects without psychotic symptoms, matched for age, sex, race/ethnicity, and clinical severity. Tau was assessed on a region-of-interest and voxel level, corrected for amyloid PET burden., Results: Tau was greater in individuals with psychotic symptoms in the amygdala in region-of-interest analyses, and in amygdala, thalamus, putamen, right hippocampus, right entorhinal cortex, and right frontal cortex in voxel-based analyses. When considering different onset and type of psychotic symptoms, tau binding was greatest in those with concurrent delusions., Conclusion: Elevated tau in limbic regions may be relevant for psychotic symptoms in aging and AD.

Infection of rhesus macaques with simian-human immunodeficiency viruses (SHIVs) is the preferred model system for vaccine development because SHIVs encode human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Envs)-a key target of HIV-1 neutralizing antibodies. Since the goal of vaccines is to prevent new infections, SHIVs encoding circulating HIV-1 Env are desired as challenge viruses. Development of such biologically relevant SHIVs has been challenging, as they fail to infect rhesus macaques, mainly because most circulating HIV-1 Envs do not use rhesus CD4 (rhCD4) receptor for viral entry. Most primary HIV-1 Envs exist in a closed conformation and occasionally transit to a downstream, open conformation through an obligate intermediate conformation. Here, we provide genetic evidence that open Env conformations can overcome the rhCD4 entry barrier and increase replication of SHIVs in rhesus lymphocytes. Consistent with prior studies, we found that circulating HIV-1 Envs do not use rhCD4 efficiently for viral entry. However, by using HIV-1 Envs with single amino acid substitutions that alter their conformational state, we found that transitions to intermediate and open Env conformations allow usage of physiological levels of rhCD4 for viral entry. We engineered these single amino acid substitutions in the transmitted/founder HIV-1 BG505 Envs encoded by SHIV-BG505 and found that open Env conformation enhances SHIV replication in rhesus lymphocytes. Lastly, CD4-mediated SHIV pulldown, sensitivity to soluble CD4, and fusogenicity assays indicated that open Env conformation promotes efficient rhCD4 binding and viral-host membrane fusion. These findings identify the conformational state of HIV-1 Env as a major determinant for rhCD4 usage, viral fusion, and SHIV replication. IMPORTANCE Rhesus macaques are a critical animal model for preclinical testing of HIV-1 vaccine and prevention approaches. However, HIV-1 does not replicate in rhesus macaques, and thus, chimeric simian-human immunodeficiency viruses (SHIVs), which encode HIV-1 envelope glycoproteins (Envs), are used as surrogate challenge viruses to infect rhesus macaques for modeling HIV-1 infection. Development of SHIVs encoding Envs from clinically relevant, circulating HIV-1 variants has been extremely challenging, as such SHIVs replicate poorly, if at all, in rhesus lymphocytes. This is most probably because many circulating HIV-1 Envs do not use rhesus CD4 efficiently for viral entry. In this study, we identified conformational state of HIV-1 envelope as a key determinant for rhesus CD4 usage, viral-host membrane fusion, and SHIV replication in rhesus lymphocytes.