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Background: Canada’s population is aging, with nearly forty percent of Canadians aged 50 years or more. As the population ages, unique challenges related to health are becoming evident, including increasing rates of sexually transmitted and bloodborne infections. Understanding the epidemiology of HIV in older adults is important to guide prevention and control programs. Objective: To assess trends in newly diagnosed cases of HIV in Canada among those aged 50 years and older (≥50 years) and those aged less than 50 (<50 years), and to compare their basic demographic characteristics and exposure categories for the period of 2008 to 2017. Methods: National surveillance of HIV is conducted by the Public Health Agency of Canada through voluntary submission of data by provincial/territorial public health authorities. Descriptive analyses were conducted on reported cases of HIV between January 1, 2008, to December 31, 2017 to compare the demographic profiles and exposure category for the two age groups. Results: Between 2008 and 2017, the proportion of newly diagnosed HIV cases among those ≥50 years increased from 15.1% to 22.8%. The HIV diagnosis rates for both older males and older females increased over time, with a relatively higher increase for females. A higher proportion of newly diagnosed HIV cases were male in the older group (81.2%) compared to the younger group (74.6%). Among both older and younger males, the most common exposure category for HIV was being gay, bisexual and other men who have sex with men (gbMSM), followed by heterosexual contact and injection drug use; however, the relative proportions varied by age with the gbMSM category being higher in the <50 group. Conclusion: In Canada, over 20% of all newly diagnosed cases of HIV are now in people 50 years of age and older. HIV testing and prevention initiatives, historically aimed at younger populations, may not have the same impact for older populations. These data can be used to inform future public health actions designed to address HIV in older populations. [ABSTRACT FROM AUTHOR]

Education is key to behavioural adoption and acceptability of health interventions. We evaluated the impact of an educational intervention administered 1:1 to individuals incarcerated in four Canadian federal prisons on COVID-19 vaccine uptake. Eligible individuals (those who had refused all COVID-19 vaccines) were randomized 2:1 to receive the educational intervention or not (control group); those who received the intervention completed questionnaires assessing COVID-19 vaccine-related knowledge, attitudes, and beliefs pre- and post-educational intervention. The primary and secondary outcome measures were COVID-19 vaccine uptake and vaccine confidence, respectively. Between May 3 and September 9, 2022, 202 participants were randomized to receive the intervention, of whom 127 (63 %) agreed to participate. Participants who were randomized to the intervention had higher COVID-19 vaccine uptake vs. the control group (5 % vs 1 %, p = 0.046). COVID-19 vaccine-related knowledge, attitudes, and beliefs improved post-intervention. Education increases COVID-19 vaccine uptake and confidence among people in Canadian federal correctional facilities., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [TZ, HP, CD, OV, NEB, LW, PR, SD, MM, ST, MB, MM and RK have no conflicts of interest to declare. NK reports research funding from Gilead Sciences, advisory fees from Gilead Sciences, ViiV Healthcare, Merck and Abbvie, and speaker fees from Gilead Sciences and Merck.]., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Maximizing uptake of SARS-CoV-2 vaccines among people in prison is essential in mitigating future outbreaks. We aimed to determine factors associated with willingness to receive SARS-CoV-2 vaccination before vaccine availability., Methods: We chose 3 Canadian federal prisons based on their low uptake of influenza vaccines in 2019-2020. Participants completed a self-administered questionnaire on knowledge, attitude and beliefs toward vaccines. The primary outcome was participant willingness to receive a SARS-CoV-2 vaccine, measured using a 5-point Likert scale to the question, "If a safe and effective COVID-19 vaccine becomes available in prison, how likely are you to get vaccinated?" We calculated the association of independent variables (age, ethnicity, chronic health conditions, 2019-2020 influenza vaccine uptake and prison security level), identified a priori, with vaccine willingness using logistic regression and crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs)., Results: We recruited 240 participants from Mar. 31 to Apr. 19, 2021 (median age 46 years; 19.2% female, 25.8% Indigenous). Of these, 178 (74.2%) were very willing to receive a SARS-CoV-2 vaccine. Participants who received the 2019-2020 influenza vaccine (adjusted OR 5.20, 95% CI 2.43-12.00) had higher odds of vaccine willingness than those who did not; those who self-identified as Indigenous (adjusted OR 0.27, 95% CI 0.11-0.60) and in medium- or maximum-security prisons (adjusted OR 0.36, 95% CI 0.12-0.92) had lower odds of vaccine willingness than those who identified as white or those in minimum-security prisons, respectively., Interpretation: Most participants were very willing to receive vaccination against SARS-CoV-2 before vaccine roll-out. Vaccine promotion campaigns should target groups with low vaccine willingness (i.e., those who have declined influenza vaccine, identify as Indigenous or reside in high-security prisons)., Competing Interests: Competing interests: Joseph Cox reports research funding from ViiV Healthcare, Gilead Sciences and the Canadian Institutes of Health Research (CIHR), as well as remuneration for advisory work from ViiV Healthcare, Gilead Sciences and Merck Canada. Nicole Basta reports research funding from the National Institutes of Health, CIHR and McGill University’s Interdisciplinary Initiative in Infection and Immunity (MI4). Bertrand Lebouché reports research funding, consulting fees and honoraria from Gilead Sciences, Merck and ViiV Healthcare. Nadine Kronfli reports research funding from Gilead Sciences, as well as advisory fees and speaker fees from Gilead Sciences, ViiV Healthcare, Merck and AbbVie., (© 2022 CMA Impact Inc. or its licensors.)

Background: Vaccine uptake rates have been historically low in correctional settings. To better understand vaccine hesitancy in these high-risk settings, we explored reasons for COVID-19 vaccine refusal among people in federal prisons., Methods: Three maximum security all-male federal prisons in British Columbia, Alberta, and Ontario (Canada) were chosen, representing prisons with the highest proportions of COVID-19 vaccine refusal. Using a qualitative descriptive design and purposive sampling, individual semi-structured interviews were conducted with incarcerated people who had previously refused at least one COVID-19 vaccine until data saturation was achieved. An inductive-deductive thematic analysis of audio-recorded interview transcripts was conducted using the Conceptual Model of Vaccine Hesitancy., Results: Between May 19-July 8, 2021, 14 participants were interviewed (median age: 30 years; n = 7 Indigenous, n = 4 visible minority, n = 3 White). Individual-, interpersonal-, and system-level factors were identified. Three were particularly relevant to the correctional setting: 1) Risk perception: participants perceived that they were at lower risk of COVID-19 due to restricted visits and interactions; 2) Health care services in prison: participants reported feeling "punished" and stigmatized due to strict COVID-19 restrictions, and failed to identify personal benefits of vaccination due to the lack of incentives; 3) Universal distrust: participants expressed distrust in prison employees, including health care providers., Interpretation: Reasons for vaccine refusal among people in prison are multifaceted. Educational interventions could seek to address COVID-19 risk misconceptions in prison settings. However, impact may be limited if trust is not fostered and if incentives are not considered in vaccine promotion., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: NEB is supported by a Canada Research Chair (Tier 2) in Infectious Disease Prevention. BL holds a Canadian Institutes for Health Research, Strategy for Patient-Oriented Research Mentorship Chair in Innovative Clinical Trials for HIV Care and also supported by a career award, LE 250, from the Quebec’s Ministry of Health for researchers in Family Medicine. BL reports research funding from Gilead Sciences, Merck and ViiV Health care, advisory fees from Gilead Sciences, ViiV Health care, Merck, and speaker fees from Gilead Sciences, ViiV Health care and Merck. JC has research funding from ViiV Health care and Gilead Sciences, and reports remuneration for advisory work (ViiV Health care, Gilead Sciences and Merck Canada). NK is supported by a career award from the Fonds de Recherche Québec – Santé (FRQ-S; Junior 1). NK reports research funding from Gilead Sciences, advisory fees from Gilead Sciences, ViiV Health care, Merck and Abbvie, and speaker fees from Gilead Sciences and Merck. DOP, OV, JW, HP, SEM, NEB, and SJI have declared no competing interests.

Introduction: Canadian correctional institutions have been prioritized for COVID-19 vaccination given the multiple outbreaks that have occurred since the start of the pandemic. Given historically low vaccine uptake, we aimed to explore barriers and facilitators to COVID-19 vaccination acceptability among people incarcerated in federal prisons., Methods: Three federal prisons in Quebec, Ontario, and British Columbia (Canada) were chosen based on previously low influenza vaccine uptake among those incarcerated. Using a qualitative design, semi-structured interviews were conducted with a diverse sample (gender, age, and ethnicity) of incarcerated people. An inductive-deductive analysis of audio-recorded interview transcripts was conducted to identify and categorize barriers and facilitators within the Theoretical Domains Framework (TDF)., Results: From March 22-29, 2021, a total of 15 participants (n = 5 per site; n = 5 women; median age = 43 years) were interviewed, including five First Nations people and six people from other minority groups. Eleven (73%) expressed a desire to receive a COVID-19 vaccine, including two who previously refused influenza vaccination. We identified five thematic barriers across three TDF domains: social influences (receiving strict recommendations, believing in conspiracies to harm), beliefs about consequences (believing that infection control measures will not be fully lifted, concerns with vaccine-related side effects), and knowledge (lack of vaccine-specific information), and eight thematic facilitators across five TDF domains: environmental context and resources (perceiving correctional employees as sources of outbreaks, perceiving challenges to prevention measures), social influences (receiving recommendations from trusted individuals), beliefs about consequences (seeking individual and collective protection, believing in a collective "return to normal", believing in individual privileges), knowledge (reassurance about vaccine outcomes), and emotions (having experienced COVID-19-related stress)., Conclusions: Lack of information and misinformation were important barriers to COVID-19 vaccine acceptability among people incarcerated in Canadian federal prisons. This suggests that educational interventions, delivered by trusted health care providers, may improve COVID-19 vaccine uptake going forward., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DL, DO-P, HP, OV, JW, NEB, SEM, and SJI have not conflicts of interest to declare. BL reports research funding from Gilead Sciences, Merck and ViiV Healthcare, advisory fees from Gilead Sciences, ViiV Healthcare, Merck, and speaker fees from Gilead Sciences, ViiV Healthcare and Merck. JC has research funding from ViiV Healthcare and Gilead Sciences, and reports remuneration for advisory work (ViiV Healthcare, Gilead Sciences and Merck Canada). NK reports research funding from Gilead Sciences, advisory fees from Gilead Sciences, ViiV Healthcare, Merck and Abbvie, and speaker fees from Gilead Sciences and Merck., (© 2022 The Authors.)

Background: Simulations aim to supplement historic teacher-centric methods by facilitating experiential, self-guided learning and the application of students' knowledge in a controlled environment. The objective of our study is to describe the methodology of developing and facilitating simulations, and to assess their effectiveness as an educational tool for global health training., Methods: We describe the methodology used by Global Health Sim between October 2016 and March 2019 to design and facilitate simulations for participants at the high school through graduate school levels, and at conferences and online. Using a mixed-methods evaluation design, we assessed self-reported quantitative measures of content knowledge before and after participating in the simulation and different aspects of the simulation experience. We also conducted a qualitative thematic analysis of the experience and lessons learned as reported by evaluation respondents., Results: We conducted a total of 20 simulations on six unique topics for 213 evaluation respondents. Self-reported knowledge of the topic increased an average of 3.3 points on a 10-point scale (4.1-7.4) and the seven aspects of the experience were rated highly (3-5 points on a 5-point Likert scale). Thematic analysis revealed an increased understanding of the complexity of global health problems and strategies for effectively responding to issues in a multidisciplinary manner., Conclusions: Respondents valued the opportunity to learn about the complexities of responding to global health events, which confirmed that simulations can be utilized as teaching tools for students and professionals. Further research is required to assess the long-term educational impact of simulations in global health., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interest., (© International Association of Medical Science Educators 2020.)

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with a febrile illness as well as severe complications, including microcephaly and Guillain-Barré Syndrome. Antibody cross-reactivity between flaviviruses has been documented, and in regions where ZIKV is circulating, dengue virus (DENV) is also endemic, leaving the potential that previous exposure to DENV could alter clinical features of ZIKV infection. To investigate this, we performed a retrospective case-control study in which we compared Canadian travellers who had been infected with ZIKV and had serological findings indicating previous DENV or other flavivirus exposure ( n = 16) to those without any previous exposure ( n = 44). Patient samples were collected between February 2016 and September 2017 and submitted to Public Health Ontario for testing. ZIKV infection was determined using real-time RT-PCR and antibodies against DENV were identified by the plaque-reduction neutralization test. The mean time from symptom onset to sample collection was 5 days for both groups; the magnitude of viremia was not statistically different (Ct values: 35.6 vs. 34.9, p -value = 0.2). Clinical scores were also similar. Our findings indicate that previous DENV or other flavivirus exposure did not result in greater viremia or a higher illness score., Competing Interests: The authors declare no conflict of interest.

Background: The Public Health Agency of Canada reviewed sexual transmission of HIV between serodiscordant partners to support examination of the criminal justice system response to HIV nondisclosure by the Department of Justice of Canada. We sought to determine HIV transmission risk when an HIV-positive partner takes antiretroviral therapy, has a suppressed viral load or uses condoms., Methods: We conducted an overview and systematic review update by searching MEDLINE and other databases (Jan. 1, 2007, to Mar. 13, 2017; and Nov. 1, 2012, to Apr. 27, 2017, respectively). We considered reviews and studies about absolute risk of sexual transmission of HIV between serodiscordant partners to be eligible for inclusion. We used A Measurement Tool to Assess Systematic Reviews (AMSTAR) for review quality, Quality in Prognosis Studies (QUIPS) instrument for study risk of bias and then the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence across studies. We calculated HIV incidence per 100 person-years with 95% confidence intervals (CIs). We assigned risk categories according to potential for and evidence of HIV transmission., Results: We identified 12 reviews. We selected 1 review to estimate risk of HIV transmission for condom use without antiretroviral therapy (1.14 transmissions/100 person-years, 95% CI 0.56-2.04; low risk). We identified 11 studies with 23 transmissions over 10 511 person-years with antiretroviral therapy (0.22 transmissions/ 100 person-years, 95% CI 0.14-0.33; low risk). We found no transmissions with antiretroviral therapy and a viral load of less than 200 copies/mL across consecutive measurements 4 to 6 months apart (0.00 transmissions/100 person-years, 95% CI 0.00-0.28; negligible risk regardless of condom use)., Interpretation: Based on high-quality evidence, there is a negligible risk of sexual transmission of HIV when an HIV-positive sex partner adheres to antiretroviral therapy and maintains a suppressed viral load of less than 200 copies/mL measured every 4 to 6 months. Sexual transmissions of HIV have occurred when viral load was more than 200 copies/mL with antiretroviral therapy or condoms alone were used, although the risk remains low. These findings will help to support patient and clinician decision-making, affect public health case management and contact tracing, and inform justice system responses to HIV nondisclosure., Competing Interests: Competing interests: None declared., (© 2018 Joule Inc. or its licensors.)

: Despite major advances in HIV testing, early detection of infection at the point of care (PoC) remains a key challenge. Although rapid antibody PoC and laboratory-based nucleic acid amplification tests dominate the diagnostics market, the viral capsid protein p24 is recognized as an alternative early virological biomarker of infection. However, the detection of ultra-low levels of p24 at the PoC has proven challenging. Here we review the landscape of p24 diagnostics to identify knowledge gaps and barriers and help shape future research agendas. Five hundred and seventy-four research articles to May 2018 that propose or evaluate diagnostic assays for p24 were identified and reviewed. We give a brief history of diagnostic development, and the utility of p24 as a biomarker in different populations such as infants, the newly infected, those on preexposure prophylaxis and self-testers. We review the performance of commercial p24 assays and consider elements such as immune complex disruption, resource-poor settings, prevalence, and assay antibodies. Emerging and ultrasensitive assays are reviewed and show a number of promising approaches but further translation has been limited. We summarize studies on the health economic benefits of using antigen testing. Finally, we speculate on the future uses of high-performance p24 assays, particularly, if available in self-test format.

Introduction: We aimed to establish how effective community-based HIV testing services (HTS), including home and community location based (non-health facility) HIV testing services (HB-/CLB-HTS), are in improving care in sub-Saharan Africa (SSA), with a view to achieving the 90-90-90 targets., Methods: We conducted a systematic review of published literature from 2007-17 which reported on the proportion of individuals who link-to-care and/or initiate ART after detection with HIV through community-based testing. A meta-analysis was deemed inappropriate due to heterogeneity in reporting., Results and Discussion: Twenty-five care cascades from 6 SSA countries were examined in the final review- 15 HB-HTS, 8 CLB-HTS, 2 combined HB-/CLB-HTS. Proportions linked-to-care over 1-12 months ranged from 14-96% for HB-HTS and 10-79% for CLB-HTS, with most studies reporting outcomes over short periods (3 months). Fewer studies reported ART-related outcomes following community-based testing and most of these studies included <50 HIV-positive individuals. Proportions initiating ART ranged from 23-93%. One study reported retention on ART (76% 6 months after initiation). Viral suppression 3-12 months following ART initiation was 77-85% in three studies which reported this. There was variability in definitions of outcomes, numerators/denominators and observation periods. Outcomes varied between studies even for similar time-points since HTS. The methodological inconsistencies hamper comparisons. Previously diagnosed individuals appear more likely to link-to-care than those who reported being newly-diagnosed. It appears that individuals diagnosed in the community need time before they are ready to link-to-care/initiate ART. Point-of-care (POC) CD4-counts at the time of HTS did not achieve higher proportions linking-to-care or initiating ART. Similarly, follow-up visits to HIV-positive individuals did not appear to enhance linkage to care overall., Conclusion: This systematic review summarises the available data on linkage to care/ART initiation following community-based detection of HIV, to help researchers and policy makers evaluate findings. The available evidence suggests that different approaches to community-based HTS including HB-HTS and CLB-HTS, are equally effective in achieving linkage to care and ART initiation among those detected. Engagement and support for newly diagnosed individuals may be key to achieving all three UNAIDS 90-90-90 targets. We also recommend that standardised measures of reporting of steps on the cascade of care are needed, to measure progress against targets and compare across settings., Competing Interests: The authors have declared that no competing interests exist.

Background: Although direct-acting antivirals can achieve sustained virological response rates greater than 90% in Hepatitis C Virus (HCV) infected persons, at present the majority of HCV-infected individuals remain undiagnosed and therefore untreated. While there are a wide range of HCV serological tests available, there is a lack of formal assessment of their diagnostic performance. We undertook a systematic review and meta-analysis to evaluate he diagnostic accuracy of available rapid diagnostic tests (RDT) and laboratory based EIA assays in detecting antibodies to HCV., Methods: We used the PRISMA checklist and Cochrane guidance to develop our search protocol. The search strategy was registered in PROSPERO (CRD42015023567). The search focused on hepatitis C, diagnostic tests, and diagnostic accuracy within eight databases (MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, SCOPUS, Literatura Latino-Americana e do Caribe em Ciências da Saúde and WHO Global Index Medicus. Studies were included if they evaluated an assay to determine the sensitivity and specificity of HCV antibody (HCV Ab) in humans. Two reviewers independently extracted data and performed a quality assessment of the studies using the QUADAS tool. We pooled test estimates using the DerSimonian-Laird method, by using the software R and RevMan. 5.3., Results: A total of 52 studies were identified that included 52,673 unique test measurements. Based on five studies, the pooled sensitivity and specificity of HCV Ab rapid diagnostic tests (RDTs) were 98% (95% CI 98-100%) and 100% (95% CI 100-100%) compared to an enzyme immunoassay (EIA) reference standard. High HCV Ab RDTs sensitivity and specificity were observed across screening populations (general population, high risk populations, and hospital patients) using different reference standards (EIA, nucleic acid testing, immunoblot). There were insufficient studies to undertake subanalyses based on HIV co-infection. Oral HCV Ab RDTs also had excellent sensitivity and specificity compared to blood reference tests, respectively at 94% (95% CI 93-96%) and 100% (95% CI 100-100%). Among studies that assessed individual oral RDTs, the eight studies revealed that OraQuick ADVANCE® had a slightly higher sensitivity (98%, 95% CI 97-98%) compared to the other oral brands (pooled sensitivity: 88%, 95% CI 84-92%)., Conclusions: RDTs, including oral tests, have excellent sensitivity and specificity compared to laboratory-based methods for HCV antibody detection across a wide range of settings. Oral HCV Ab RDTs had good sensitivity and specificity compared to blood reference standards.

Background: Chronic Hepatitis B Virus (HBV) infection is characterised by the persistence of hepatitis B surface antigen (HBsAg). Expanding HBV diagnosis and treatment programmes into low resource settings will require high quality but inexpensive rapid diagnostic tests (RDTs) in addition to laboratory-based enzyme immunoassays (EIAs) to detect HBsAg. The purpose of this review is to assess the clinical accuracy of available diagnostic tests to detect HBsAg to inform recommendations on testing strategies in 2017 WHO hepatitis testing guidelines., Methods: The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using 9 databases. Two reviewers independently extracted data according to a pre-specified plan and evaluated study quality. Meta-analysis was performed. HBsAg diagnostic accuracy of rapid diagnostic tests (RDTs) was compared to enzyme immunoassay (EIA) and nucleic-acid test (NAT) reference standards. Subanalyses were performed to determine accuracy among brands, HIV-status and specimen type., Results: Of the 40 studies that met the inclusion criteria, 33 compared RDTs and/or EIAs against EIAs and 7 against NATs as reference standards. Thirty studies assessed diagnostic accuracy of 33 brands of RDTs in 23,716 individuals from 23 countries using EIA as the reference standard. The pooled sensitivity and specificity were 90.0% (95% CI: 89.1, 90.8) and 99.5% (95% CI: 99.4, 99.5) respectively, but accuracy varied widely among brands. Accuracy did not differ significantly whether serum, plasma, venous or capillary whole blood was used. Pooled sensitivity of RDTs in 5 studies of HIV-positive persons was lower at 72.3% (95% CI: 67.9, 76.4) compared to that in HIV-negative persons, but specificity remained high. Five studies evaluated 8 EIAs against a chemiluminescence immunoassay reference standard with a pooled sensitivity and specificity of 88.9% (95% CI: 87.0, 90.6) and 98.4% (95% CI: 97.8, 98.8), respectively. Accuracy of both RDTs and EIAs using a NAT reference were generally lower, especially amongst HIV-positive cohorts., Conclusions: HBsAg RDTs have good sensitivity and excellent specificity compared to laboratory immunoassays as a reference standard. Sensitivity of HBsAg RDTs may be lower in HIV infected individuals.

Background: The development of envelope-specific neutralizing antibodies that can interfere with viral entry into target cells is important for the development of an HIV-1 vaccine. Another means of blocking viral entry is through the use of entry inhibitors such as the CCR5 inhibitor maraviroc (MVC), which can also repel cell-free virus particles from the cell surface. For this reason, we hypothesized that exposure to entry inhibitors might alter viral infectiousness and sensitivity to antibody-mediated neutralization., Methods: The CCR5-tropic HIV-1 variants BaL, AD8, and CC 1/85 were used to infect PM-1 cells in the presence of 2 entry inhibitors, enfuvirtide and MVC. After 4 hours, culture fluids were ultrafiltered and the infectiousness and susceptibility to broadly neutralizing antibodies (2F5, 4E10, 2G12, b12, VRC01, PG9) of viruses exposed to these entry inhibitors were assessed using TZM-bl cells., Results: Viruses exposed to the entry inhibitor MVC exhibited lower infectiousness than controls. Enfuvirtide exposure increased AD8 sensitivity to 2F5, 4E10, VRC01, and b12 and increased BaL sensitivity to 4E10 while lowering BaL sensitivity to b12 and VRC01. MVC-exposed BaL became less susceptible to the gp120-specific antibodies b12, 2G12, and VRC01., Conclusions: Exposure to entry inhibitors altered HIV-1 infectiousness and sensitivity to gp120-specific neutralizing antibodies. This alteration of entry inhibitor-exposed virus has implications for the development of future entry inhibitors and for vaccine development.