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  • 1
    Online Resource
    Online Resource
    Enhanced Cross-Reactive and Polyfunctional Effector-Memory T Cell Responses by ICVAX—a Human PD1-Based Bivalent HIV-1 Gag-p41 Mosaic DNA Vaccine
    American Society for Microbiology ; 2022
    In:  Journal of Virology Vol. 96, No. 7 ( 2022-04-13)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 96, No. 7 ( 2022-04-13)
    Abstract: Vaccine-induced protective T cell immunity is necessary for HIV-1 functional cure. We previously reported that rhesus PD1-Gag-based DNA vaccination sustained simian-human immunodeficiency virus (SHIV) suppression by inducing effector-memory CD8 + T cells. Here, we investigated a human PD1-Gag-based DNA vaccine, namely, ICVAX, for clinical translation. PD1-based dendritic cell targeting and mosaic antigenic designs were combined to generate the ICVAX by fusing the human soluble PD1 domain with a bivalent HIV-1 Gag-p41 mosaic antigen. The mosaic antigen was cross-reactive with patients infected with B, CRF07/08_BC, and CRF01_AE variants. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses than mosaic Gag-p41 alone, and suppressed EcoHIV infection more efficiently. In macaques, ICVAX elicited polyfunctional effector-memory T cell responses that targeted multiple nonoverlapping epitopes of the Gag-p41 antigen. Furthermore, ICVAX manufactured following good manufacturing practices proved potent immunogenicity in macaques after biannual homologous vaccination, warranting clinical evaluation of ICVAX as an immunotherapy against HIV-1. IMPORTANCE This study presents that ICVAX, a PD1-based DNA vaccine against HIV-1, could induce broad and polyfunctional T cell responses against different HIV-1 subtypes. ICVAX encodes a recombinant antigen consisting of the human soluble PD1 domain fused with two mosaic Gag-p41 antigens. The mosaic antigens cover more than 500 HIV-1 strains circulating in China including the subtypes B/B’, CRF01_AE, and CRF07/08_BC. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses, with better EcoHIV suppression than the nontargeting mosaic Gag-p41 DNA vaccine. Moreover, both lab-generated and GMP-grade ICVAX also elicited strong polyfunctional effector-memory T cell responses in rhesus macaques with good immunogenicity against multiple nonoverlapping epitopes of the Gag-p41 antigen. This study therefore highlights the great potential to translate the PD1-based DNA vaccine approach into clinical use, and opens up new avenues for alternative HIV-1 vaccine design for HIV-1 preventive and functional cure.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.02161-21
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
    detail.hit.zdb_id: 1495529-5
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  • 2
    Online Resource
    Online Resource
    Transforming Growth Factor β Signaling Promotes HIV-1 Infection in Activated and Resting Memory CD4 + T Cells
    American Society for Microbiology ; 2023
    In:  Journal of Virology Vol. 97, No. 5 ( 2023-05-31)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 97, No. 5 ( 2023-05-31)
    Abstract: Understanding the facilitator of HIV-1 infection and subsequent latency establishment may aid the discovery of potential therapeutic targets. Here, we report the elevation of plasma transforming growth factor β (TGF-β) during acute HIV-1 infection among men who have sex with men (MSM). Using a serum-free in vitro system, we further delineated the role of TGF-β signaling in mediating HIV-1 infection of activated and resting memory CD4 + T cells. TGF-β could upregulate both the frequency and expression of the HIV-1 coreceptor CCR5, thereby augmenting CCR5-tropic viral infection of resting and activated memory CD4 + T cells via Smad3 activation. The production of live HIV-1 JR-FL upon infection and reactivation was increased in TGF-β-treated resting memory CD4 + T cells without increasing CD4 expression or inducing T cell activation. The expression of CCR7, a central memory T cell marker that serves as a chemokine receptor to facilitate T cell trafficking into lymphoid organs, was also elevated on TGF-β-treated resting and activated memory CD4 + T cells. Moreover, the expression of CXCR3, a chemokine receptor recently reported to facilitate CCR5-tropic HIV-1 infection, was increased on resting and activated memory CD4 + T cells upon TGF-β treatment. These findings were coherent with the observation that ex vivo CCR5 and CXCR3 expression on total resting and resting memory CD4 + T cells in combination antiretroviral therapy (cART)-naive and cART-treated patients were higher than in healthy individuals. Overall, the study demonstrated that TGF-β upregulation induced by acute HIV-1 infection might promote latency reservoir establishment by increasing infected resting memory CD4 + T cells and lymphoid organ homing of infected central memory CD4 + T cells. Therefore, TGF-β blockade may serve as a potential supplementary regimen for HIV-1 functional cure by reducing viral latency. IMPORTANCE Incomplete eradication of HIV-1 latency reservoirs remains the major hurdle in achieving a complete HIV/AIDS cure. Dissecting the facilitator of latency reservoir establishment may aid the discovery of druggable targets for HIV-1 cure. This study showed that the T cell immunomodulatory cytokine TGF-β was upregulated during the acute phase of infection. Using an in vitro serum-free system, we specifically delineated that TGF-β promoted HIV-1 infection of both resting and activated memory CD4 + T cells via the induction of host CCR5 coreceptor. Moreover, TGF-β-upregulated CCR7 or CXCR3 might promote HIV-1 latent infection by facilitating lymphoid homing or IP-10-mediated viral entry and DNA integration, respectively. Infected resting and central memory CD4 + T cells are important latency reservoirs. Increased infection of these cells mediated by TGF-β will promote latency reservoir establishment during early infection. This study, therefore, highlighted the potential use of TGF-β blockade as a supplementary regimen with cART in acute patients to reduce viral latency.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.00270-23
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 1495529-5
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  • 3
    Online Resource
    Online Resource
    Effects of a culturally adapted counselling service for low-income ethnic minorities experiencing mental distress: a pragmatic randomised clinical trial
    BMJ ; 2023
    In:  BMJ Mental Health Vol. 26, No. 1 ( 2023-08), p. e300788-
    Details
    In: BMJ Mental Health, BMJ, Vol. 26, No. 1 ( 2023-08), p. e300788-
    Abstract: Culturally competent early mental health interventions for ethnic minorities (EMs) with no formal diagnoses are needed. Objectives To determine whether 8–12 weeks culturally adapted counselling (CAC) is better than waiting (waitlist (WL) group) to reduce depressive and anxiety symptoms and stress levels among EMs with elevated mental distress. Methods Hong Kong EMs with mild and above-mild mental distress were randomly assigned to CAC or WL in this pragmatic, randomised, WL-controlled trial. The CAC group received the intervention after randomisation and the WL group received the intervention after 8–12 weeks (T 1 ). The prespecified primary outcomes were depressive and anxiety symptoms and stress levels measured by the Depression, Anxiety and Stress subscales of the Depression, Anxiety and Stress Scale (DASS-D, DASS-A and DASS-S, respectively) at postintervention (T 1 , 8–12 weeks). Findings A total of 120 participants were randomly assigned to either CAC (n=60) or WL (n=60), of whom 110 provided primary outcome data. At T1, CAC led to significantly lower depressive and anxiety symptom severity and stress levels compared with waiting, with unstandardised regression coefficients of −8.91 DASS-D points (95% CI −12.57 to −5.25; d=−0.90),–6.33 DASS-A points (95% CI −9.81 to −2.86; d=−0.68) and −8.60 DASS-S points (95% CI −12.14 to −5.06; d=−0.90). Conclusions CAC clinically outperformed WL for mild and above-mild levels of mental distress in EMs. Clinical implications Making CAC routinely available for EMs in community settings can reduce healthcare burden. Trial registration number NCT04811170 .
    Type of Medium: Online Resource
    ISSN: 2755-9734
    URL: Article
    DOI: 10.1136/bmjment-2023-300788
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 3160283-6
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  • 4
    Online Resource
    Online Resource
    Nasal prevention of SARS-CoV-2 infection by intranasal influenza-based boost vaccination in mouse models
    Elsevier BV ; 2022
    In:  eBioMedicine Vol. 75 ( 2022-01), p. 103762-
    Details
    In: eBioMedicine, Elsevier BV, Vol. 75 ( 2022-01), p. 103762-
    Type of Medium: Online Resource
    ISSN: 2352-3964
    URL: Article
    DOI: 10.1016/j.ebiom.2021.103762
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2799017-5
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  • 5
    Online Resource
    Online Resource
    Generation of DelNS1 Influenza Viruses: a Strategy for Optimizing Live Attenuated Influenza Vaccines
    American Society for Microbiology ; 2019
    In:  mBio Vol. 10, No. 5 ( 2019-10-29)
    Details
    In: mBio, American Society for Microbiology, Vol. 10, No. 5 ( 2019-10-29)
    Abstract: Nonstructural protein 1 (NS1) of influenza virus is a key virulence element with multifunctional roles in virus replication and a potent antagonist of host immune response. Deletion of NS1 (DelNS1) would create a safer and more extensively immunogenic live attenuated influenza virus (LAIV) vaccine. However, DelNS1 viruses are very difficult to grow in regular vaccine-producing systems, which has hampered the application of DelNS1 LAIV vaccines in humans. We have developed two master backbones of deleted-NS1 (DelNS1) viral genomes from influenza A or B viruses which contain novel adaptive mutations to support DelNS1-LAIV replication. These DelNS1-LAIVs are highly attenuated in human cells in vitro and nonpathogenic in mice but replicate well in vaccine-producing cells. Both influenza A and influenza B DelNS1 LAIVs grow better at 33°C than at 37 to 39°C. Vaccination with DelNS1 LAIV performed once is enough to provide potent protection against lethal challenge with homologous virus and strong long-lasting cross protection against heterosubtypic or antigenically distantly related influenza viruses in mice. Mechanistic investigations revealed that DelNS1-LAIVs induce cross protective neutralizing antibody and CD8 + and CD4 + T cell immunities. Importantly, it has been shown that DelNS1-LAIV can be used to enhance specific anti-influenza immunity through expression of additional antigens from the deleted-NS1 site. Generation of DelNS1 viruses which are nonpathogenic and able to grow in vaccine-producing systems is an important strategy for making highly immunogenic LAIV vaccines that induce broad cross protective immunity against seasonal and emerging influenza. IMPORTANCE Current seasonal influenza vaccines are suboptimal and low in immunogenicity and do not provide long-lasting immunity and cross protection against influenza virus strains that have antigenically drifted. More-effective influenza vaccines which can induce both humoral immunity and T cell immunity are needed. The NS1 protein of influenza virus is a virulence element and the critical factor for regulation of the host immune response during virus infection. Deletion of the NS1 protein is a strategy to make an optimal LAIV vaccine. However, DelNS1 viruses are very difficult to grow in regular vaccine-producing systems, hampering the application of DelNS1 LAIV vaccines in humans. We have generated a panel of both influenza A and influenza B DelNS1 LAIVs which are able to grow in regular vaccine-producing cells. These DelNS1 LAIV vaccines are completely nonpathogenic, exhibit potent and long-lasting immunity, and can be used to express extra viral antigen to induce cross protective immunity against seasonal and emerging influenza.
    Type of Medium: Online Resource
    ISSN: 2161-2129 , 2150-7511
    URL: Article
    DOI: 10.1128/mBio.02180-19
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2019
    detail.hit.zdb_id: 2557172-2
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  • 6
    Online Resource
    Online Resource
    Double stigma in mental health service use: Experience from ethnic minorities in Hong Kong
    SAGE Publications ; 2023
    In:  International Journal of Social Psychiatry Vol. 69, No. 6 ( 2023-09), p. 1345-1353
    Details
    In: International Journal of Social Psychiatry, SAGE Publications, Vol. 69, No. 6 ( 2023-09), p. 1345-1353
    Abstract: Ethnic minorities (EMs) typically underutilise mental health services (EMs) with issues that are not shared by the local population. Understanding the underlying perceived factors could help reduce their mental health disparities. Aims: This is a qualitative study aiming to examine the barriers that prevent EMs from seeking mental health services in Hong Kong. Methods: Six semistructured focus groups with 31 EMs who resided in Hong Kong were conducted from May 31 to June 26, 2021. The outcome measures were the themes and subthemes of perspectives on mental health service use. Results: Among 31 adults (20 [64.5%] women, 11 [35.5%] men; 17 [54.8%] aged 25–39 years) who participated, most participants self-identified as Indian (13 [41.95] ) or Pakistani (10 [32.3]). There were 16 individuals (51.6%) who reported severe or higher levels of anxiety or depressive symptoms, while 12 individuals (38.7%) reported moderate levels. Three emerging themes identified for the barriers to help-seeking for psychiatric intervention were (1) preexisting problems, (2) psychaitric service lacks cultural sensitivity and (3) personal or family limitation, while that for the recommendations to improve help-seeking had six themes: (1) improve cultural sensitivity, (2) make EM mental health practitioners available, (3) improve professional conduct, (4) improve on-site support, (5) improve financial support and (6) improve mental health promotion in schools. Conclusion: This study found that EMs in Hong Kong experience double stigma, which keeps them away from seeking professional mental health care. There were also disparities in the use of mental health services by ethnicity. The study also made recommendations for promoting EM help-seeking at the individual, governmental and community levels.
    Type of Medium: Online Resource
    ISSN: 0020-7640 , 1741-2854
    URL: Article
    DOI: 10.1177/00207640231161301
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2023
    detail.hit.zdb_id: 2066492-8
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  • 7
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    Online Resource
    A qualitative study exploring the factors influencing perceptions of mental illness and coping strategies in ethnic minority populations experiencing negative mood symptoms in Hong Kong
    Elsevier BV ; 2022
    In:  Journal of Affective Disorders Reports Vol. 9 ( 2022-07), p. 100360-
    Details
    In: Journal of Affective Disorders Reports, Elsevier BV, Vol. 9 ( 2022-07), p. 100360-
    Type of Medium: Online Resource
    ISSN: 2666-9153
    URL: Article
    DOI: 10.1016/j.jadr.2022.100360
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 3053325-9
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  • 8
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    Online Resource
    Tandem bispecific antibody prevents pathogenic SHIVSF162P3CN infection and disease progression
    Elsevier BV ; 2021
    In:  Cell Reports Vol. 36, No. 8 ( 2021-08), p. 109611-
    Details
    In: Cell Reports, Elsevier BV, Vol. 36, No. 8 ( 2021-08), p. 109611-
    Type of Medium: Online Resource
    ISSN: 2211-1247
    URL: Article
    DOI: 10.1016/j.celrep.2021.109611
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2649101-1
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  • 9
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    Online Resource
    Surprisingly Effective Priming of CD8 + T Cells by Heat-Inactivated Vaccinia Virus Virions
    American Society for Microbiology ; 2020
    In:  Journal of Virology Vol. 94, No. 20 ( 2020-09-29)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 94, No. 20 ( 2020-09-29)
    Abstract: Robust priming of CD8 + T cells by viruses is considered to require infection and de novo expression of viral antigens. A corollary of this is that inactivated viruses are thought of as being inevitably poor vaccines for eliciting these responses. In contrast to this dogma, we found that some antigens present in vaccinia virus (VACV) virions prime strong CD8 + T cell responses when the virus was rendered noninfectious by heat. More surprisingly, in some cases these responses were similar in magnitude to those primed by infectious virus administered at an equivalent dose. Next, we tested whether this was a special property of particular antigens and their epitopes and found that foreign epitopes tagged onto three different VACV virion proteins were able to elicit CD8 + T cell responses irrespective of whether the virus was viable or heat killed. Further, the polyfunctionality and cytotoxic ability of the CD8 + T cells primed by these VACVs was equivalent irrespective of whether they were administered to mice as inactivated or live viruses. Finally, we used these VACVs in prime-boost combinations of inactivated and live virus and found that priming with dead virus before a live booster was the most immunogenic regime. We conclude that VACV virions can be efficient vectors for targeting antigens to dendritic cells for effective priming of CD8 + T cells, even when rendered noninfectious and speculate that this might also be the case for other viruses. IMPORTANCE The design of viral vectored vaccines is often considered to require a trade-off between efficacy and safety. This is especially the case for vaccines that aim to induce killer (CD8 + ) T cells, where there is a well-established dogma that links infection in vaccinated individuals with effective induction of immunity. However, we found that some proteins of vaccinia virus generate strong CD8 + T cell responses even when the virus preparation was inactivated by heat prior to administration as a vaccine. We took advantage of this finding by engineering a new vaccine vector virus that could be used as an inactivated vaccine. These results suggest that vaccinia virus may be a more versatile vaccine vector than previously appreciated and that in some instances safety can be prioritized by the complete elimination of viral replication without a proportional loss of immunogenicity.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01486-20
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
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  • 10
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    Acute SARS-CoV-2 Infection Impairs Dendritic Cell and T Cell Responses
    Elsevier BV ; 2020
    In:  Immunity Vol. 53, No. 4 ( 2020-10), p. 864-877.e5
    Details
    In: Immunity, Elsevier BV, Vol. 53, No. 4 ( 2020-10), p. 864-877.e5
    Type of Medium: Online Resource
    ISSN: 1074-7613
    URL: Article
    DOI: 10.1016/j.immuni.2020.07.026
    RVK:
    XA 48754.8
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2001966-X
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