HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusio...HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusion inhibitors with excellent pharmacokinetic properties are still needed for development of anti-HIV drugs. We found that all-hydrocarbon staples inserted in SC34 EK could not only enhance the inhibitory activity of inhibitors against HIV-1, but also improve protease resistance. Further study revealed that SC34 EK-1 containing a staple was a potent fusion inhibitor with IC;value of 0.04-6.4 nmol/L towards diverse HIV-1 subtypes and half-life value of 112 min against protease hydrolysis. X-ray crystallography studies indicated that introduction of a hydrocarbon staple in SC34 EK could make the amino acid at the interaction surface form perfect conformation to promote inhibitor peptide interacting with target.展开更多
An effcient formal synthesis of（＋）-tashiromine was achieved by employing an intermolecular asymmetric Mannich-type reaction as the key step.Concurrently,a novel approach toward the total synthesis of（＋）-stemoami...An effcient formal synthesis of（＋）-tashiromine was achieved by employing an intermolecular asymmetric Mannich-type reaction as the key step.Concurrently,a novel approach toward the total synthesis of（＋）-stemoamide through dyotropic rearrangement of 3,4-cis-b-lactone was also explored.展开更多
Severely immunosuppressed AIDS patients with recurrent opportunistic infections(Ols)represent an unmet medical need even in the era of antiretroviral therapy(ART).Here we report the development of a human leukocyte an...Severely immunosuppressed AIDS patients with recurrent opportunistic infections(Ols)represent an unmet medical need even in the era of antiretroviral therapy(ART).Here we report the development of a human leukocyte antigen(HLA)-mismatched allogeneic adaptive immune therapy(AAIT)for severely immunosuppressed AIDS patients.Twelve severely immunosuppressed AIDS patients with severe Ols were enrolled in this single-arm study.Qualified donors received subcutaneous recombinant granulocyte-colony-stimulating factor twice daily for 4-5 days to stimulate hematopoiesis.Peripheral blood mononuclear cells were collected from these donors via leukapheresis and transfused into the coupled patients.Clinical,immunological,and virological parameters were monitored during a 12-month follow-up period.We found AAIT combined with ART was safe and well-tolerated at the examined doses and transfusion regimen in all 12 patients.Improvements in clinical symptoms were evident throughout the study period.All patients exhibited a steady increase of peripheral CD4^(+)T cells from a median 10.5 to 207.5 cells/μl.Rapid increase in peripheral CD8^(+)T-cell count from a median 416.5 to 1206.5 cells/μl was found in the first 90 days since initiation of AAIT.In addition,their inflammatory cytokine levels and HIV RNA viral load decreased.A short-term microchimerism with donor cells was found.There were no adverse events associated with graft-versus-host disease throughout the study period.Overall,AAIT treatment was safe,and might help severely immunosuppressed AIDS patients to achieve a better immune restoration.A further clinical trial with control is necessary to confirm the efficacy of AAIT medication.展开更多
Remarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I(HIV-1)through antiretroviral therapy.However,vaccine development has remained challengin...Remarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I(HIV-1)through antiretroviral therapy.However,vaccine development has remained challenging.Recent discoveries in broadly neutralizing monoclonal antibodies(bNAbs)has led to the development of multiple novel vaccine approaches for inducing bNAbs-like antibody response.Structural and dynamic studies revealed several vulnerable sites and states of the HIV-1 envelop glycoprotein(Env)during infection.Our review aims to highlight these discoveries and rejuvenate our endeavor in HIV-1 vaccine design and development.展开更多
VRC01, a broadly neutralizing monoclonal antibody （bnmAb）, can neutralize a diverse array of HIV-1 isolates by mimicking CD4 binding to the envelope glycoprotein gpl20. We have previously demonstrated the presence o...VRC01, a broadly neutralizing monoclonal antibody （bnmAb）, can neutralize a diverse array of HIV-1 isolates by mimicking CD4 binding to the envelope glycoprotein gpl20. We have previously demonstrated the presence of VRC01-resistant strains in an HIV-1 infected patient during antiretroviral therapy. Here, we report follow-up studies of two subsequent samples from the same patient. With genetic and phenotypic analysis of over 70 full-length molecular clones of the HIV-1 envelope, we show that VRC01-resistant HIV-1 continued to exist and change in its proportion of the infecting virus during treatment with a highly active antiretroviral therapy. Consistent with our previous observation, the resistant phenotype was associated with a single asparagine residue at position 460 （N460）, a potential N-linked glycosylation site in the V5 region. The persistence and continuing evolution of VRC01-resistant HIV-1 in vivo presents a great challenge to our future preventative and therapeutic interventions based on VRC01.展开更多
Dear Editor,Antibody-dependent enhancement（ADE）has long been recognized for dengue virus（DENV）in vitro and in vivo.It is now clear that antibodies to DENV can also enhance Zika virus（ZIKV）infection in vitro,and ...Dear Editor,Antibody-dependent enhancement（ADE）has long been recognized for dengue virus（DENV）in vitro and in vivo.It is now clear that antibodies to DENV can also enhance Zika virus（ZIKV）infection in vitro,and vice versa（Dejnirattisai et al.,2016;Stettler et al.,2016）.The characteristics of enhancing antibodies,however,remain elusive.展开更多
Antibody response plays a critical role in protective immunity against SARS-CoV-2 infection and disease progression[1–3].As the current COVID-19 pandemic continues to rage around the world,there is growing concern th...Antibody response plays a critical role in protective immunity against SARS-CoV-2 infection and disease progression[1–3].As the current COVID-19 pandemic continues to rage around the world,there is growing concern that new SARS-CoV-2 variants may emerge that are antigenically distinct from the prototype strain,rendering the current antibody and vaccine strategies ineffective[4–15].展开更多
The Fourth Symposium of Grand Challenges on HIV was held on December 28,2023,in Beijing,China.Fu-Sheng Wang(the National Clinical Research Center for Infectious Disease)and Zhang Linqi(Tsinghua University School of Me...The Fourth Symposium of Grand Challenges on HIV was held on December 28,2023,in Beijing,China.Fu-Sheng Wang(the National Clinical Research Center for Infectious Disease)and Zhang Linqi(Tsinghua University School of Medicine),as the chairpersons of the conference,organized this meeting.At the conference,almost all famous top scientists and clinicians in Acquired Immune Deficiency Syndrome(AIDS)from China(Figure 1)were invited to present and discuss the most recent advances in the science of a cure for human immunodeficiency virus(HIV)and share new technologies,new therapies and new achievements,and hoping to make major breakthroughs in AIDS intervention and AIDS functional cure.展开更多
HIV,the virus that causes acquired immunodeficiency syndrome(AIDS),can integrate into the genome of host cells and form latent reservoirs,making it undetectable by the immune system.Two studies published in Nature in ...HIV,the virus that causes acquired immunodeficiency syndrome(AIDS),can integrate into the genome of host cells and form latent reservoirs,making it undetectable by the immune system.Two studies published in Nature in January 2020 reported a'shock and kill*strategy that aimed to activate the transcription of the latent reservoirs and render infected cells vulnerable to elimination by the immune system.Both study groups described interventions that were the most effective activation to date and were also reproducible.Nixon et al.used a drug called AZD5582 to activate the transcription of nuclear factor kappa B(NF-/cB),a major inducer of HIV-1 gene expression[1]McBrien et al.combined two immunological interventions by first depleting CD8 T cells(immune cells that reduce the level of viral transcription)followed by treatment with a drug called N-803,which activated HIV-1 transcription[2].In addition to these advances,these two studies also demonstrated the conceptual and technical challenges of pharmacological latency reversal.展开更多
Human immunodeficiency virus(HIV)-1 infection creates a persistent latent reservoir even after antiretroviral therapy,which is the main barrier to HIV cure.One of the most explored strategies is the use of latent reve...Human immunodeficiency virus(HIV)-1 infection creates a persistent latent reservoir even after antiretroviral therapy,which is the main barrier to HIV cure.One of the most explored strategies is the use of latent reversal agents(LRAs)to activate HIV latent reservoirs,followed by immunotherapy to remove infected cells.Immunomodulatory LRAs have the dual advantage of activating viral latency and promoting immune cell elimination of HIV-infected cells.The emergence of novel immunotherapies has also enhanced the possibility ofHIV clearance.Here we review the activity and potential mechanisms of immunomodulatory agonists and immunotherapies.The possible combinational strategies to achieve HIV functional cure and the problems encountered using this approach are discussed.展开更多
基金supported by the National Natural Science Foundation of China (No. 21602121)the Natural Science Foundation of Inner Mongolia (No. 2016BS0201)+2 种基金the Inner Mongolia Autonomous Region Higher School Youth scientific Talents Support Project(No. NJYT-17-B22)the Research Funds of Baotou Medical College(Nos. BSJJ201620, BYJJ-YF 201707)Beijing Tongzhou District Science and Technology Project(No. KJ2017CX039-14)
文摘HIV fusion inhibitors are promising therapeutic agents for AIDS treatment. One fusion inhibitor has been approved as anti-HIV drug, while more of them are in preclinical studies or clinical trials. Highly active fusion inhibitors with excellent pharmacokinetic properties are still needed for development of anti-HIV drugs. We found that all-hydrocarbon staples inserted in SC34 EK could not only enhance the inhibitory activity of inhibitors against HIV-1, but also improve protease resistance. Further study revealed that SC34 EK-1 containing a staple was a potent fusion inhibitor with IC;value of 0.04-6.4 nmol/L towards diverse HIV-1 subtypes and half-life value of 112 min against protease hydrolysis. X-ray crystallography studies indicated that introduction of a hydrocarbon staple in SC34 EK could make the amino acid at the interaction surface form perfect conformation to promote inhibitor peptide interacting with target.
基金the financial supports from Beijing Natural Science Foundation (No. 2132037)NSFC (Nos. 21102081, 21272133)+1 种基金New Teachers’ Fund for Doctor Stations Ministry of Education (No. 20110002120011)Scientifc Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education (No. 20121027968)
文摘An effcient formal synthesis of（＋）-tashiromine was achieved by employing an intermolecular asymmetric Mannich-type reaction as the key step.Concurrently,a novel approach toward the total synthesis of（＋）-stemoamide through dyotropic rearrangement of 3,4-cis-b-lactone was also explored.
基金By grants from National Science and Technology Major Program(2018ZX10302104-002)Innovative Research Group Project of the National Natural Science Foundation of China(81721002)Peking University Clinical Scientist Program supported by"the Fundamental Research Funds for the Central Universities"(BMU2019LCKXJ013).
文摘Severely immunosuppressed AIDS patients with recurrent opportunistic infections(Ols)represent an unmet medical need even in the era of antiretroviral therapy(ART).Here we report the development of a human leukocyte antigen(HLA)-mismatched allogeneic adaptive immune therapy(AAIT)for severely immunosuppressed AIDS patients.Twelve severely immunosuppressed AIDS patients with severe Ols were enrolled in this single-arm study.Qualified donors received subcutaneous recombinant granulocyte-colony-stimulating factor twice daily for 4-5 days to stimulate hematopoiesis.Peripheral blood mononuclear cells were collected from these donors via leukapheresis and transfused into the coupled patients.Clinical,immunological,and virological parameters were monitored during a 12-month follow-up period.We found AAIT combined with ART was safe and well-tolerated at the examined doses and transfusion regimen in all 12 patients.Improvements in clinical symptoms were evident throughout the study period.All patients exhibited a steady increase of peripheral CD4^(+)T cells from a median 10.5 to 207.5 cells/μl.Rapid increase in peripheral CD8^(+)T-cell count from a median 416.5 to 1206.5 cells/μl was found in the first 90 days since initiation of AAIT.In addition,their inflammatory cytokine levels and HIV RNA viral load decreased.A short-term microchimerism with donor cells was found.There were no adverse events associated with graft-versus-host disease throughout the study period.Overall,AAIT treatment was safe,and might help severely immunosuppressed AIDS patients to achieve a better immune restoration.A further clinical trial with control is necessary to confirm the efficacy of AAIT medication.
文摘Remarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I(HIV-1)through antiretroviral therapy.However,vaccine development has remained challenging.Recent discoveries in broadly neutralizing monoclonal antibodies(bNAbs)has led to the development of multiple novel vaccine approaches for inducing bNAbs-like antibody response.Structural and dynamic studies revealed several vulnerable sites and states of the HIV-1 envelop glycoprotein(Env)during infection.Our review aims to highlight these discoveries and rejuvenate our endeavor in HIV-1 vaccine design and development.
基金supported by the National Grand Program on Key Infectious Disease Control(2012ZX10001-006,2012ZX10001-009 and 2012ZX10001-003)the National Outstanding Youth Award(30825035)+1 种基金the National Natural Science Foundation of China(81101236)the Tsinghua University Initiative Scientific Research Program
文摘VRC01, a broadly neutralizing monoclonal antibody （bnmAb）, can neutralize a diverse array of HIV-1 isolates by mimicking CD4 binding to the envelope glycoprotein gpl20. We have previously demonstrated the presence of VRC01-resistant strains in an HIV-1 infected patient during antiretroviral therapy. Here, we report follow-up studies of two subsequent samples from the same patient. With genetic and phenotypic analysis of over 70 full-length molecular clones of the HIV-1 envelope, we show that VRC01-resistant HIV-1 continued to exist and change in its proportion of the infecting virus during treatment with a highly active antiretroviral therapy. Consistent with our previous observation, the resistant phenotype was associated with a single asparagine residue at position 460 （N460）, a potential N-linked glycosylation site in the V5 region. The persistence and continuing evolution of VRC01-resistant HIV-1 in vivo presents a great challenge to our future preventative and therapeutic interventions based on VRC01.
基金supported by National Key Program Project Grant of Ministry of Science and Technology of China(2016YFC1201000)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDBP 030405)grants from the Municipal Science and Technology Bureau Foundation of Guangzhou(2014Y2-00550,201508020263)
文摘Dear Editor,Antibody-dependent enhancement（ADE）has long been recognized for dengue virus（DENV）in vitro and in vivo.It is now clear that antibodies to DENV can also enhance Zika virus（ZIKV）infection in vitro,and vice versa（Dejnirattisai et al.,2016;Stettler et al.,2016）.The characteristics of enhancing antibodies,however,remain elusive.
基金supported by the National Key Plan for Scientific Research and Development of China(2020YFC0849900 and 2021YFC0864500)the National Natural Science Foundation of China(92169205).
文摘Antibody response plays a critical role in protective immunity against SARS-CoV-2 infection and disease progression[1–3].As the current COVID-19 pandemic continues to rage around the world,there is growing concern that new SARS-CoV-2 variants may emerge that are antigenically distinct from the prototype strain,rendering the current antibody and vaccine strategies ineffective[4–15].
文摘The Fourth Symposium of Grand Challenges on HIV was held on December 28,2023,in Beijing,China.Fu-Sheng Wang(the National Clinical Research Center for Infectious Disease)and Zhang Linqi(Tsinghua University School of Medicine),as the chairpersons of the conference,organized this meeting.At the conference,almost all famous top scientists and clinicians in Acquired Immune Deficiency Syndrome(AIDS)from China(Figure 1)were invited to present and discuss the most recent advances in the science of a cure for human immunodeficiency virus(HIV)and share new technologies,new therapies and new achievements,and hoping to make major breakthroughs in AIDS intervention and AIDS functional cure.
文摘HIV,the virus that causes acquired immunodeficiency syndrome(AIDS),can integrate into the genome of host cells and form latent reservoirs,making it undetectable by the immune system.Two studies published in Nature in January 2020 reported a'shock and kill*strategy that aimed to activate the transcription of the latent reservoirs and render infected cells vulnerable to elimination by the immune system.Both study groups described interventions that were the most effective activation to date and were also reproducible.Nixon et al.used a drug called AZD5582 to activate the transcription of nuclear factor kappa B(NF-/cB),a major inducer of HIV-1 gene expression[1]McBrien et al.combined two immunological interventions by first depleting CD8 T cells(immune cells that reduce the level of viral transcription)followed by treatment with a drug called N-803,which activated HIV-1 transcription[2].In addition to these advances,these two studies also demonstrated the conceptual and technical challenges of pharmacological latency reversal.
基金funded by the Beijing Municipal Science and Technology Commission(No.D17110700050000).
文摘Human immunodeficiency virus(HIV)-1 infection creates a persistent latent reservoir even after antiretroviral therapy,which is the main barrier to HIV cure.One of the most explored strategies is the use of latent reversal agents(LRAs)to activate HIV latent reservoirs,followed by immunotherapy to remove infected cells.Immunomodulatory LRAs have the dual advantage of activating viral latency and promoting immune cell elimination of HIV-infected cells.The emergence of novel immunotherapies has also enhanced the possibility ofHIV clearance.Here we review the activity and potential mechanisms of immunomodulatory agonists and immunotherapies.The possible combinational strategies to achieve HIV functional cure and the problems encountered using this approach are discussed.
