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AIDS severely affects human health and socio-economic development, but there is currently no effective preventive vaccine or medicine that can cure the virus infection
.
High-efficiency antiretroviral therapy (HAART program) can effectively inhibit HIV replication and reduce the viral load to an undetectable level in the blood.
However, due to the existence of the virus latent pool, HIV will rebound rapidly after stopping the drug
.
At the same time, because of long-term medication, patients also face problems such as drug toxicity accumulation and virus mutation resistance
.
Therefore, researching new long-term treatment and prevention methods for AIDS is a major scientific problem at present, and it is also a difficult point in research.
Probing the characteristics of the virus latent pool and blocking strategies are the key to researching treatment and prevention methods
.
Realizing "stable virus control after drug withdrawal", that is, functional cure, is the ideal goal in the field of AIDS prevention and treatment at this stage
.
"Berlin patient" and "London patient" are the only AIDS patients considered to be successfully cured in the world, igniting people's hope for cure research and exploration of cure strategies
.
Recently, "San Francisco patients" and "Esperanza patients" as cases of clear cure without treatment have once again attracted widespread attention
.
In addition, in some cases (posttreatment controllers, PTC) represented by "Argentine patients", they can maintain a stable HIV control state for a longer period of time after the long-term antiviral treatment is stopped
.
The continuous emergence of these cases suggests that the scientific community needs to explore in depth the virus latent pool and immune regulation mechanisms behind the realization of "stable virus control"
.
On December 16, 2021, the team of Professor Yuxian He from the Institute of Pathogenic Biology of the Chinese Academy of Medical Sciences and the team of Researcher Xue Jing from the Institute of Medical Experimental Animals of the Chinese Academy of Medical Sciences published the title on Cell: Efficient treatment and pre-exposure prophylaxis in rhesus macaques by an HIV fusion-inhibitory lipopeptide research paper
.
The study discovered powerful AIDS treatment and prevention drugs, and revealed the latent reservoir of the virus and immune control mechanisms
.
The research team designed a lipopeptide virus fusion inhibitor with extremely high anti-HIV activity and long-acting effect.
Through a rhesus monkey model study, it was found that low-dose monotherapy can effectively inhibit SIV (a HIV and SIV chimeric virus) virus replication , And maintain long-term effective treatment effect
.
More meaningfully, they found that some rhesus monkeys can achieve stable virus control after drug withdrawal
.
In-depth research found that the virus stably controls monkey viral DNA at a low level hidden in deep lymph nodes, with less live virus production and PD-1+ central memory CD4+ T cells; on the contrary, the virus rebounds monkey viral DNA after drug withdrawal It gathers in the superficial lymph nodes at a high level
.
The study also proved that CD8+ T cells played a key role in the outcome of virus control after drug withdrawal
.
The prophylactic administration of new inhibitors in rhesus monkeys can effectively block the infection of SIV and SIV (monkey immunodeficiency virus) via rectal, vaginal or intravenous routes, so it can be used as a new strategy for pre-exposure prophylaxis (PrEP)
.
The team of Professor Yuxian He from the Institute of Pathogenic Biology of the Chinese Academy of Medical Sciences has been committed to the research and development of new HIV membrane fusion inhibitors for many years, and has achieved a series of research results
.
Through in-vitro, ex-vivo and in-vivo experiments to screen candidate lipopeptides, this thesis obtained two lipopeptide virus fusion inhibitors (LPs) with strong anti-HIV activity.
-97 and LP-98) (Figure 1)
.
The authors found that LP-98 has a long-term and stable therapeutic effect in the rhesus monkey model of chronic infection with SIV.
The drug can be used in low doses in the body and has a long-term effect
.
Figure 1 Schematic diagram of HIV fusion protein gp41 structure and lipopeptide structure and antiviral activity.
More importantly, after 21 infected monkeys were treated with LP-98 and the drug was stopped, it was found that about 40% of the treated monkeys showed stable virus after drug withdrawal Stable virologic rebound (SVR), about 30% of the treated monkeys showed unstable virologic rebound (UVR) after drug withdrawal, while about 20% of the treated monkeys showed the most ideal "stable virologic rebound after drug withdrawal" "Stable virologic control" status (stable virologic control, SVC)
.
By comparing the characteristics of the virus latent pool of the three treatment monkeys, the authors found that the latent virus pool of SVC monkeys was hidden in deep lymph nodes such as the mesenteric and paragut at a low level.
The latent pool of SVR monkeys was mainly distributed in the neck with higher levels of viral DNA.
In the superficial lymph nodes such as the axillary and axillary areas, the latent pool of UVR monkeys is distributed in the superficial and deep lymph nodes with moderate levels of viral DNA, suggesting that the location and level of the latent pool of viral DNA are related to whether the virus rebounds after drug withdrawal (Figure 2)
.
Further studies have confirmed that the latent tissue pool of SVC monkeys has less ability to produce live viruses, and the proportion of PD-1 positive central memory CD4+ T cells is lower
.
Figure 2 The distribution characteristics of the latent pool of LP-98 treatment of monkey virus is to explore the mechanism of virus control or partial control after drug withdrawal.
After knocking out CD8+ T cells in SVC monkeys and UVR monkeys, the viral load rebounded rapidly
.
By comparing the virus-specific CD8+ T cell responses of the three treatment monkeys, it was found that the virus-specific CD8+ T cell responses of SVC monkeys were stronger and the multifunctional CD8+ T cell responses increased
.
Furthermore, they sorted and obtained three groups of therapeutic monkey CD8+ T cells.
Transcriptome sequencing found that the three groups of differential genes were enriched in immune response-related pathways
.
The article also conducted an experimental study on pre-exposure prevention of LP-98
.
First, LP-98 was administered 2 hours, 1 week, and 2 weeks before the SIV intravenous challenge.
Compared with the model control group, the rhesus monkeys in the 2 hours before challenge and the 1 week group were completely protected, while the 2 weeks group did not.
Obvious protective effect, which confirmed that the drug can achieve protection within 1 week, suggesting that the effective protection period of preventive medication before exposure is 1 week
.
Furthermore, in the rectal and vaginal SIV challenge experiments that administered once a week, challenged twice a week, and continued to challenge for 12 times, it was found that rhesus monkeys could completely block the infection of SIV virus, and none was detected in vivo.
To viral RNA, viral DNA and specific antibodies
.
The study also found that LP-98 can also completely block SIV attacks through rectal and vaginal routes
.
In order to clarify the pre-exposure prevention and protection effect of SIV, 6 rhesus monkeys that were completely protected by the rectal route were randomly selected for the second challenge 150 days after the first challenge.
These 3 rhesus monkeys were successfully infected while the others The three rhesus monkeys that were fully protected for the first time did not detect the virus during more than 500 days of surveillance
.
In summary, LP-98 lipopeptide can be used as an effective HIV treatment and prevention strategy (Figure 3)
.
Figure 3 Abstract of the paper.
Professor Yuxian He from the Institute of Pathogenic Biology, Chinese Academy of Medical Sciences and researcher Xue Jing from the Institute of Medical Laboratory Animals, Chinese Academy of Medical Sciences are the co-corresponding authors of the paper
.
Researcher Xue Jing, researcher Zhong Huihui and teacher Zhu Yuanmei of the Institute of Pathogenic Biology, Chinese Academy of Medical Sciences are the co-first authors
.
Paper link: https://doi.
org/10.
1016/j.
cell.
2021.
11.
032 is open for reprinting, welcome to forward to Moments and WeChat groups
.
High-efficiency antiretroviral therapy (HAART program) can effectively inhibit HIV replication and reduce the viral load to an undetectable level in the blood.
However, due to the existence of the virus latent pool, HIV will rebound rapidly after stopping the drug
.
At the same time, because of long-term medication, patients also face problems such as drug toxicity accumulation and virus mutation resistance
.
Therefore, researching new long-term treatment and prevention methods for AIDS is a major scientific problem at present, and it is also a difficult point in research.
Probing the characteristics of the virus latent pool and blocking strategies are the key to researching treatment and prevention methods
.
Realizing "stable virus control after drug withdrawal", that is, functional cure, is the ideal goal in the field of AIDS prevention and treatment at this stage
.
"Berlin patient" and "London patient" are the only AIDS patients considered to be successfully cured in the world, igniting people's hope for cure research and exploration of cure strategies
.
Recently, "San Francisco patients" and "Esperanza patients" as cases of clear cure without treatment have once again attracted widespread attention
.
In addition, in some cases (posttreatment controllers, PTC) represented by "Argentine patients", they can maintain a stable HIV control state for a longer period of time after the long-term antiviral treatment is stopped
.
The continuous emergence of these cases suggests that the scientific community needs to explore in depth the virus latent pool and immune regulation mechanisms behind the realization of "stable virus control"
.
On December 16, 2021, the team of Professor Yuxian He from the Institute of Pathogenic Biology of the Chinese Academy of Medical Sciences and the team of Researcher Xue Jing from the Institute of Medical Experimental Animals of the Chinese Academy of Medical Sciences published the title on Cell: Efficient treatment and pre-exposure prophylaxis in rhesus macaques by an HIV fusion-inhibitory lipopeptide research paper
.
The study discovered powerful AIDS treatment and prevention drugs, and revealed the latent reservoir of the virus and immune control mechanisms
.
The research team designed a lipopeptide virus fusion inhibitor with extremely high anti-HIV activity and long-acting effect.
Through a rhesus monkey model study, it was found that low-dose monotherapy can effectively inhibit SIV (a HIV and SIV chimeric virus) virus replication , And maintain long-term effective treatment effect
.
More meaningfully, they found that some rhesus monkeys can achieve stable virus control after drug withdrawal
.
In-depth research found that the virus stably controls monkey viral DNA at a low level hidden in deep lymph nodes, with less live virus production and PD-1+ central memory CD4+ T cells; on the contrary, the virus rebounds monkey viral DNA after drug withdrawal It gathers in the superficial lymph nodes at a high level
.
The study also proved that CD8+ T cells played a key role in the outcome of virus control after drug withdrawal
.
The prophylactic administration of new inhibitors in rhesus monkeys can effectively block the infection of SIV and SIV (monkey immunodeficiency virus) via rectal, vaginal or intravenous routes, so it can be used as a new strategy for pre-exposure prophylaxis (PrEP)
.
The team of Professor Yuxian He from the Institute of Pathogenic Biology of the Chinese Academy of Medical Sciences has been committed to the research and development of new HIV membrane fusion inhibitors for many years, and has achieved a series of research results
.
Through in-vitro, ex-vivo and in-vivo experiments to screen candidate lipopeptides, this thesis obtained two lipopeptide virus fusion inhibitors (LPs) with strong anti-HIV activity.
-97 and LP-98) (Figure 1)
.
The authors found that LP-98 has a long-term and stable therapeutic effect in the rhesus monkey model of chronic infection with SIV.
The drug can be used in low doses in the body and has a long-term effect
.
Figure 1 Schematic diagram of HIV fusion protein gp41 structure and lipopeptide structure and antiviral activity.
More importantly, after 21 infected monkeys were treated with LP-98 and the drug was stopped, it was found that about 40% of the treated monkeys showed stable virus after drug withdrawal Stable virologic rebound (SVR), about 30% of the treated monkeys showed unstable virologic rebound (UVR) after drug withdrawal, while about 20% of the treated monkeys showed the most ideal "stable virologic rebound after drug withdrawal" "Stable virologic control" status (stable virologic control, SVC)
.
By comparing the characteristics of the virus latent pool of the three treatment monkeys, the authors found that the latent virus pool of SVC monkeys was hidden in deep lymph nodes such as the mesenteric and paragut at a low level.
The latent pool of SVR monkeys was mainly distributed in the neck with higher levels of viral DNA.
In the superficial lymph nodes such as the axillary and axillary areas, the latent pool of UVR monkeys is distributed in the superficial and deep lymph nodes with moderate levels of viral DNA, suggesting that the location and level of the latent pool of viral DNA are related to whether the virus rebounds after drug withdrawal (Figure 2)
.
Further studies have confirmed that the latent tissue pool of SVC monkeys has less ability to produce live viruses, and the proportion of PD-1 positive central memory CD4+ T cells is lower
.
Figure 2 The distribution characteristics of the latent pool of LP-98 treatment of monkey virus is to explore the mechanism of virus control or partial control after drug withdrawal.
After knocking out CD8+ T cells in SVC monkeys and UVR monkeys, the viral load rebounded rapidly
.
By comparing the virus-specific CD8+ T cell responses of the three treatment monkeys, it was found that the virus-specific CD8+ T cell responses of SVC monkeys were stronger and the multifunctional CD8+ T cell responses increased
.
Furthermore, they sorted and obtained three groups of therapeutic monkey CD8+ T cells.
Transcriptome sequencing found that the three groups of differential genes were enriched in immune response-related pathways
.
The article also conducted an experimental study on pre-exposure prevention of LP-98
.
First, LP-98 was administered 2 hours, 1 week, and 2 weeks before the SIV intravenous challenge.
Compared with the model control group, the rhesus monkeys in the 2 hours before challenge and the 1 week group were completely protected, while the 2 weeks group did not.
Obvious protective effect, which confirmed that the drug can achieve protection within 1 week, suggesting that the effective protection period of preventive medication before exposure is 1 week
.
Furthermore, in the rectal and vaginal SIV challenge experiments that administered once a week, challenged twice a week, and continued to challenge for 12 times, it was found that rhesus monkeys could completely block the infection of SIV virus, and none was detected in vivo.
To viral RNA, viral DNA and specific antibodies
.
The study also found that LP-98 can also completely block SIV attacks through rectal and vaginal routes
.
In order to clarify the pre-exposure prevention and protection effect of SIV, 6 rhesus monkeys that were completely protected by the rectal route were randomly selected for the second challenge 150 days after the first challenge.
These 3 rhesus monkeys were successfully infected while the others The three rhesus monkeys that were fully protected for the first time did not detect the virus during more than 500 days of surveillance
.
In summary, LP-98 lipopeptide can be used as an effective HIV treatment and prevention strategy (Figure 3)
.
Figure 3 Abstract of the paper.
Professor Yuxian He from the Institute of Pathogenic Biology, Chinese Academy of Medical Sciences and researcher Xue Jing from the Institute of Medical Laboratory Animals, Chinese Academy of Medical Sciences are the co-corresponding authors of the paper
.
Researcher Xue Jing, researcher Zhong Huihui and teacher Zhu Yuanmei of the Institute of Pathogenic Biology, Chinese Academy of Medical Sciences are the co-first authors
.
Paper link: https://doi.
org/10.
1016/j.
cell.
2021.
11.
032 is open for reprinting, welcome to forward to Moments and WeChat groups
