August 2017 HIV research highlights
September 15, 2017 Source: Bio Valley
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)]; Human immunodeficiency virus (HIV), an AIDS (AIDS, acquired immunodeficiency syndrome) virus, is a virus that causes defects in the human immune system. In 1983, HIV was first discovered in the United States. It is a lentivirus that infects cells of the human immune system and is a type of retrovirus. By destroying the body's T lymphocytes, HIV blocks cellular and humoral immune processes, causing the immune system to paralyze, causing various diseases to spread in the human body and eventually leading to AIDS. Due to the extremely rapid variation of HIV, it is difficult to produce a specific vaccine, and there is no effective treatment method to date, which poses a great threat to human health.
According to WHO statistics, there were approximately 36.7 million HIV carriers in the world in 2015, most of them in low- and middle-income countries. It is estimated that the number of new HIV infections in 2015 was approximately 2.1 million. To date, 35 million people have died of HIV infection, including 1.1 million in 2015. Since the WHO declared the HIV pandemic in 1987, HIV infection has caused 39 million deaths. So far, HIV remains one of the world's largest public health challenges, so there is an urgent need to delve into the function of HIV to help researchers develop effective New treatments against this disease. In order to prevent the virus from causing damage to the immune system, HIV-infected people need to take ART every day or even for life. Although taking ART has been shown to be effective in suppressing AIDS episodes, these drugs are expensive, time consuming, and have serious side effects. There is an urgent need to find ways to cure HIV infection.
Major HIV research or discovery:
1.EBioMedicine: There is a drama to eradicate HIV! Drug Vorino makes it easy for latent HIV to be cleared
Doi:10.1016/j.ebiom.2017.07.019
HIV can be hidden in the human body under the stagnation, which makes it possible to cure 40 million HIV-infected people. Now, in a new study, researchers from the University of North Carolina at Chapel Hill have confirmed that the drug vorinostat can reverse this latency, leading to the expression of HIV antigen by resting CD4 T cells. They developed an assay to detect the production of HIV antigen, and the method includes an immune effector that is capable of clearing the virus. The relevant findings were published online July 28, 2017 in the EBio Medicine Journal, entitled "Vorinostat Renders the Replication-Competent Latent Reservoir of Human Immunodeficiency Virus (HIV) Vulnerable to Clearance by CD8 T Cells".
Vorino produces a window of vulnerability by eliminating the generation of HIV antigens to clear the HIV virus library. These researchers developed a latent clearance assay (LCA) to measure HIV antigen activity produced by vorinostat triggering. Such assays also include immunological effectors that are capable of clearing cells expressing the viral antigen.
Julia Sung, Ph.D., the first author of the paper and assistant professor of infectious diseases at the University of North Carolina at Chapel Hill, said, "It is technically challenging to measure the ability of a latent reversal agent to induce the production of HIV antigens. Using a latent clearance assay We detected that vorinostat, a latent reversal agent that enters clinical trials, is capable of inducing identifiable levels of HIV protein on the cell surface, allowing subsequent clearance of infected cells."
2.PNAS: A new way to track HIV infection
Doi:10.1073/pnas.1706245114
Recently, scientists from Northwestern University have developed a new way to track HIV infection, linking each individual virus infecting particle to the process of organizing the disease. This discovery will promote our understanding of the HIV life cycle and help build new HIV prevention and treatment methods. The results were published in the latest issue of PNAS.
During the course of the infection, HIV will fuse with the target immune cells and release its capsid, the outer shell enveloping the genetic material, into the cytoplasm of the target cell. From then on, the capsid will be depolymerized by the process of "uncoating", which is critical for the reverse transcription of viral RNA and for attacking the normal function of cells.
In this study, researchers used a new method of live cell fluorescence imaging to identify a single virus particle associated with an infection for the first time. The authors found that the process of "uncoating" occurred early in the invading cytoplasm and began within 30 minutes of cell fusion.
3. Priority review of Gilead AIDS new drugs is expected to accelerate listing
Gillead Sciences recently announced that the US FDA has granted its HIV-infected cocktail therapy bictegravir and emtricitabine/tenofovir alafenamide (FTC/TAF) priority review and is expected to make a decision no later than February 12, 2018.
The therapy is a single-dose treatment regimen with a fixed dose of 50 mg of the integrase chain transfer inhibitor bictegravir (BIC) and a 200 mg/25 mg FTC/TAF backbone for HIV-1 infected individuals. treatment. Gilead filed a new drug application for the therapy with the FDA in June this year and was awarded the priority review.
The new drug application is based on excellent data from its Phase 3 clinical trials. These data come from four independent studies, which all demonstrate that the cocktail therapy has a high rate of inhibition of the virus and is not inferior to the treatment regimen of 50 mg of dolutegravir (DTG) in the treatment of newly diagnosed patients. The main end point.
4.PLoS Pathog: Identifying the “culprit†of early HIV infection. HIV new therapies are expected to be developed.
Doi:10.1371/journal.ppat.1006441
HIV-1 is the most common form of HIV, and HIV is the culprit in AIDS. Recently, a study published in the international journal PLoS Pathogens, researchers from Tokyo Medical and Dental University (TMDU) identified A special protein produced by a host cell that is important for the efficient removal of the protein envelope of HIV-1.
In the search for multiple risk factors involved in HIV-1 infection, the researchers identified the key factors that promote cell survival in the presence of the virus by interfering with the activity of more than 15,000 host cell genes, and the researchers then A protein called maternal embryonic leucine zipper kinase (MELK) was studied.
Researcher Hiroaki Takeuchi said that knocking out cells containing MELK can reduce the infectivity of HIV-1. Normally, the virus can enter the cells that MELK is knocked out, but the protein shell of the virus cannot be properly removed and the virus is removed. It is impossible to use its own genetic material for DNA replication, and once MELK is restored in the cell, HIV-1 induced infection is restored.
As a result, researchers began investigating how MELK proteins interfere with the removal of viral protein coats during infection. They found that MELK can alter the protein's outer shell structure by adding biologically active modifications at specific sites, thereby enabling the realization of viral protein shells. Accurate removal; when the researchers developed a mutant version of HIV-1 that could be modified at a particular site, they found that the virus does not require MELK protein for protein shell removal.
5.Cell issue: Chinese scientists successfully use CRISPR/Cas9 to target CCR5 gene to produce HIV resistance
Doi:10.1016/j.ymthe.2017.04.027
A small number of people carry homozygous mutations in the gene CCR5, which encodes a receptor found on the surface of immune cells, which inhibits HIV from invading these immune cells. Now, in a new study, in order to simulate this natural resistance, researchers from the Chinese Center for Disease Control and Prevention, Peking University, People's Liberation Army 307 Hospital, Academy of Military Medical Sciences and Guangzhou General Hospital of Guangzhou Military Region in the human fetal liver hematopoietic stem The CCR5 gene was mutated in the hematopoietic stem/progenitor cell (HSPC) and confirmed that these HSPC cells were able to block HIV infection after transplantation into mice. The results of the study were published in the Molecular Therapy Journal on August 2, 2017, entitled "CRISPR/Cas9-Mediated CCR5 Ablation in Human Hematopoietic Stem/Progenitor Cells Confers HIV-1 Resistance In Vivo".
In this new study, Professor Hu Chen, director of the Hematopoietic Stem Cell Transplantation Unit at the 307 Hospital of the People's Liberation Army, and Professor Hongkui Deng, director of the Center for Stem Cell Research at Peking University, and their colleagues used the CRISPR/Cas9 to destroy CD34+HSPC. The CCR5 gene in the cell. They confirmed that their gene editing efficiency was 21% to 28%, which was higher than the gene editing efficiency reported by the ZFN method: 17%.
This study is the first to use CRISPR in the animal model to successfully cause HSC cells to undergo long-lasting CCR5 mutations. Professor Deng Hongkui and Professor Chen Hu wrote in an email they sent to Scientists magazine, "One of the advantages of CRISPR is that it has high cell transfection efficiency."
These researchers confirmed that these CRISPR-edited HSPC cells were successfully colonized in mice, and that these cells were able to differentiate and produce a series of normal immune cells within 47 weeks. They also confirmed that these CRISPR-edited HSPC cells were isolated from these HSPC-bearing mice and were subsequently transplanted into another group of mice.
Next, the researchers exposed mice transplanted with human CD34+ HSPC cells that had undergone CCR5 gene editing or unedited exposure to an HIV strain that invaded T cells using CCR5. Compared to mice bearing normal human HSPC, HIV RNA levels decreased in the first few weeks of infection in mice bearing these edited human HSPC cells, and the number of CD4+ T cells decreased more. less.
6. The gospel of HIV patients! The new long-acting injection clinical phase II is a gratifying result, every 4 weeks or 8 weeks. News source: New injectable antiretroviral treatment for HIV patients
Recently, a phase II clinical trial of an antiretroviral compound long-acting injection by ViiV Healthcare and Janssen has yielded encouraging results. A total of 286 HIV patients were enrolled in the trial, and the long-acting injection was administered every 4 weeks or every 8 weeks and compared with the standard three-agent oral regimen (carbotegravir/abacavir/lamivudine). The drug combination consists of ViiV Healthcare's long-acting integrase inhibitor carbotegravir and Janssen's non-nucleoside reverse transcriptase inhibitor rippivirine, and is made into nanoparticles to achieve a long-lasting therapeutic effect.
The results of the test showed that after 96 weeks of treatment, the virological inhibition rate of the treatment group reached 87% every 4 weeks, and the virological inhibition rate of the treatment group reached 94% every 8 weeks, and the patient's satisfaction rate with the injection treatment method. Up to 90%. This result is undoubtedly surprising for the majority of HIV patients. If it can be successfully marketed, patients can be treated at a lower frequency and achieve similar therapeutic effects without having to insist on oral administration of up to 14 tablets per day. .
The two companies are currently preparing Phase III clinical trials of the combination drug, continuing to investigate the efficacy, safety and tolerability of the drug every 4 weeks or every 8 weeks.
7. Gilead pan-gene hepatitis C cocktail Epclusa approved by the US FDA for HCV/HIV co-infection, the cure rate is 95%
News source: US FDA Approves Expanded Labeling for Epclusa? (Sofosbuvir/Velpatasvir) for the Treatment of Chronic Hepatitis C in Patients Co-Infected with HIV
Hepatitis C treatment giant Gilead recently announced that the US Food and Drug Administration (FDA) has approved a drug label for the update of hepatitis C cocktail therapy Epclusa (sofosbuvir 400mg/velpatasvir 100mg), allowing the drug to be used for hepatitis C and AIDS (HCV/HIV) ) co-infected. Epclusa is the first fully oral, pan-gene, once-daily monolithic regimen (STR) approved by the FDA on June 28, 2016 for all six genes without cirrhosis or with compensatory cirrhosis Type (GT 1-6) adult patients with hepatitis C, and combined with ribavirin (RBV) for adult patients with hepatitis C with decompensated cirrhosis.
The FDA's approval of Epclusa for HCV/HIV co-infection is based on an open-label phase III clinical study of ASTRAL-5. The study enrolled 106 patients with genotype 1-4 hepatitis C who were also infected with HIV and were receiving stable antiretroviral therapy. The study evaluated the efficacy and safety of Epclusa for 12 weeks. The data showed that the virological cure rate of the Epclusa 12-week regimen (SVR12, defined as the viral load below the detection limit at 12 weeks after completion of treatment) reached 95% (n=101/106). In this study, the safety of Epclusa in HCV/HIV co-infected patients was consistent with safety in patients infected with HCV alone. The most common adverse events (incidence ≥10%) were fatigue (22%) and headache (10%).
Dr. David Wyles, an associate professor at the University of Colorado School of Medicine and chief of the Denver Health Care Center, said that HCV co-infection remains a major cause of HIV infection. With the approval of this extended drug, Epclusa will provide a much-needed daily treatment regimen for HCV/HIV co-infected populations that is compatible with all widely used antiretroviral therapies for all HCV genotypes.
8.Mol Cell: An anticancer drug that reactivates HIV
Doi:10.1016/j.molcel.2017.07.025
Potential HIV can be hidden in cells for many years and is a key barrier to cure. Researchers are exploring two main strategies to solve this problem - restarting and destroying latent viruses (called "shock and killing"), or finding a way to silence them.
To address both strategies, a team of scientists at the Gladstone Institute studied drugs that could block the incubation period and eventually be used to treat infected patients. They recently discovered a new drug called JQ1, which is currently undergoing an early human cancer trial that can restart latent HIV.
Gladstone senior researcher Melanie Ott explained that his research was published today in the journal Molecular Cell. "We already know that drug JQ1 targets a protein called BRD4, but our experiments did not produce consistent results, then we began to study different forms of protein, and unexpectedly found that a simple form is to make HIV The key to silence."
9.Human Gene Therapy: Chen Xiaoping, Chinese Academy of Sciences, Guangzhou Institute of Biological Sciences, published research progress on primary T cell gene editing and AIDS gene therapy
Doi:10.1089/hum.2017.032
CD4+ T cells are the main target cells of HIV-1 infection in humans and are also important functional cells for AIDS gene therapy. CCR5 is the major co-receptor for HIV-1 infected CD4+ T cells. As viral infection progresses, viral tropism shifts from R5-tropic to X4-tropic, and eventually leads to progression to the AIDS phase. Therefore, for patients with chronic HIV-1 infection, simultaneous knockout of CXCR4 and CCR5 may block any single tropic and amphotropic viruses, providing dual protection and achieving a functional cure for AIDS.
Using the latest CRISPR/Cas9 gene editing tools, the researchers optimized the transfection conditions by improving delivery methods, and finally achieved multi-gene knockout of primary T cells. Functional verification of the modified cells showed that the growth and proliferation ability and apoptosis levels of CXCR4/CCR5 double knockout T cells were not significantly different from unmodified T cells. However, CD4+ T cells modified by the dual receptor gene are effective against infection by the amphotropic HIV-1 strain. Considering the in vivo model, the patient's own HIV-1 can provide the virus selection pressure, naturally select the CXCR4/CCR5 gene knockout CD4+ T cells, thus establishing effective protection against the virus, so it can be expected in vivo research. Or you can get more significant antiviral treatment effects.
10.JAIDS: Self-test based on family mode or can significantly improve the detection of HIV
Doi:10.1097/QAI.0000000000001410 Recently, researchers from Louisiana State University found that 86% of high-risk HIV heterosexuals usually use the home-based testing tools provided by mail to test HIV, and 99% of the population will Seeking treatment based on positive results, this new method of self-selection may allow some high-risk unidentified individuals to be treated early, and the study was published in the journal Journal of Acquired Immune Deficiency Syndrome.
Researcher Dr. William Robinson pointed out that in 2014, 24% of new HIV infections were attributed to heterosexual sexual activity, but many risk groups did not check by routine means, and some even never tested for HIV. In 2013, a study conducted by the researchers found that a total of 470 people surveyed had a higher risk of HIV infection, and the requirements for participation in the study included ages 18 and above, and New Orleans urban residents were able to complete the survey in English. And there have been sexual relationships with heterosexual partners in the past 12 months.
Among all the participants analyzed, 85.56% of the participants indicated that they were willing to participate in a home-based self-test survey sent by the research institution or the health department via email, and 54.19% of the participants said they would self-test results. Feedback was returned; 43% of participants said they were more willing to tell the doctor about their condition, and only 8 (1.7%) participants said they would not disclose the results to anyone.
11.PLoS Pathog: A major breakthrough! Scientists deeply understand the reasons why HIV is difficult to cure
Doi:10.1371/journal.ppat.1006509
Researchers from the University of Michigan have recently clarified the hidden places of HIV through research, and at the same time clarified why HIV has been lurking in the body for many years. The research is published in the international journal PLoS Pathogens, which is a late development of new drugs. Effectively clearing the latent HIV in the patient's body provides new deaths. According to Kathleen Collins, MD, in this study, we found that HIV may be hidden in a variety of bone marrow cells, and this may be far beyond our previous knowledge. When these bone marrow cells divide, they will complete the genetic material of the virus. It is transmitted to the daughter cells, and this invisibly hides the virus in the body for several years without being noticed by the immune system.
The researchers found that HIV can be hidden in hematopoietic progenitor cells (HPCs), which can produce new blood cells to remove dead blood cells, and HIV can induce these cells to insert viral genetic material into the body's own cells. Collins said that finding cells with hidden HIV is like finding a needle in a haystack. However, in this study we found a place where HIV is hidden. This is like a cancer biology problem, perhaps just a mutation in a cell. Insert the same viral genome.
Hematopoietic stem cells are capable of producing HPCs, which are the main cells responsible for blood production in the bone marrow. Previous studies have found that HIV can hide in the bone marrow for many years. Researchers are not clear whether the virus will remain in stem cells for many years or whether the virus's repository contains more differentiated progenitor cells; the researchers point out that HIV genetic material can lurk in blood progenitor cells, and then they find such Cells can survive for many years, so finding cell types that can conceal HIV for many years is important for developing new therapies that effectively inhibit or fight HIV.
12. IAS 2017: Gilead 3-in-1 HIV Compound Monolithic BIC/FTC/TAF Phase III Clinical Success Source: Gilead Announces Phase 3 Results for Investigational Fixed-Dose Combination of Bictegravir, Emtricitabine and Tenofovir Alafenamide for Treatment of HIV
US pharmaceutical giant Gilead recently announced two phase III clinical trials of three-in-one HIV compound monolithic BIC/FTC/TAF at the 9th International AIDS Conference (IAS 2017) in Paris, France (Studies 1489, 1490) Detailed 48-week data.
BIC/FTC/TAF is a daily oral tablet consisting of a novel integrase chain transfer inhibitor (INSTI) bictegravir (BIC, 50 mg) and two nucleoside reverse transcriptase inhibitors [NRTI] Trithopabine/tenofovir alafenamide fumarate (FTC/TAF, 200/25 mg). In phase III clinical studies, BIC/FTC/TAF achieved very high virological inhibition rates in the treatment of adult patients who had not received treatment (initial treatment) and adult patients who achieved virological suppression and switched treatment regimens. And no drug resistance occurred in the treatment.
In study 1489, a total of 629 adults with newly diagnosed HIV were randomized to receive BIC/FTC/TAF or abacavir/DTG/lamivudine (ABC/DTG/3TC, 600/50/300 mg) in a 1:1 ratio. . At week 48 of treatment, 92.4% of patients in the BIC/FTC/TAF treatment group and 93.0% of the ABC/DTG/3TC treatment group achieved a primary endpoint of HIV-1 viral RNA levels <50 copies/mL (difference: -0.60%, 95CI: -4.80 to 3.60%, p = 0.78), achieving the non-inferiority defined by the study.
In study 1490, a total of 645 newly diagnosed HIV adult patients were randomized to receive BIC/FTC/TAF or DTG+FTC/TAF at a 1:1 ratio. At week 48 of treatment, 89.4% of patients in the BIC/FTC/TAF-treated group and 92.9% of patients in the DTG+FTC/TAF-treated group achieved a primary endpoint of HIV-1 viral RNA levels <50 copies/mL (difference: -3.5%, 95CI: -7.9% to 1.0%, p=0.12), meeting the non-inferiority defined by the study. None of the 2 treatment groups developed resistance.
In terms of regulation, Gilead submitted a BIC/FTC/TAF listing application to the US FDA and the European Union EMA in June and July this year to seek approval for the treatment of HIV-1 adult infected people. In addition to studies 1489 and 1490, the BIC/FTC/TAF regulatory document also included positive data from two clinical studies (Studies 1844 and 1878) conducted in previously treated HIV-1 patients.
13. Merck's HIV drug doravirine is not inferior to Efavirenz
On July 25th, Merck Pharmaceuticals Inc. (known as Merck in the United States and Canada) published the second trial of DRIVE-AHEAD, a key clinical trial of the efficacy and safety of doravirine in the treatment of HIV-1 infection. Where doravirine belongs to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI). The 48-week trial showed a fixed-dose combination of efavirenz (EFV, Efavirenz), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) based on HIV- 1 The level of RNA is lower than that of 50 copies/mL. For patients with newly diagnosed HIV-1 infection, once a day, they contain doravirine (DOR), lamivudine (3TC) and tenofovir disoproxil fumarate. Fixed-dose combination tablets of ester (TDF) achieved a major non-inferior efficacy endpoint.
In addition, in the 48-week period, patients taking DOR/3TC/TDF had pre-defined neuropsychiatric events (dizziness, sleep disturbances, disorders, and unclear thinking) compared with patients taking EFV/FTC/TDF. Or the proportion of statistics in which the mind is not concentrated is significantly lower. At the same time, patients taking DOR/3TC/TDF had significantly lower changes in fasting low-density lipoprotein (LDL-C) and non-high-density lipoprotein compared to baseline. The results of the ongoing Phase 3 DRIVE-AHEAD study will be presented orally at the 2017 International Conference on HIV Science (IAS 2017) in Paris, France.
After 48 weeks of treatment, 84% of the 364 newly diagnosed patients who received DOR/3TC/TDF once a day had HIV-1 RNA <50 copies/mL; 364 patients who took EFV/FTC/TDF, The proportion of patients with HIV-1 RNA <50 copies/mL was 81%, and the estimated treatment difference was 3.5% (95% confidence interval; -2.0, 9.0). The mean levels of CD4+ T-cell counts in the DOR/3TC/TDF group and the EFV/FTC/TDF group were 198 and 188 cells/mm3, respectively, and 10.1% of treatment differences (95% confidence interval; -16.1, 36.3). In addition, patients with high viral load at baseline (HIV-1 RNA >100,000 copies/mL) also observed a therapeutic effect. The number of patients in this group was in the DOR/3TC/TDF group and the EFV/FTC/TDF group. There were 69 and 73, respectively, and 81% of these patients in the DOR/3TC/TDF group achieved the primary efficacy endpoint of HIV-1 RNA <50 copies/mL, which was also 81 for the EFV/FTC/TDF group. %, the treatment difference was 1% (95% confidence interval; -12.4, 14.3).
The study also reached a safety endpoint: the DOR/3TC/TDF treatment group had a lower incidence of 48-week neuropsychiatric events compared with the EFV/FTC/TDF group, with dizziness (8.8% vs 37.1%), Sleep disturbances and disorders (12.1% vs 25.5%), unclear and inconsistent (4.4% vs 8.2%), the 2-sided p-values ​​for the three indicators were p<0.001, p<0.001 and p, respectively. =0.033.
In this study, the incidence of reported and drug-related adverse events was lower in the DOR/3TC/TDF group (31%, 113/364); in the EFV/FTC/TDF group, 63%, 229/364 (- 31.9% treatment difference) (95% confidence interval, -38.6, -24.8). The study discontinuation rates due to adverse events were DOR/3TC/TDF (3%, 11/364) and EFV/FTC/TDF (7%, 24/364), respectively.
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