Podcasts about hiv rna

In this episode of the Life Science Success podcast, we have Dr. David E. Martin, the President and CEO of TrippBio, Inc., a distinguished translational scientist with over 30 years of experience in drug development. Dr. Martin has led numerous groundbreaking projects and is here to share his insights on the future of therapeutic advancements.  

Episode 120: Immune Reconstitution Inflammatory Syndrome (IRIS) Abeda Faharti and Dr. Schlaerth present the definition, diagnosis, and treatment of IRIS. Moderated by Dr. Arreaza. Written by Abeda Farhati, MS4, Ross University School of Medicine. Editing and comments by Katherine Schlaerth, MD, and Hector Arreaza, MD.You are listening to Rio Bravo qWeek Podcast, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California, a UCLA-affiliated program sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. This podcast was created for educational purposes only. Visit your primary care provider for additional medical advice.Definition.Have you heard of IRIS? No, not the color portion of our eyes. IRIS is short for Immune Reconstitution Inflammatory Syndrome. This condition occurs in immunocompromised patients with HIV/AIDS due to an overactive inflammatory response. In most cases, it occurs after initiating antiretroviral therapy (ART). To understand IRIS in HIV patients, we must first understand HIV.HIV.The Human Immunodeficiency Virus (HIV) infection was first reported in 1981. The virus attacks the immune system, destroying white blood cells called CD4+ T lymphocytes, which are part of our body's defense mechanism. These cells are also known as "helper T cells" and are responsible for destroying viruses, bacteria, and other germs that make us sick.When your CD4+ count is low, you are more likely to get serious infections from viruses, bacteria, and fungi, which usually do not cause problems in otherwise healthy individuals. These infections are called Opportunistic infections, and they can be deadly. To restore CD4+ T lymphocytes, HIV patients are started on ART to normalize their immune response to pathogens. As a result of these treatments, HIV patients' lives have been significantly improved and prolonged. [Comment by Dr. Arreaza: It is paradoxical, but some HIV patients are among the healthiest patients I have seen.]Despite this, no treatment is guaranteed to be without side effects. Increases in CD4+ T lymphocytes trigger the immune system to respond to any persisting antigen, regardless of whether it is fragments or intact organisms. As a result, a hyperinflammatory response may occur.Diagnosis.There are no established criteria for diagnosing IRIS. It is generally accepted that IRIS requires the worsening of an existing infection or an unrecognized, preexisting infection in the context of improved immune function. For a diagnosis to be made, most, if not all of the following features must be present:The presence of a low CD4 count (less than 100 cells) before initiating treatment with ART (Except IRIS secondary to preexisting TB infection can occur with CD4 counts >200 cells).The presence of an inflammatory condition, especially after ART is initiated.The absence of drug-resistant infection, bacterial superinfection, drug allergy, or other adverse drug reactions.The absence of patient noncompliance or reduced drug levels due to drug-drug interactions or malabsorption.Clinical Manifestations.IRIS can be presented in patients in 2 ways:Patient's with a preexisting infectious disease that has NOT been treated, getting paradoxically worse after initiating treatment with ART ---this is known as “unmasking IRIS” ORPatient's with a preexisting infectious disease that has been previously diagnosed and treated but regained capacity after treatment with ART, causing it to mount an inflammatory response – this is known as “paradoxical IRIS.”In summary: Unmasking IRIS and paradoxical IRIS.Patients with IRIS have clinical features that vary widely. The presentations are strongly dependent on the type of preexisting opportunistic infection. For example, about 75% of patients with a mycobacterial or cryptococcal-related infection will develop a fever. In contrast, fever is rarely seen in cytomegalovirus (CMV) infections.Risk & Prevention.Researchers have found that lower CD4 cell counts or high HIV RNA levels at the time of anti-retroviral treatment initiation increase the risk of developing IRIS. One way to prevent IRIS development is to treat opportunistic infections prior to starting ART. Although this reduces the risk of IRIS development, it does not guarantee it.Treatment.In “unmasking IRIS,” patients can be treated with antibiotics, antivirals, or antifungals against the underlying infectious organism. In severe cases, steroids can also be used to suppress inflammation until the infection has been eradicated. Unfortunately, there is no treatment for paradoxical IRIS. Most patients who experience “paradoxical IRIS” reactions will get better spontaneously without additional therapy.Incidence of IRIS.The overall incidence of IRIS is unknown; however, studies have shown that anywhere from 25 to 30% of HIV patients who start antiretroviral treatment develop IRIS in the first six months. You may ask, which preexisting infections can lead to patients developing IRIS?Pathogens associated with IRIS.Different pathogens have been associated with the development of IRIS. The leading pathogens include:Mycobacterium tuberculosisMycobacterium avium complexCytomegalovirusCryptococcus neoformansPneumocystis jiroveciiHerpes simplex virusHepatitis B virusHuman herpes virus 8 (associated with Kaposi sarcoma)Non-HIV etiologies.IRIS can also be seen in other immunocompromised conditions, such as:Solid organ transplant recipients Postpartum period – 3 to 6 weeks after giving birthNeutropenic patients – with an absolute neutrophil count of less than 500Patients on Tumor Necrosis Factor Antagonists (TNF antagonists)- are used to treat chronic conditions such as ulcerative colitis, Crohn's disease, or sarcoidosis.In summary, Immune Reconstitution Inflammatory Syndrome (IRIS) is a hyper-inflammatory state seen after initiating ART in HIV patients whose improved immune system responds to previously acquired opportunistic infection, whether treated or not.The treatment is directed to the unmasked specific opportunistic infection or support therapy if no active infection is found.____________________________Conclusion: Now we conclude episode number 121, “Immune Reconstitution Inflammatory Syndrome (IRIS).” This syndrome presents in about 30% of HIV patients when they start ART. A stronger immune system means a stronger immune reaction. So, keep in mind this diagnosis when your HIV patients get sicker when they are supposed to get better after starting ART. This week we thank Hector Arreaza, Abeda Farhati, and Katherine Schlaerth. Audio edition by Adrianne Silva.Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week! _____________________Links:“CD4 Lymphocyte Count: MedlinePlus Medical Test.” Medlineplus.gov, accessed on November 4, 2022.https://medlineplus.gov/lab-tests/cd4-lymphocyte-count/#:~:text=A%20CD4%20count%20is%20mostly,have%20trouble%20fighting%20off%20infections.Sun HY, Singh N. Immune reconstitution inflammatory syndrome in non-HIV immunocompromised patients. Curr Opin Infect Dis. 2009 Aug;22(4):394-402. doi: 10.1097/QCO.0b013e32832d7aff. PMID: 19483618. https://pubmed.ncbi.nlm.nih.gov/19483618/Thapa, Sushma, and Utsav Shrestha. “Immune Reconstitution Inflammatory Syndrome.” PubMed, StatPearls Publishing, 2022, www.ncbi.nlm.nih.gov/books/NBK567803/.Wolfe, Cameron. Immune reconstitution inflammatory syndrome, UpToDate. ww.uptodate.com, https://www.uptodate.com/contents/immune-reconstitution-inflammatory-syndrome. Accessed November 14, 2022.Royalty-free music used for this episode: “Keeping Watch,” New Age Landscapes. Downloaded on October 13, 2022, from https://www.videvo.net/royalty-free-music-albums/new-age-landscapes/. 

In this episode, Chloe Orkin, MBChB, FRCP, MD, discusses new HIV data from AIDS 2022, including:Prevention strategiesOral therapiesLA therapiesCureCOVID-19 in PWHFacultyChloe Orkin, MBChB, FRCP, MDProfessor of HIVQueen Mary, University of LondonConsultant PhysicianLead for HIV ResearchBarts Health NHS TrustThe Royal London HospitalLondon, United KingdomFollow along with the slides atbit.ly/3SLuhBq

1 Aralık Dünya AIDS Günü nedeniyle HIV hakkında farkındalık yaratmak ve bilgilerimizi tazelemek adına bu yazıyı kaleme almak istedim. HIV + bireylerin acil servise başvuru nedenleri üzerine ikinci bir yazıyı ilerleyen tarihlerde sizinle paylaşacağım. Keyifli okumalar dilerim! Tanımlar ve Genel Bilgiler HIV yani Human immunodeficiency virus, lentivirüs ailesinde yer alan bir retrovirüstür. CD4+ T lenfositlerini hedef alarak immün sisteme zarar verir. Korunmasız cinsel ilişkiyle, kan yoluyla, anneden bebeğe (gebelik, doğum ve emzirme ile) bulaşır. HIV ter, tükürük, idrar, göz yaşı gibi vücut sıvılarıyla, hapşurma ya da öksürmeyle, aynı tabak, çatal, bıçak, havlu kullanımıyla, aynı tuvalet ve duşun kullanımıyla, sivrisinek, böcek ve diğer hayvan ısırıklarıyla, tokalaşma, sarılma, öpüşme, aynı ortamda bulunma gibi sosyal davranışlarla bulaşmaz. AIDS yani Edinilmiş Bağışıklık Yetersizliği Sendromu ise HIV enfeksiyonunun etkin tedavi almamış kişilerde görülen ileri evresi olarak adlandırılır. Günümüzde HIV ile yaşayan bireyler tedavi ile enfeksiyonun kontrol altına alınması halinde standart yaşam sürelerini HIV kaynaklı bir sağlık sorunu olmaksızın yaşayabilmektedir. Bu nedenle HIV + bireylerin çeşitli nedenlerle sağlık bakımından uzak kalmamaları oldukça önemlidir. Ülkemizde HIV bildirimi zorunlu hastalıklar listesinde yer almakta olup 1985 yılındaki ilk vaka bildiriminden bu yana sürveyansı yürütülmektedir.​1​ HIV konusunda toplumda farkındalığın düşük olması nedeniyle ve bireylerin ayırımcılık ve damgalanmaya uğramalarına engel olmak amacıyla HIV enfeksiyonunun bildiriminde hastaların güvenliği ve kişilik haklarına zarar verilmemesi esastır. Bu nedenle HIV nedeniyle sağlık kuruluşlarına başvuran, tedavi ve testlerini yaptıran hastaların veya yeni tespit edilen HIV + bireylerin kimliği ile ilgili bilgiler kodlanarak bildirilir. Ülkemizde HIV ile ilgili yıllık sayısal verilere Halk Sağlığı Genel Müdürlüğü'nün ilgili sayfasından ulaşılabilir. HIV Enfeksiyon Evreleri ​2​ ​3​ 1. Primer HIV enfeksiyonu: Virüs bulaşı sonucu ilk belirtilerin ortaya çıktığı akut HIV enfeksiyonu (1-6 hafta) ve serokonversiyonla (6-12 hafta) birlikte immün restorasyonun sağlanmaya başlandığı erken dönem HIV enfeksiyonudur. Akut dönemde klinik bulgular, HIV infeksiyonuna özgü değildir ve değişkendir. Sıklıkla görülen bulgular ateş, lenfadenopati, cilt döküntüleri, miyalji ve eklem ağrıları, ishal, baş ağrısı, bulantı, hepatosplenomegali ve oral aftlardır. 2. Kronik HIV enfeksiyonu: Persistan, asemptomatik, latent ya da inaktif dönem olarak da bilinir. Bu dönemde virüsün replikasyon hızı ve CD4+ T lenfosit kaybı azalır. Bu dönemde kişilerde belirti yoktur ama bulaştırıcıdırlar. Asemptomatik dönem ortalama 8-10 yıl sürer. Ancak vakaların %20 ila 30'unda ortalama 1.5-5 yıl içerisinde bir sonraki döneme geçiş olabilir. Asemptomatik süre hastaya ait faktörler ve HIV virülansı ile değişir. 3. İleri evre hastalık/AIDS: Tedavi edilmeyen HIV olgularının çoğunluğunda virüsün edinilmesinden ortalama 8-10 yıl sonra AIDS açığa çıkar. AIDS, CD4+ T lenfositi sayısının

Initiating Pharmacologic Treatment in Tobacco-Dependent Adults. An Official American Thoracic Society Clinical Practice Guideline https://www.atsjournals.org/doi/full/10.1164/rccm.202005-1982ST ultimate take home- varenicline is first line!! For Tobacco-Dependent Adults in Whom Treatment Is Being InitiatedShould Treatment Be Started with Varenicline or a Nicotine Patch? 40 more per 1,000 patients; Compared with a nicotine patch, varenicline increased long-term abstinence, measured at 6-month follow-up (RR, 1.20; 95% CI, 1.09 to 1.32; ARR, 40 more per 1,000 patients;) For Tobacco-Dependent Adults in Whom Treatment Is Being Initiated Should Treatment Be Started With Varenicline or Bupropion? 77 more per 1,000 patients taking Varenicline increased tobacco abstinence at 6-month follow-up compared with bupropion (RR, 1.30; 95% CI, 1.19 to 1.42; ARR, 77 more per 1,000 patients;) who andrew so just varenicline by itself?? thats it?? should Treatment Be Started with Varenicline plus Nicotine-Replacement Therapy or Varenicline Alone? 105 more per 1,000 patients; taking Varenicline plus a nicotine patch significantly increased abstinence compared with varenicline alone, (RR, 1.36; 95% CI, 1.07 to 1.72; ARR, 105 more per 1,000 patients; 95% CI, 21 more to 211 more; high certainty in the estimated effects) they mention ecigs vs varenicline and admit we dont have direct evidence but indirect evidence says varenicline is better but they admit because we dont have good evidence and all we have is indirect evidence then base on that go with varenicline but it is given a conditional rec with very low certainty of evidence. In Tobacco-Dependent Adults Who Are Not Ready to Discontinue Tobacco Use, Should Clinicians Begin Treatment with the Optimal Controller or Wait Until They Are Ready to Stop Tobacco Use? to me this was huge maybe one of the biggest recommendation because I always wait till the person is ready to stop but in studies where people could stop or were not interested in stopping those started on varenicline were more like to stop smoking. my mind was blown!! and the evidence on this gives a strong recommendation, with moderate certainty in the estimated effects. infact 173 more per 1,000 smokers were able to stop smoking at 6 months after starting varenicline despite the provider not waiting for affirmation of readiness (RR, 2.00; 95% CI, 1.70 to 2.35; ARR, 173 more per 1,000 patients; 95% CI, 121 more to 234 more; high certainty in the estimated effects). Tobacco-Dependent Adults with Comorbid Psychiatric Conditions, Including Substance-Use Disorder, Depression, Anxiety, Schizophrenia, and/or Bipolar Disorder, for Whom Treatment Is Being Initiated, Should Clinicians Start with the Optimal Controller Identified for Patients without Psychiatric Conditions or Use a Nicotine Patch? “boxed warning regarding possible neuropsychiatric adverse events for both varenicline and bupropion. These concerns stemmed from case reports and postmarketing surveillance, as no RCTs found evidence for these events and early observations suggested no significant increase in neuropsychiatric adverse events with pharmacotherapy compared with placebo, even among patients with preexisting mental illness.” to summarize --with moderate certainty compared with nicotine patches, varenicline 1) may result in a large benefit for nicotine abstinence and 2) compared with nicotine patches, varenicline would likely result in little to no difference in SAEs and last but not least- if you are given the choice to write a script for an Extended-Duration (>12 wk) or Standard-Duration (6–12 wk) then with a strong recommendation and moderate certainty in the estimated effects you should always chose the longer- go with 12 weeks! Guntupalli SR et al. Safety and efficacy of apixaban vs enoxaparin for preventing postoperative venous thromboembolism in women undergoing surgery for gynecologic malignant neoplasm: A randomized clinical trial. JAMA Netw Open 2020 Jun 1; 3:e207410. Following surgery for gynecologic malignancies, The American Society of Clinical Oncology has developed guidelines for postoperative VTE prophylaxis and they recommend almost 1 month of subcutaneous low-molecular-weight heparin is recommended to prevent venous thromboembolism (VTE); however, patients' hate this!! giving shots! randomized trial of 28 days of subcutaneous enoxaparin (40 mg daily) versus oral apixaban (2.5 mg twice daily) in 400 women (median age, 58) undergoing open or minimally invasive surgery for gynecologic cancer. primary end point of this study was the incidence of major bleeding events occurring during the treatment phase and in the 30 days after treatment. Major bleeding was defined as fatal bleeding and/or symptomatic bleeding in a critical area or organ or bleeding requiring the transfusion of 2 units of packed red blood cells. Major bleeding was limited to one participant in each group, incidence of clinically relevant nonmajor bleeding (hematoma, bruising, epistaxis, and vaginal bleeding) was similar between groups (12 [apixaban] and 19 [enoxaparin]), and VTE occurred in 2 and 3 patients, respectively. In the apixaban group, satisfaction was greater regarding ease of use (99% vs. 59%; P

Episode 2: B is for Butt Stuff Why do straight women engage in anal intercourse? CORRECTION: At the end of the video, Rob and Angel (1:31:00) answer a listener question about anal fluids and risk. Rob says that anal sex is 400x riskier than vaginal sex for HIV transmission, but said he thought he was misremembering that statistic. So, we looked it up. He was misremembering. According to a Canadian AIDS Treatment Information Exchange (CATIE) review of several HIV meta-analyses, risk of HIV transmission is up to 18x higher from receptive anal sex than from receptive vaginal sex.https://www.catie.ca/en/pif/summer-2012/putting-number-it-risk-exposure-hiv Where did that first, high number come from? Studies have shown that viral loads are up to 500% higher in rectal secretions (the mucous membrane fluid near the rectum) than in blood and up to 2500% higher than in semen! Should I be worried about HIV rectal secretions?  https://www.hivplusmag.com/sex-dating/2017/1/04/should-i-be-worried-about-hiv-rectal-secretions Zuckerman, R. A., Whittington, W. L., Celum, C. L., Collis, T. K., Lucchetti, A. J., Sanchez, J. L., ... & Coombs, R. W. (2004). Higher concentration of HIV RNA in rectal mucosa secretions than in blood and seminal plasma, among men who have sex with men, independent of antiretroviral therapy. The Journal of infectious diseases, 190(1), 156-161. https://academic.oup.com/jid/article/190/1/156/2191562i-base Viral Load Guide http://i-base.info/guides/testing/viral-load4. Getting to the Bottom of It: Anal sex, rectal fluid, and HIV transmission https://www.catie.ca/en/pif/fall-2014/getting-bottom-it-anal-sex-rectal-fluid-and-hiv-transmission#footnote8_3tk2r8q Links and Resources: The Article: Reynolds, G. L., Fisher, D. G., & Rogala, B. (2015). Why women engage in anal intercourse: results from a qualitative study. Archives of sexual behavior, 44(4), 983–995. doi:10.1007/s10508-014-0367-2https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379393/ This link has the images of the graphs we discussed in it as well. Twitter thread from @dmalebranche re: language around anal sex sexual encounters and HIV riskhttps://twitter.com/DMalebranche/status/1211270578382032896?s=20 Booty Basics and Backdoor BDSMhttps://professorsex.com/blog/booty-basics-and-backdoor-bdsm-anal-play-for-everyone This link has the anal anatomy photos I talked about on the show. The Great Lube Episode: https://youtu.be/NAncWg2jFuE  Satisyfer anal plug set I talked about during the Kink Crate promohttps://www.kinkcrate.com/shop/plugs/  Supplemental Reading:Bottom’s Up: Exploring Anal Play Beyond Penetrationhttps://professorsex.com/blog/bottom-s-up-exploring-anal-play-beyond-penetration  Teen Vogue: A guide to anal sex:https://www.teenvogue.com/story/anal-sex-what-you-need-to-know  Scarleteen: Anal sex low downhttps://www.scarleteen.com/article/advice/anal_sex_lowdown  Scarleteen: Meet your prostratehttps://www.scarleteen.com/article/advice/meet_your_prostate  The B-Vibe guide to Anal Play:https://www.bvibe.com/anal-sex-guide  This episode is sponsored by Kink Crate (KinkCrate.com). Podcast listeners can sign up and get 35% off their first crate by using code: AtoZ. Kink Crate is a monthly subscription box service, for adults, that contains kink and BDSM products, personal items, candy, stickers and other creative treats. Every month, for less than $50 (which includes shipping) your Kink Crate will be packed with 5 to 9 items, a kinky new theme, as well as the informative Kink Crate Handbook which often features content from Professor Sex. The handbook is the ultimate guide to your monthly crate, it will give you info on your items, useful tips for how to use them, and other pleasure-based sex ed content. Multiple crate options are available for every kind of couple and they also have a “single ladies” crate option. There’s no contract, so you can join or quit anytime you like. Kink Crate announces their themes every month, so you get a hint about what they’re up to, but the specific contents of the boxes are always a surprise. You can see Angel unbox some past Kink Crates on our YouTube channelhttps://youtu.be/ZdSdh0M5j_w https://youtu.be/scGGQCobct0 and read many articles that have featured in their handbook on the Professor Sex blog.https://professorsex.com/blog/come-to-your-senses-engaging-all-your-senses-to-enhance-sexual-desire-and-pleasure  Kink Crate Giveaway Details:Kink Crate is also giving away a Naughty Librarian crate box to one lucky Sex from A to Z listener. To enter to win, subscribe to the podcast or the YouTube channel and email us a screenshot and your contact info. (Email to info@professorsex.com) Refer a friend who subscribes and enters, and if they tell us you sent them each new friend will count as an additional entry for you. US Shipping only (sorry, friends). Contest ends on February 5, 2020 and winners will be announced on the podcast on February 7. About “Sex from A to Z”"Sex from A to Z" is a sex science podcast discussing in plain language the actual studies that inform how sex therapists, sex researchers, sex educators, and medical professionals make decisions about sexual health and wellness. On each episode we take a deep dive into a different piece of peer-reviewed literature, break it down and explore the social, scientific, and personal implications. This is a podcast for anyone interested in understanding the psychological, medical, and other scientific research behind sexual issues that impact all of us.“Sex from A to Z” is hosted by Angel Russell and Dr. Robert Zeglin, and produced by Steven Russell. Art for the podcast was created by Angel Russell. We will post links to all the articles we discuss and additional resources for exploring each topic. You can watch on YouTube or listen anywhere you find your favorite podcasts. 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Theodora Hatziioannou joins the TWiV team to discuss a macaque model for AIDS, and how a cell protein that blocks HIV-1 infection interacts with double-stranded RNA. Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, and Kathy Spindler Guest: Theodora Hatziioannou Become a patron of TWiV! Links for this episode ASU-UofA Joint Virology Symposium Laboratory of Retrovirology, Rockefeller University HIV-1-induced AIDS in monkeys (Science) APOBEC3H bound to duplex RNA (Nat Comm) Center for HIV RNA studies Image: Two molecules of APOBEC3H bound to dsRNA This episode is brought to you by Blue Apron. Blue Apron is the #1 fresh ingredient and recipe delivery service in the country. Get $30 off your first delivery and FREE SHIPPING by going to blueapron.com/twiv. This episode is brought to you by the Defense Threat Reduction Agency. Part of the U.S. Department of Defense, the Agency’s Chemical and Biological Technologies Department hosts the 2017 Chemical and Biological Defense Science & Technology Conference to exchange information on the latest and most dynamic developments for countering chemical and biological weapons of mass destruction. Find out more at http://www.cbdstconference.com Weekly Science Picks Theodora - To Kill A Mockingbird by Harper Lee Kathy - 25 MILLION Orbeez in a pool Dickson - Fluid Dynamics of Paint Rich - The Hitchhiker's Guide to the Galaxy by Douglas Adams Alan - 30 days at sea: timelapse Vincent - TWiEVO 24 and Every Time Zone Listener Picks Fernando - Lego Women of NASA Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

原创 造就 2017-05-05 11:10“究竟是我们工具的局限性，还是我们忽略了什么？如果我们能弄清楚这个过程，将大大加深我们对进化的了解。”上世纪50年代，芬兰生物学家比约恩·库尔滕（Björn Kurtén）发现，在他研究的马化石中，有一种异乎寻常的现象。当他对比只相隔了几代的马骨形状时，发现了很多细微但重要的变化。而相隔数百万年的马骨，表现出来的形态差异却要少得多。随后半个世纪的研究发现了类似的现象：当科学家用更短的时间跨度来对化石进行观察比对时，发现生物的进化速度似乎比过去所认为的更快。2005年前后，悉尼大学进化生物学家西蒙·何（Simon Ho）在他研究的基因组中，发现了类似的现象。他在计算鸟类和灵长类动物的DNA突变在数千年内的积累速度时发现，基因组充斥着细微的突变。这说明，“进化钟”在快速转动。但当他着眼于更长的历史跨度，对相隔数百万年的DNA序列进行比较时，结果却截然不同：“进化钟”的速度慢如龟爬。这使西蒙十分困惑，于是，他试图找出背后的原因。他偶然得知了库尔滕在1959年的研究，他意识到，生物形态变化速率的那种差异在基因序列中同样存在。作为进化生物学家，直觉告诉他，他发现的短期突变速率是正确的。基因组只在少数几个地方有所不同，但每个突变就像是在白色墙壁上泼一片油漆那么明显。而如果墙上出现更多的油漆，新泼的油漆会逐渐遮盖原来的墙壁颜色。类似的道理，进化和自然选择也会覆盖掉原先在短期内曾经出现的突变。在数百万年的时间里，DNA中的一个A可能变成T，但在这个过程中，它可能变成过C，也变成过G。西蒙认为，这种突变饱和是进化速率随时间改变（他称之为时间相关速率现象）的主要原因。悉尼大学进化生物学家西蒙·何发现，进化速度并非一成不变。“这好比股市。”他说。看看标普500指数在一天或者一小时之内的波动，它显得非常不稳定，起伏剧烈。但在更长的时间段内，股市看上去就要稳定得多，因为每天的变化开始向平均水平靠拢。同样，随着时间的推移，自然选择的力量会逐渐淘汰那些对生物体不利的突变。对生物学家来说，在基因组中发现时间相关速率现象，具有重大意义。这意味着，在解读生命进化过程时——从几十亿年前真核细胞和原核生物的首次分裂，到2014年埃博拉病毒的再次出现——生物学家用来作为标记的许多时间点，可能都是错的。“当这一发现公布时，所有人都惊呆了。”澳大利亚国立大学进化生物学家罗布·兰菲尔（Rob Lanfear）说。一开始，时间相关速率现象并没有被完全认可。首先，这是一个意义重大的概念，生物学家需要时间来思考。但更大的阻碍在于，这一概念几乎不可能得到应用。生物学家无法完全确定，他们应该在多大程度上改变他们在整个进化史中，对进化事件所发生时间的估计。如果没有一种具体可行的方法来计算进化速率的变化，科学家就无法对时间点进行比较。近日，牛津大学古生物病毒学家阿里斯·卡祖拉奇斯（Aris Katzourakis）将时间相关速率现象运用到了病毒进化的研究中。他不仅把某种逆转录病毒的起源时间回溯至大约5亿年前（远早于动物首次从海洋登上陆地的时间），而且还建立了一个数学模型，用来分析时间相关速率现象，从而让生物学家可以更加准确地估计进化事件的发生时间。美好的前景令其他科学家激动不已。“这就像爱因斯坦的相对论，只不过是在病毒领域。”墨尔本大学计算进化生物学家塞巴斯蒂安·杜赫（Sebastián Duchêne）说。根据时间相关速率现象，生物的进化速度取决于观察者所着眼的时间范围。就像有了相对论一样，现在，生物学家知道该如何调整他们对进化时间点的估计了。寻找病毒化石卡祖拉奇斯的主要工作是确定艾滋病病毒（HIV）和其他逆转录病毒的起源。逆转录病毒由单链核糖核酸（RNA）组成。他在研究HIV的突变速率时发现，它是进化速度最快的已知病毒之一。其快速突变是有原因的：像DNA这样的双链分子拥有分子校对机制，常常可以纠正复制过程中产生的错误，但HIV和其他单链RNA病毒却没有。错误只会导致错上加错。因此，病毒学家只能直接研究这类病毒的近期历史。时间更久远的样本已经达到突变饱和，积累的错误太多，科学家无法一一解释清楚。将逆转录病毒的历史往前推几千年或几百万年，这需要一种不同的方法来计算突变速率。卡祖拉奇斯采用了另一种方法。他在宿主的DNA内寻找类似于病毒化石的东西。逆转录病毒常常把它们的基因副本插入宿主的细胞。大多数时候，DNA上的信息会随着宿主的死亡而消失。不过，偶尔会有一个逆转录病毒在进化的道路上运气爆棚，溜进精子或卵细胞的基因组。在宿主的DNA中安全定居后，那个病毒就会一代一代传下去。卡祖拉奇斯就是利用这些病毒残骸来研究逆转录病毒的古老起源。在此过程中，他有了一个意外的发现：逆转录病毒的长期进化速率似乎大幅放缓，几乎与人类和其他复杂生物体相当。复杂生物体拥有校对机制，其进化速率理应比逆转录病毒慢得多。如果病毒的进化速度比科学家料想的要慢得多，这可能意味着，这些病毒比科学家预计的要古老得多。毕竟，与进化较快的病毒相比，进化较慢的病毒需要更长时间才能达到同样的进化程度。于是，他开始寻找逆转录病毒的准确起源时间。他研究了一类最古老的逆转录病毒，也就是泡沫病毒，猴子、牛等许多种动物都会感染这种病毒。通过这种方式，卡祖拉奇斯可以校准“进化钟”，以确定泡沫病毒出现的确切时间。如果两个物种拥有相同的泡沫病毒基因序列，那么在这两个物种分化之前，泡沫病毒肯定已感染了它们共同的祖先。“如此一来，我们就可以得知远古进化事件的发生时间，而这种方法不依赖于基因序列本身。”卡祖拉奇斯说。牛津大学古生物病毒学家阿里斯·卡祖拉奇斯把一类病毒的起源时间推回到了约5亿年前，远早于动物首次从海洋迁徙至陆地的时间。此前，研究人员已逐渐把泡沫病毒的起源时间回溯至1亿年前。但卡祖拉奇斯发现，有迹象显示，泡沫病毒感染爬行动物、两栖动物甚至鱼类的历史远远超过1亿年。但1亿年这个时间已被广泛认可，想要证明逆转录病毒的历史不止1亿年，卡祖拉奇斯必须确定泡沫病毒的起源时间才行。他查阅了西蒙关于时间相关速率现象的论文，想知道如何将它应用到病毒研究中。他还想建立一个通用模型，让研究人员输入他们观察的时间范围，便可得到生物进化速率的相关细节。为了确定进化速率如何随不同的时间范围而改变，卡祖拉奇斯和他的学生帕坤·埃尤萨昆（Pakorn Aiewsakun）尝试了四种不同的方法。他们发现，一个幂律衰减模型最符合他们的数据。该模型显示，进化速率随着时间范围扩大而以指数方式减小。随后一项对396种病毒的研究显示，几乎所有基因组类型和复制策略的进化速率都以相同的速度放缓。现有的“进化钟”没有考虑到时间相关速率现象，因而对古病毒的起源时间判断有误，实际上，它们的历史要古老得多。然后，卡祖拉奇斯和埃尤萨昆利用新建的数学模型，重新计算泡沫病毒的起源时间。他们发现，泡沫病毒出现于4.6亿至5.5亿年前。亚利桑那大学病毒学家迈克尔·沃洛贝（Michael Worobey）进行的独立研究也显示，这些病毒的起源时间比预想的要早。他们的研究使泡沫病毒成为了所有已知病毒类型中最古老的一种，不过卡祖拉奇斯认为，可能还有比它更古老的病毒。上述发现的意义远远不只是找到了最古老的病毒那么简单。关于泡沫病毒的起源时间，两组科学家得出了相同的结论，这表明，时间相关速率现象不只是统计学的遗珠，也不只是研究人员用来确定物种起源时间的方法。除了这些，卡祖拉奇斯的模型还为研究人员提供了一种工具，以此来确定时间相关速率现象所产生的影响，而这反过来又能帮助我们了解造成这种现象的原因。从更广泛的意义上来说，卡祖拉奇斯和西蒙的研究对进化速率保持不变的观点提出了挑战。“这改变了我们对分子进化的认知方式。”杜赫说，“它表明，进化速率并非一成不变。即便是同样的生物，进化速率也会随时间而改变。”卡祖拉奇斯说，这还意味着，科学家可能需要重新确定远古进化事件的发生时间，因为他们可能低估了这些事件的“年龄”。卡祖拉奇斯还想知道，自然选择和突变饱和所导致的某些突变被删除，这是否是造成时间相关速率现象的唯一原因，抑或是，有其他因素在这种现象中发挥了作用。“究竟是我们工具的局限性，还是我们忽略了什么？如果我们能弄清楚这个过程，将大大加深我们对进化的了解。”卡祖拉奇斯说。翻译：于波

To compare the presence and quantity of cervicovaginal HIV among HIV seropositive women with clinical herpes, subclinical HSV-2 infection and without HSV-2 infection respectively; to evaluate the association between cervicovaginal HIV and HSV shedding; and identify factors associated with quantity of cervicovaginal HIV. Four groups of HIV seropositive adult female barworkers were identified and examined at three-monthly intervals between October 2000 and March 2003 in Mbeya, Tanzania: (1) 57 women at 70 clinic visits with clinical genital herpes; (2) 39 of the same women at 46 clinic visits when asymptomatic; (3) 55 HSV-2 seropositive women at 60 clinic visits who were never observed with herpetic lesions; (4) 18 HSV-2 seronegative women at 45 clinic visits. Associations of genital HIV shedding with HIV plasma viral load (PVL), herpetic lesions, HSV shedding and other factors were examined. Prevalence of detectable genital HIV RNA varied from 73% in HSV-2 seronegative women to 94% in women with herpetic lesions (geometric means 1634 vs 3339 copies/ml, p = 0.03). In paired specimens from HSV-2 positive women, genital HIV viral shedding was similar during symptomatic and asymptomatic visits. On multivariate regression, genital HIV RNA (log10 copies/mL) was closely associated with HIV PVL (β = 0.51 per log10 copies/ml increase, 95%CI:0.41-0.60, p

Das Auftreten von Resistenzen ist eines der Hauptprobleme der heute angewandten antiretroviralen Therapie. Resistenzen können diagnostisch mit dem sog. genotypischen oder dem phänotypischen Verfahren festgestellt werden. Die genotypische Diagnostik beruht auf der Nukleotid-Sequenzierung der viralen Target-Gene Reverse Transkriptase (RT) oder Protease (PR), die relativ einfach zu bewerkstelligen ist. Ein phänotypischer Resistenztest und damit direkter Aktivitätstest der Enzyme RT und PR ist sehr viel präziser. Dies ist z.B. beim Vorliegen komplexer Resistenzmuster oder einem Mangel an genotypischer Information von resistenzrelevanten Mutationen bei einem neu verwendeten antiviralen Medikament von großer Bedeutung. Die zu testenden Enzyme werden entweder aus DNA, isoliert aus PBMCs aus Patientenvollblut oder Plasma-RNA rekombinant hergestellt. Vor kurzem wurde nun die Frage erhoben, ob die diagnostisch gemessenen Werte Unterschiede aufweisen, je nachdem ob DNA oder RNA als Ausgangsmaterial verwendet wurde. Die Veröffentlichungen zu diesem Thema waren diskreptant in ihren Aussagen. Zur Klärung dieser Frage wurde in der vorliegenden Arbeit das phänotypische Resistenzverhalten der HIV-Protease von 12 Patienten gegenüber 5 verschiedenen Proteaseinhibitoren untersucht. Aus jedem der Patienten wurde ein "Protease-Paar" sowohl aus HIV-DNA als auch HIV-RNA (via cDNA) rekombinant produziert. Die Patienten wiesen eine unterschiedliche Höhe der Viruslast auf, sie lag zwischen 1.900 cp/ml und 230.000 cp/ml, und hatten unterschiedlich hohe CD4-Zellzahlen. Mit dieser Untersuchung sollte also erstens die Frage beantwortet werden, ob zu einem gegebenen Zeitpunkt Abweichungen im Resistenzprofil zwischen den beiden Formen genetischer Information von HIV im Körper vorliegen können. Im positiven Fall sollte festgestellt werden, welchen Einfluss die Virusvermehrung/Virusdynamik und der Immunstatus des betroffenen Patienten, ausgedrückt durch die Laborparameter Viruslast und CD4-Zellzahl, darauf haben. Zweitens sollte dasjenige Probenmaterial gefunden werden, welches für den phänotypischen Resistenztest das optimale Resultat ergibt: entweder HIV-DNA aus PBMCs im Vollblut oder HIV-RNA aus Blutplasma. Der hier verwendete phänotypische Resistenztest (PRT) basiert auf der direkten Messung der HIV-Proteaseaktivität, die durch rekombinante Expression der gesamten Population von HIV-Protease eines Patienten hergestellt wurde. Für die vorliegende Arbeit wurde parallel sowohl HIV-DNA aus PBMCs im Vollblut als auch cDNA aus viraler RNA im Blutplasma des Patienten als Ausgangsmaterial für die nested PCR verwendet. Nach erfolgter Expression des Enzyms in E. coli und effektiver Ein-Schritt-Aufreinigung wurde die Proteaseaktivität mit einem neuen und schnellen phänotypischen Testsystem mittels eines Fluoreszenzsubstrates in Ab- und Anwesenheit der verschiedenen Inhibitoren gemessen. Durch den Vergleich mit Wildtyp-Werten konnten die entsprechenden Resistenzfaktoren berechnet werden. Ergebnis: Von den 12 untersuchten Patienten zeigten sich in 3 "DNA/RNA-Paaren" signifikante Unterschiede in mindestens einem Proteaseinhibitor, während bei 9 Patienten übereinstimmende Resistenzmuster gefunden wurden. Schlussfolgernd wird festgestellt, dass die Verwendung von entweder DNA oder RNA als Ausgangssubstanz für den benutzten Resistenztest unterschiedliche Ergebnisse im Resistenzmuster erbringen kann, dies aber nicht notwendigerweise der Fall ist. Zwischen dem Auftreten bzw. Fehlen von unterschiedlichen Resistenzmustern und den virologischen und immunologischen Parametern Viruslast und Anzahl der CD4 positiven Zellen konnte keine klare Korrelation festgestellt werden. Ein Auftreten von Differenzen zwischen den Resistenzmustern von DNA und RNA kann die Folge eines Populationswechsels der HIV-RNA sein, die im Gegensatz zur archivarischen Natur der meist integrierten DNA aus ruhenden CD4 positiven T-Gedächtniszellen oder Monozyten erst kürzlich von aktiv infizierten Zellen produziert wurde. Ein Fehlen von Unterschieden kann bedeuten, dass die Hauptfraktion der DNA entweder erst kürzlich generiert wurde oder die RNA sich nicht verändert hat. Für die diagnostische Anwendung des PRT haben diese Ergebnisse folgende Konsequenzen: um die aktuelle Resistenzsituation abzubilden, ist virale RNA aus dem Blutplasma das bevorzugte Ausgangsmaterial. Um dagegen stille Mutationen aufzudecken, die z.B. für zukünftige Therapien oder eine adäquate Postexpositionsprophylaxe von Bedeutung sind, sollte virale DNA, stammend aus PBMCs des Vollblutes, verwendet werden.

This study deals with the effects of treatment withdrawal in HIV-infected children. In a retrospective survey 35 HIV-infected children who were under medical treatment in the Hôpital Necker-Enfants Malades in Paris, France, were observed concerning their discontinuation of antiretroviral therapy after months or years of receiving treatment. All children had acquired HIV infection through vertical transmission and received antiretroviral therapy for at least ten months before interrupting therapy for different reasons between 1996 and 2000 (insufficiency, toxicity, inconvenience). The study group consisted of 16 girls and 19 boys with an average age of 10.4 ± 4.9 years at the time treatment was stopped. The average time of observation after treatment interruption was 325 ± 294 days. Plasma HIV RNA was tested approximately every three months using an RNA polymerase chain reaction test. The CD4 cell count was regularly checked approximately at the same time as the viral load and measured by flow cytometry. To estimate the presence of major mutations in the HIV reverse transcrip-tase and protease genes, genotypic resistance was tested before treatment interruption, in the absence of antiretroviral treatment and in the case of a restart of therapy, when a new combination of efficient agents had to be defined. Based on the assumption that the course of HIV RNA viral load and CD4 cell count depended on certain factors, distinctions were made between the medical history of viral load and CD4 cell count, age, sex and reason for treatment interruption. The changes of CD4 cell count and viral loads were then analysed to calculate the percentage of lost CD4 cells and the increase of viral load per day of treatment interruption. By the time the study was finished in December 2000, 21 children were still without any further anti-retroviral therapy whereas 14 children had to restart therapy. Even though we noticed a viral rebound in all patients within the first few weeks of treatment interruption, there were different profiles of immunological reaction. Especially children, who had good immune responses before treatment interruption and who had stopped therapy at an early age (under 5 years) before running the risk of virological treatment failure, showed the best results. On the contrary, patients who had stopped therapy because of virological treatment failure had a greater loss of CD4 cells and showed an important increase of viral load in the time off therapy so that a prolonged treatment interruption was not advisable for them. But even though therapy had to be restarted for 14 patients, a general reduction of time on drug therapy could be achieved. Similar to adult studies, our data suggest, that a significant proportion of HIV-infected children can be safely taken off therapy for a prolonged period of time in order to reduce toxicity and costs.