2013年11月13日水曜日

Cured Baby of HIV

HIV薬剤投与を中断した新生児の再発が見られないようだ。
 生後すぐにHIVの治療を受けた少女が、HIV感染から治癒したとみられる
との報告があった。3歳になった現在、少女にHIV感染の兆候はみられない。

報告書(New England Journal of Medicine)
・少女には抗レトロウイルス薬が生後18か月まで投与。
・経過を1年半にわたって見守ったが、HIV感染の兆候が検出されなかった。
・医療チームは、治療の成功の要因は早期介入にあったと考えている。
・少女に「特有」な事例である可能性もある。

HIV透明マント
・TSRIとWeill Cornell Medical Collegeの共同研究
・電子顕微鏡検査とX線結晶構造解析により、HIVのマントのたんぱく質を
 原子レベルで調査。
・マントのたんぱく質は三層構造で、感染の際、複雑に変化。
・効果的ワクチンの開発を進める。

ミシシッピ州で誕生した少女が3歳を迎えた。
母親がHIVに感染していたため、出産時にはHIV抗体検査で陽性反応。
投薬後、中断したが、3歳を迎えてもHIV抗体検査は陰性を継続。

HIVワクチンは失敗したが、いわゆるHIVの透明マントの解析が進み、
ワクチン開発の道が開かれそうとのこと。

2014年に米政府の支援で、大規模な試験を実施する予定とのこと。
2011年の国連統計では、HIV感染の新生児は33万人。
毎日1000人のHIV感染の新生児が世界で生まれる。
2010年、CDCは200人以下の新生児がHIV感染している。
ミシシッピ州の少女だけが、特異体質なのか、薬剤投与の効果も含め、
多数への効果があるのかが見つかる可能性がある。
失敗したHIVワクチンの開発が進むかもしれない。

A Baby With HIV Is Deemed Cured
HIV Vaccine Fails


---HIVから治癒した子ども、「偶然ではない」 米研究---
2013年10月28日 18:10 発信地:ワシントンD.C.
http://www.afpbb.com/articles/-/3002113

 【10月28日 AFP】生後すぐにヒト免疫不全ウイルス(HIV)の治療を受けた少女が、HIV感染から治癒したとみられるとの報告が、23日の米医学誌「ニューイングランド医学ジャーナル(New England Journal of Medicine)」に掲載された。3歳になった現在、少女にHIV感染の兆候はみられないという。
 報告書では、誕生翌日にHIVの陽性反応を示したDNA(デオキシリボ核酸)とRNA(リボ核酸)の検査結果にも触れており、本当は感染していなかったのではとの一部専門家から挙がっていた意見への回答が試みられている。
 少女には抗レトロウイルス薬が生後18か月まで投与された。その後の経過を1年半にわたって見守ったが、HIV感染の兆候が再び検出されることはなかった。
 「われわれの発見は、症状がみられない現状が単なる偶然ではなく、積極的な初期治療が寄与している可能性が高いことを示している」「最大の問いはもちろん『HIVが治癒したのかどうか』だ。現時点での最善の答えは『おそらく』だ」と、報告書は述べている。
 一方で研究チームは、今後長期にわたる追跡調査が必要と指摘。この少女の事例が将来のより綿密な研究につながるような理論的根拠を示しているとはいえ、少女に「特有」な事例である可能性もあると警告した。
 担当した医療チームは、治療の成功の要因は早期介入にあったと考えている。2014年には、米政府支援の下でより大規模な試験が開始される予定だ。


---Scientists determine atomic-level structure of key HIV protein---
Published on November 6, 2013 by Bryan Cohen
http://vaccinenewsdaily.com/medical_countermeasures/328266-scientists-determine-atomic-level-structure-of-key-hiv-protein/

Researchers determined the first atomic-level structure of the tripartite HIV envelope protein, which was long thought to be one of the most difficult targets in structural biology, The Scripps Research Institute said on Thursday.

Collaborating scientists at TSRI and Weill Cornell Medical College determined the structure for the protein, which is so complex and delicate that prior scientists had difficulty obtaining the protein in a suitable form for atomic-resolution imaging. The scientists engineered a version of the protein with the stability and other properties needed for the imaging. The researchers then used cutting-edge imaging methods, electron microscopy and X-ray crystallography to look see the atomic-level structure of the envelope protein, known as Env.

The findings provide the most detailed picture yet of the HIV’s complex envelope, including sites that could be targeted by future vaccines.

“Most of the prior structural studies of this envelope complex focused on individual subunits; but we’ve needed the structure of the full complex to properly define the sites of vulnerability that could be targeted, for example with a vaccine,” Ian Wilson, a senior author of the new research, said.

The data highlighted the complex process by which the Env three-component structure assembles and undergoes dramatic shape changes during infection. The imaging clarified how the Env trimer compares to envelope proteins on other dangerous viruses, like Ebola and flu.

“It has been a privilege for us to work with the Scripps team on this project,” John Moore, a senior author of the research with Weill Cornell, said. “Now we all need to harness this new knowledge to design and test next-generation trimers and see if we can induce the broadly active neutralizing antibodies an effective vaccine is going to need.”

The researchers published the findings in two papers in Science Express on Thursday.


---Mississippi toddler still HIV free---
By Saundra Young, CNN
October 24, 2013 -- Updated 2021 GMT (0421 HKT)
http://edition.cnn.com/2013/10/24/health/mississippi-toddler-hiv-free/

(CNN) -- Just hours after delivery, a baby born with HIV in Mississippi was given high doses of three antiretroviral drugs. Two and half years later, doctors say the little girl still has no evidence of the life-threatening disease in her blood, despite being taken off medication.

It's a potential game changer in the fight against the virus that causes AIDS, and it happened almost by accident.

The unidentified girl was born to a mother who received no prenatal care and was not diagnosed as HIV positive herself until just before delivery, according to a case report published this week in the New England Journal of Medicine.

"We didn't have the opportunity to treat the mom during the pregnancy as we would like to be able do to prevent transmission to the baby," said Dr. Hannah Gay, a pediatric HIV specialist at the University of Mississippi Medical Center.

Doctors administered the antiretroviral drugs 30 hours after the girl was born in hopes of controlling the virus. Within a couple of days, Gay confirmed the child was HIV positive. She said the baby had probably been infected in the womb.

The child remained on antiretroviral drugs for approximately 15 months. Her mother then stopped administering the drug for some reason, Gay said. The child has not received any antiretroviral drugs since that time, according to the report.

In March, researchers announced that the girl was the first child to be "functionally cured" of HIV. A "functional cure" is when the presence of the virus is so small, lifelong treatment is not necessary and standard clinical tests cannot detect the virus in the blood.

Gay told CNN the timing of intervention -- before the baby's HIV diagnosis -- may deserve "more emphasis than the particular drugs or number of drugs used."

"We are hoping that future studies will show that very early institution of effective therapy will result in this same outcome consistently," she said.

High-risk exposure

In March, Dr. Katherine Luzuriaga, an immunologist at the University of Massachusetts who worked closely with Gay, called the developments fascinating, including the fact that the toddler was found to have no virus in her blood even after her mother stopped giving her treatment.

"This is the very first case in which we've conclusively been able to document that the baby was infected and then after a period of treatment has been able to go off treatment without viral rebound," Luzuriaga told CNN.

Researchers have long known that treating HIV-positive mothers early on is important, because they pass antibodies on to their babies.

"One hundred percent of (HIV-positive) moms will pass those antibodies, but in the absence of treatment, only 30% of moms will transmit the actual virus," Luzuriaga told CNN.

HIV-positive mothers given appropriate treatment pass on the virus in less than 2% of cases, Luzuriaga said.

"So all babies are born antibody positive, but only a fraction of babies born to HIV-positive women will actually get the virus, and that fraction depends on whether the mom and baby are getting antiviral prophylaxis (preventative treatment) or not," Luzuriaga said.

Newborns are considered high-risk if their mothers' HIV infections are not under control or if they are found to be HIV positive when they're close to delivering.

Moving quickly to suppress the virus

Usually, these infants would get antiviral drugs at preventative doses for six weeks to prevent infection, then start therapy if HIV is diagnosed.

Investigators said the Mississippi case may change that practice because it highlights the potential for cure with early standard antiretroviral therapy, or ART.

ART is a combination of at least three drugs used to suppress the virus and stop the progression of the disease.

But they do not kill the virus. Tests showed the virus in the Mississippi baby's blood continued to decrease and reached undetectable levels within 29 days of the initial treatment.

Dr. Deborah Persaud, a virologist with Johns Hopkins Children's Center, was lead author on an early report about this case that was presented at a conference.

The early treatment likely led to the infant's cure, she said.

"Prompt antiviral therapy in newborns that begins within days of exposure may help infants clear the virus and achieve long-term remission without lifelong treatment by preventing such viral hideouts from forming in the first place," Persaud said.

Persaud and Luzuriaga are part of a group of researchers working to explore and document possible pediatric HIV cure cases. The group was funded by a grant from amfAR, the Foundation for AIDS Research, and the National Institutes of Health.

Dr. Rowena Johnston, amfAR vice president and director of research, said it is "imperative that we learn more about a newborn's immune system, how it differs from an adult's and what factors made it possible for the child to be cured."

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, said in March that he was enthusiastic about the findings.

"The best way to either eliminate the virus or allow the immune system to suppress residual virus is to treat someone as early as possible after infection so as not to allow a substantial reservoir of the virus to take hold," Fauci told CNN.

"At the same time, you prevent the immune system from being severely damaged by the continual replication of (the) virus for an extended period of time," he said. "The situation with a child born of an infected mother where most of the infections are transmitted to the newborn at or around the time of delivery provides an excellent opportunity to cure an infected baby, and this approach deserves further study."

'Berlin patient'

Researchers say the only other documented case of an HIV cure is that of Timothy Brown, known as the "Berlin patient." In 2007, Brown, an HIV-positive American living in Germany, was battling both leukemia and HIV when he underwent a bone marrow transplant that cured not only his cancer but his HIV.

In an interview last year, Brown told Dr. Sanjay Gupta, CNN's chief medical correspondent, he was still HIV-free.

"I've been tested everywhere possible," said Brown, who now lives in San Francisco. "My blood's been tested by many, many agencies. I've had two colonoscopies to test to see if they could find HIV in my colon, and they haven't been able to find any."

But Brown's case is rare.

And the procedure, which is extremely dangerous, won't work in most patients because the bone marrow he received had a special genetic mutation that made the stem cells in it naturally resistant to the virus.

Researchers tell CNN only 1% of Caucasians -- mostly Northern Europeans -- and no African-Americans or Asians have this particular mutation.

In June, five years after he was "cured," reports surfaced that "traces" of the virus had been found in Brown's blood.

Even then, some HIV experts said that doesn't matter, that he's been cured. In fact, many AIDS experts said they believe Brown has experienced what's called a "sterilizing" cure, meaning the virus has been eliminated from the body entirely.

Routine clinical testing on the Mississippi toddler continues.

"We have formed a hypothesis," Luzuriaga said, "and that is already driving the design of new studies and clinical trials that will help us to answer the question of whether by coming in very early we will be able to treat children for a while and then remove them from therapy."


---Baby 'cured' of HIV: New details offer hope for other patients---
By Karen Kaplan
October 23, 2013, 3:16 p.m.
http://www.latimes.com/science/sciencenow/la-sci-sn-baby-cured-of-hiv-report-20131023,0,2346578.story#axzz2kOPyLP4C

New details about the first person to be cured of HIV through drug therapy alone offer hope that others who are born with the virus may be able to beat it back and avoid a lifetime of treatment, researchers reported Wednesday.

The formerly HIV-positive Mississippi girl drew widespread interest in March when doctors presented her case in March at a medical meeting in Atlanta. Now they have published a full account of the girl’s treatment and recovery in New England Journal of Medicine.

The 3-year-old girl has not taken any antiretroviral drugs for at least 18 months - yet tests find “no detectable level of HIV-1 RNA” in her blood, according to the report.

The only other person considered functionally cured of HIV is Timothy Ray Brown,  also known as the “Berlin patient.” Brown’s cure was brought about by more radical means - a bone marrow transplant. He needed the transplant because he had acute myeloid leukemia, and his doctors used it as an opportunity to find a donor who had a rare genetic mutation that blocks HIV from entering cells.

But there are several reasons why this approach can’t be extended to the estimated 34 million people worldwide who are HIV-positive. For one, bone marrow transplants are risky. The risk of death is acceptable for patients with cancer but not for patients with HIV who can control their infection with drugs, doctors say.

Also, very few patients would be able to find a bone marrow donor who is a match for their immune system and who also has the genetic mutation that keeps HIV at bay. Researchers are trying to introduce the rare mutation directly to patients using gene therapy, though more research is needed before clinical trials can begin.

The girl’s case is enticing because her cure came about through antiretroviral drug treatment, or ART. Experts suspect that the three-drug cocktail was so successful because it prevented HIV from establishing itself in the patient’s immune system. Once the virus digs in, it evades drugs and remains dormant until the opportunity arises to strike again.

Thanks to preventive treatments, babies born with HIV are rare in the U.S. - the Centers for Disease Control and Prevention said that fewer than 200 infants were infected at birth in 2010. But around the world, about 1,000 babies are born with the virus every day, experts estimate. Those are the patients who stand to gain from the unintentional experiment involving the Mississippi girl, according to the authors of the New England Journal of Medicine report.

The girl’s doctors didn’t stop her treatment to see if she could get along without her drugs, because a test like that would have been considered unethical. Instead, the mother stopped filling the girl’s prescriptions when she was 15 months old. She also told doctors her daughter hadn’t taken the ART drugs since she was 18 months old.

Five months later, the girl came to a clinic for a checkup. Her doctors expected to find that her viral load, which had been undetectable since she was 29 days old, had built back up. But blood tests found no signs of the virus - a complete surprise.

The results were confirmed by additional blood tests. No HIV antibodies were found in samples drawn when the girl was 24, 26 and 28 months old, according to the New England Journal of Medicine report. A single copy of viral RNA was found in blood plasma drawn when the girl was 24 months old, but ultra-sensitive tests failed to detect any copies two months later.

“At the age of 36 months, at least 18 months after the cessation of ART, the child has no detectable level of HIV-1 RNA,” the authors wrote.

When the girl’s case was first announced, some doctors wondered whether the child really had HIV in the first place. The New England Journal of Medicine report offers much evidence that she was infected in utero. A blood sample drawn 30 hours after birth contained HIV-1 DNA. Another sample drawn an hour later had enough HIV RNA - 19,812 copies per milliliter of blood - to qualify for an HIV-positive diagnosis.

Doctors initially treated the baby with a three-drug cocktail that included zidovudine, lamivudine and nevirapine. Her first doses were administered when she was 30 hours old. After one week, doctors switched her from nevirapine to ritonavir-boosted lopinavir. As treatment continued, her viral load declined in a manner “similar to that described previously in HIV-1 infected infants and adults receiving ART,” they wrote.

Back in March, some experts also wondered whether the girl happened to have the rare mutation that makes people naturally immune to HIV. She does not, according to the study.

The doctors also noted that the girl’s “growth and development have been normal.”

The girl’s case supports the idea that starting antiretroviral therapy very soon after birth prevents the virus from getting any traction in the immune system, the report’s authors concluded. Further studies already in the planning stages might be able to show that the strategy can spare infected infants from “a lifetime of therapy,” they concluded.

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