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Published Date: 2017-05-04 12:11:52

Subject: PRO/EDR> HIV - USA: (AZ) CRISPR

Archive Number: 20170504.5010676
HIV - USA: (ARIZONA) CRISPR

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Date: Mon 1 May 2017 4:26 AM MST

Source: ABC15 Arizona [edited]

http://www.abc15.com/news/state/arizona-seeing-an-increase-in-hiv-cases





Arizona is dealing with a spike in HIV cases, according to the latest national numbers and local prevention groups. "This is a public health issue that we now have the resources to completely prevent," said Glen Spencer, executive director of Aunt Rita's Foundation in Phoenix.



Between 2010 and 2015, the rate of HIV infections nationwide decreased 9 per cent, according to the Centers for Disease Control and Prevention [CDC]. In the same time period, the infection rate in Arizona increased 35 per cent, Spencer's data shows. "Right now there are some limitations in state law that put up barriers to young kids getting education -- comprehensive sex education in school," he said.



Since 1991, state law has prohibited schools from teachings that promote "a homosexual lifestyle" or suggest that safe-sex methods are safe, or safer, for homosexual sex. A bill that would've changed that was voted down last year [2016] by state legislators.



"There's still a perception that talking honestly about HIV and HIV transmission somehow is a bad thing," he said. Spencer is also pushing for increased awareness of PrEP [pre-exposure prophylaxis], a once-a-day drug that greatly decreases the risk of HIV infection.



[byline: John Genovese]



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ProMED-mail

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[This upswing in HIV infection is implied to be primarily in the MSM (men who have sex with men) community and state laws seem to have thwarted education efforts in this regard. The availability of highly active antiretroviral therapy has made overwhelmingly differences in the morbidity and mortality of HIV infection but requires, at this point, life-long therapy to control. Education regarding safe sex practices in both homosexual and heterosexual situations and the availability of pre-exposure prophylaxis therapy should directly affect this increase in cases. Infected bisexual males represent a reservoir to infect women as well.



Whether life-long therapy will always be required continues to be investigated.



One approach, studied in a simian model uses monoclonal antibodies and a human trial is being organized: dual antibody treatment suppresses HIV-like virus in monkeys https://www.nih.gov/news-events/nih-research-matters/dual-antibody-treatment-suppresses-hiv-virus-monkeys/:



"HIV, the virus that causes AIDS, attacks the body's immune system. This assault leaves people vulnerable to developing other infections and diseases. Although treatments can control HIV infection, HIV persists in the body for a lifetime.



"Researchers have isolated many human antibodies that neutralize multiple strains of HIV. Scientists have gained important insights into how these broadly neutralizing antibodies bind to the virus and why they're effective. However, designing a strategy that allows the human immune system to mount an effective attack against the virus remains a challenge.



"A team led by Dr Malcolm A Martin at NIH's National Institute of Allergy and Infectious Diseases (NIAID) and Dr Michel C Nussenzweig at Rockefeller University has been exploring therapeutic approaches using broadly neutralizing antibodies. Their latest study, in rhesus macaques, appeared online on 13 Mar 2017, in Nature (Nishimura Y, Gautam R, Chun TW, et al. Early antibody therapy can induce long-lasting immunity to SHIV. Nature. 2017. doi: 10.1038/nature21435. [Epub ahead of print]. PMID: 28289286; http://www.nature.com/nature/journal/v543/n7646/full/nature21435.html).



"The researchers inoculated 13 monkeys with SHIV, an HIV-like virus that infects monkeys. 3 days afterward, when infection could first be confirmed, the scientists began intravenous infusions of 2 potent, broadly neutralizing HIV antibodies. The antibodies, called 3BNC117 and 10-1074, each bind to a different site on SHIV. The animals received 3 antibody infusions over a 2-week period. The infusions suppressed SHIV to levels near or below the limit of standard detection methods for as long as 6 months. The virus then rebounded in all but one animal. However, 5 to 22 months later, the immune systems of 6 monkeys regained control of the virus, and the virus remained undetectable for another 5 to 13 months. These monkeys had continuously maintained healthy levels of key immune cells after receiving the antibody infusions. 4 other monkeys that failed to regain complete control of the virus maintained extremely low levels of SHIV in their blood for 2-3 years after infection. Thus, 10 of the 13 monkeys gained lasting benefits from the neutralizing HIV antibodies.



"Immune cells called CD8+ T cells help destroy infected cells. To test whether these immune cells played a role in the extended control of SHIV, the scientists depleted CD8+ T cells in the 6 controller monkeys. Without these immune cells, SHIV levels in the monkeys' blood rose, showing that CD8+ T cells were responsible for controlling SHIV after the antibody infusions.



"What really surprised us was that we could control SHIV for 2 to 3 years without any anti-viral drugs by infusing the antibodies right after the animals became infected," Martin says.



"Studies are now under way to test whether receiving neutralizing antibodies 2 to 6 weeks after infection -- timing that more closely resembles how soon an HIV-infected person first seeks medical attention -- will still enable monkeys to control SHIV. Clinical trials testing the antibody combination in people are also underway. Researchers are now recruiting HIV-infected and uninfected adults."



Another approach involves the CRISPR [clustered regularly interspaced short palindromic repeats] system to extract the integrated HIV provirus from the genome of infected individuals (http://www.philly.com/philly/health/health-news/Temple-uses-gene-editing-to-eliminate-HIV-infection-in-mice.html):



"Temple University researchers on [Mon 1 May 2017] said they had used a gene-editing technique to snip out HIV DNA from the genetic code of mice, bolstering the hope that the infection can be cured.



"The work, done with University of Pittsburgh scientists and published in the journal Molecular Therapy, builds on several years of Temple experiments that initially showed the AIDS virus could be cut from cells in lab dishes. A permanent cure for HIV has been elusive because the virus can maintain a simmering reservoir of infection in certain cells. Antiviral drugs suppress replication so that only a tiny minority of immune cells have the infection, but if the drugs are stopped, the latent virus can break out and resume its destructive course.



"The new study is the 1st to demonstrate that HIV replication can be shut down and the virus eliminated from animal cells by using the gene editing technology, called CRISPR/Cas 9. It combines a synthetic "guide RNA" -- a genetic analogue of the search function in a word processor -- with an enzyme that acts like a molecular scissors.



"The study, co-led by Kamel Khalili, director of Temple's center for neurovirology, successfully used the gene editing strategy in 2 mouse models -- one representing a newly acquired infection, when the virus is actively replicating, the other representing chronic, or latent, infection. The next step would be to repeat the study in primates such as monkeys, because they more closely mimic human HIV infection, Khalili said in a news release.



"CRISPR technology is barely 6 years old and has not been used in humans. Last year [2016], a federal advisory panel approved a University of Pennsylvania proposal to use CRISPR to engineer immune cells to fight certain types of cancer, but the trial must still be approved by the FDA."



[byline: Marie McCullough]



One of the group's papers is:



Chaoran Y, Zhang T, Qu X, et al. In vivo excision of HIV-1 provirus by saCas9 and multiplex single-guide RNAs in animal models. Molecular Therapy 2017; pii: S1525-0016(17)30110-7; https://doi.org/10.1016/j.ymthe.2017.03.012.



Abstract

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"CRISPR-associated protein 9 (Cas9)-mediated genome editing provides a promising cure for HIV-1/AIDS; however, gene delivery efficiency in vivo remains an obstacle to overcome. Here, we demonstrate the feasibility and efficiency of excising the HIV-1 provirus in 3 different animal models using an all-in-one adeno-associated virus (AAV) vector to deliver multiplex single-guide RNAs (sgRNAs) plus _Staphylococcus aureus_ Cas9 (saCas9). The quadruplex sgRNAs/saCas9 vector outperformed the duplex vector in excising the integrated HIV-1 genome in cultured neural stem/progenitor cells from HIV-1 Tg26 transgenic mice. Intravenously injected quadruplex sgRNAs/saCas9 AAV-DJ/8 excised HIV-1 proviral DNA and significantly reduced viral RNA expression in several organs/tissues of Tg26 mice. In EcoHIV acutely infected mice, intravenously injected quadruplex sgRNAs/saCas9 AAV-DJ/8 reduced systemic EcoHIV infection, as determined by live bioluminescence imaging. Additionally, this quadruplex vector induced efficient proviral excision, as determined by PCR genotyping in the liver, lungs, brain, and spleen. Finally, in humanized bone marrow/liver/thymus (BLT) mice with chronic HIV-1 infection, successful proviral excision was detected by PCR genotyping in the spleen, lungs, heart, colon, and brain after a single intravenous injection of quadruplex sgRNAs/saCas9 AAV-DJ/8. In conclusion, in vivo excision of HIV-1 proviral DNA by sgRNAs/saCas9 in solid tissues/organs can be achieved via AAV delivery, a significant step toward human clinical trials."

- Mod.LL



A HealthMap/ProMED-mail map can be accessed at: http://healthmap.org/promed/p/207.]

See Also

Syphilis - USA: (NC) increased incidence, ocular, HIV-coinfection 20170330.4935408

HIV - China: (ZJ) nosocomial transmission 20170210.4830673

2016

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Syphilis, gonococcal dis., HIV - Australia: (AC) increased incid & testing, 2015 20161119.4640115

Syphilis, gonococcal disease, HIV - Ireland: rising incidence, MSM 20161017.4564211

Syphilis, gonococcal disease, chlamydia, HIV - USA: (CA) LA, MSM, condom use 20160930.4527847

HIV: inaccuracy, viral load assay, RFI 20160713.4339758

HIV: USA (CO) nosocomial, India transfusion related 20160603.4264066

Syphilis - USA (04): (NC) incr. incidence, ocular, MSM, HIV, anon. online dating 20160320.4107520

Lymphogranuloma venereum - Czech Republic: incr., MSM, HIV coinfect., 2010-2015 20160320.4106603

HIV - Europe: laboratory infection 20160225.4050454

Hepatitis B & C, HIV - USA (02): (CO) nosocomial risk, alert 20160224.4041874

Syphilis, gonococcal dis., chlamydia - Canada: (BC,ON) inc. cases, MSM, HIV, RFI 20160212.4016426

Hepatitis B & C, HIV - USA: (CO) nosocomial risk, alert 20160205.3997234

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