dChan - Q Origins Project Archive

Clin Ther

. Nov-Dec1996;18(6):1080-92. doi: 10.1016/s0149-2918(96)80063-4.

Inhibition of HIV-1 replication by hydroxychloroquine: mechanism of action and comparison with zidovudine

G Chiang 1, M Sassaroli, M Louie, H Chen, V J Stecher, K Sperber

https://pubmed.ncbi.nlm.nih.gov/9001825/

Abstract

We have previously described the inhibition of human immunodeficiency virus serotype 1 (HIV-1) using the antimalarial hydroxychloroquine (HCQ), a weak base that inhibits the posttranslational modification of glycoprotein 120 (gp 120) in T cells and monocytes. The mechanism of inhibition of gp 120 production was presumed to be the ability of HCQ to increase endosomal pH and therefore alter enzymes required for gp120 production. To further clarify this action, we have determined the effect of HCQ and its enantiomers on endosomal pH. Pretreatment of cells with HCQ and the levo- and dextro-enantiomers at concentrations demonstrated to suppress anti-HIV-1 activity increased endosomal pH to levels similar to increases seen with chloroquine and ammonium chloride, two other weak bases, and decreased gp 120 production. The dextro- and levo-enantiomers suppressed HIV-1 replication to a similar extent and were no more toxic than racemic HCQ. We next compared the anti-HIV-1 effect of HCQ with zidovudine (ZDV) in both newly and chronically HIV-1-infected T-cell and monocytic cell lines (63 and 63HIV). HCQ suppressed HIV-1 replication in a dose-dependent manner in both recently and chronically infected T-cell and monocytic cell lines. In contrast, ZDV pretreatment had potent anti-HIV-1 activity in the newly infected T and monocytic cells but not in chronically infected cells. An additive effect of HCQ with ZDV was observed in the newly infected T and monocytic cells but not in the chronically infected cells. Although the anti-HIV-1 effect of HCQ was less than that of ZDV, HCQ may still be potentially useful either as an alternative HIV-1 treatment or in combination with other anti-HIV-1 agents, especially in patients who have rheumatic manifestations of HIV-1 infection.

>>15578677

Clin Ther

. Jul-Aug1995;17(4):622-36. doi: 10.1016/0149-2918(95)80039-5.

Hydroxychloroquine treatment of patients with human immunodeficiency virus type 1; HIV type 1

K Sperber 1, M Louie, T Kraus, J Proner, E Sapira, S Lin, V Stecher, L Mayer

Abstract

Hydroxychloroquine (HCQ), an antimalarial agent used to treat patients with autoimmune diseases, has been shown to suppress human immunodeficiency virus type 1 (HIV-1) replication in vitro in T cells and monocytes by inhibiting posttranscriptional modification of the virus. These in vitro observations have been expanded into an in vivo study of HCQ as a potential anti-HIV-1 agent in HIV-1-infected patients. A randomized, double-blind, placebo-controlled clinical trial was conducted in 40 asymptomatic HIV-1-infected patients who had CD4+ counts between 200 and 500 cells/mm3. Patients were randomly assigned to receive either HCQ 800 mg/d or placebo for 8 weeks. Virologic and immunologic parameters, including HIV-1 ribonucleic acid (RNA) via use of polymerase chain reaction, viral culture, antigen and mitogen responses, and proinflammatory cytokine levels were measured at the beginning and end of the study. The amount of recoverable HIV-1 RNA in plasma declined significantly in the HCQ group over the 8-week period (P = 0.022), while it increased in the placebo group. The percentage of CD4+ T cells remained stable in the HCQ-treated group (18.1 +/- 9.2% before treatment vs 18.6 +/- 10.5% after treatment) and fell significantly in the placebo group (21 +/- 7% before treatment vs 19.3 +/- 6.3% after treatment; P = 0.032). However, this was not reflected as a change in absolute CD4+ counts for either group (HCQ, 262.8 +/- 166 cells/mm3 vs 251 +/- 163 cells/mm3; placebo, 312 +/- 121 cells/mm3 vs 321 +/- 124 cells/mm3). Mitogen- and antigen-specific responses remained constant in the HCQ group while T cell proliferative responses to Candida decreased in the placebo group (4.8 +/- 3.6 x 10(3) SI [stimulation index] vs 3.0 +/- 3.0 x 10(3) SI; P = 0.032). Lastly, serum interleukin 6 levels declined in the HCQ group (14.3 +/- 13.5 U/mL vs 12.0 +/- 16.7 U/mL; P = 0.023) but not in the placebo group (11.3 +/- 8.8 U/mL vs 7.0 +/- 11.7 U/mL); this was coincident with a decrease in serum immunoglobulin (Ig)G (2563 +/- 1352 mg/mL vs 2307 +/- 1372 mg/dL; P = 0.032), compared with the placebo group (2733 +/- 1473 mg/dL vs 2709 +/- 1501 mg/dL). No other parameters, including serum p24 and beta-2 microglobulin levels, were altered by HCQ therapy. HCQ thus may be useful in the treatment of patients with HIV-1 infection.

>>15578699

>>15578677

Biochem J

.2012May 1;443(3):851-6. doi: 10.1042/BJ20120150.

Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus

Kylie M Wagstaff 1, Haran Sivakumaran, Steven M Heaton, David Harrich, David A Jans

Biochem J

. 2012 May 1;443(3):851-6. doi: 10.1042/BJ20120150.

Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus

Kylie M Wagstaff 1, Haran Sivakumaran, Steven M Heaton, David Harrich, David A Jans

https://www.fredhutch.org/en/news/center-news/2014/12/hiv-vaccine-holy-grail.html

Closing in on ‘holy grail’ of HIV vaccine

Researchers describe a way to induce long-sought broadly neutralizing antibodies

DECEMBER 11, 2014 • BY MARY ENGEL /FRED HUTCHNEWS SERVICE

HIV researchers Drs. Andy McGuire and Leo Stamatatos have found a potential new way for a vaccine to induce broadly neutralizing antibodies that work against multiple strains of HIV.

Photo by Robert Hood / Fred Hutch News Service

About three years ago, Dr. Leo Stamatatos, an internationally known immunologist then at Seattle BioMed, was ready to abandon his efforts to develop the “holy grail” of HIV vaccine research – a vaccine that would stimulate the production of so-called broadly neutralizing antibodies that defend against infection by a wide spectrum of HIV strains.

“Everything had been tried, everything had failed, and I said, ‘Come on, that’s it,’” he said. “There was no reason I was going to keep doing the same thing over and over.”

But a presentation by a visiting researcher gave him a new way of looking at the problem – and sent him and his lab team back to the drawing board to continue their quest.

The results, published today in the journal Science, suggest why previous vaccine formulations haven’t been able to elicit broadly neutralizing antibodies and describe a potential way forward to hit exactly the right B cells, which are a type of immune cell.

“This is the next wave,” said Dr. Julie McElrath, senior vice president and director of the Vaccine and Infectious Disease Division at Fred Hutchinson Cancer Research Center, where Stamatatos and his team moved in October. “Their findings give us new clues to improve our chances of inducing broadly neutralizing antibodies, which is the holy grail of an HIV vaccine.”

The long search

Most vaccines work by inducing B cells to produce antibodies so that down the road if a person is exposed to the pathogen, they will be equipped to fight it. One way that antibodies block infection is by binding to and inhibiting, or neutralizing, a pathogen. Typically, neutralizing antibodies narrowly focus on a specific pathogen; most HIV antibodies are specific for a single strain of HIV.

But scientists discovered that after several years of being infected with HIV, about 20 percent of people naturally produce rarer broadly neutralizing antibodies that work against many different strains, although by the time they develop them it is too late to block the virus. Researchers have long believed that to be effective, an HIV vaccine would have to elicit these kinds of broadly neutralizing antibodies, among other types of responses, because the global HIV pandemic mutates so prolifically. So far, there’s been no evidence that any of the candidate vaccines have been able to do so.

In fact, in the 30 years since the AIDS virus was identified, only one vaccine candidate has shown any protection at all against infection. The so-called Thai vaccine, named for the study concluded in that country in 2009, elicited a type of antibody that works by a different mechanism: Rather than neutralizing a pathogen on its own, it binds to and recruits other parts of the immune system to help kill the virus. The Thai vaccine reduced the risk of contracting HIV by 31 percent, not enough to warrant licensing but nonetheless hailed as a breakthrough because it provided the first evidence that developing a protective vaccine was even possible. (In January in South Africa, the Fred Hutch-based HIV Vaccine Trials Network will begin testing a new version of the Thai vaccine that has been modified to boost its potency and durability.)

The idea that convinced Stamatatos to not give up on the quest for a vaccine to induce broadly neutralizing antibodies came from a paper delivered by Dr. Dimiter Dimitrov, a researcher from the National Cancer Institute.

“He said the precursor of one particular broadly neutralizing antibody was not binding HIV,” Stamatatos said. “He had a very narrow sample, but basically, that’s the moment I said, ‘Well, maybe that’s the reason – things just don’t start. For me, it was a light bulb.”

pt1

>>15578733

Looking back to move forward

To elicit the type of broadly neutralizing antibody that Stamatatos is after, a vaccine has to stimulate B cells with antibodies that hit a target on the HIV envelope that has a consistent structure across strains. The vaccine candidates that have been tried in the past were effective at stimulating the production of antibodies that targeted parts of the HIV envelope that vary widely between strains, thus blocking only one or a few strains.

Antibodies evolve to bind viruses better as the immune response progresses. So working backwards from broadly neutralizing antibodies that had evolved in patients, the researchers were able to recreate the initial antibodies that first encountered the virus – the ones expressed on the B-cell surface that the virus initially bound to and stimulated. They then tested how well both the mature and precursor antibodies responded to previous vaccine candidates. In a paper published in 2013 in the Journal of Experimental Medicine, they reported that B cells with the mature antibodies on their surface – the ones that had evolved some 10 years after infection – responded well, but the precursors did not respond at all. That’s because the vaccines were made from engineered HIV proteins, and HIV has evolved specifically to avoid detection by those B cells.

“The key thing is that there are the precursors that give rise to those antibodies,” said Dr. Andy McGuire, a postdoc in Stamatatos’ lab who, as a self-described “yeast guy who works in immunology,” brought new thinking to HIV research. “You have to start the process in a naïve B cell. It’s not just broadly neutralizing antibodies per se but the B cells and precursors that give rise to them that we’re studying.”

The new paper, by McGuire, Stamatatos and collaborators at The Rockefeller University and Institut Pasteur, describes a way to modify the vaccine candidate so that neutralizing antibody precursors can target it while it slips away from the other B cells.

“The key was when Andy found out the modification that’s required to start the process,” said Stamatatos.

Next steps

The work that Stamatatos and his team are doing to stimulate broadly neutralizing antibodies so far has only been done in the lab. But if all goes according to plan, it could be in human trials in about two years.

The trials would be for proof of concept, to show whether researchers can, for the first time in humans, stimulate the right B cells and start the process of making broadly neutralizing antibodies.

“It’s something completely different – the hypothesis and the approach – from what’s been done before,” said Stamatatos. “Just for that, I feel optimistic that we’re going to be one step ahead of where we were. But it’s a long way still. It’s not going to happen overnight.”

Even if human trials show that a vaccine can elicit broadly neutralizing antibodies, researchers would need to find ways to maintain those antibodies for a long period of time. A vaccine would also probably need to elicit other immune responses as well.

“We think now that broadly neutralizing antibodies will be a critical component of an effective vaccine, but I don’t think personally it will be the only one,” Stamatatos said.

One possibility – if trials are successful – would be to combine a vaccine candidate that elicits broadly neutralizing antibodies with, for example, the Thai vaccine, adding to the effect already seen there.

Those are the kinds of challenges that keep Stamatatos and other researchers going through the long years of trying to develop a successful vaccine against HIV.

“You’re not thinking, ‘It’s a failure,’” he said. “We approach it as a problem: Why can’t we make broadly neutralizing antibodies? The daily thoughts center around solving experimental problems.”

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Infect Genet Evol. 2020 Nov; 85: 104583. Published online 2020 Oct 6. doi: 10.1016/j.meegid.2020.104583

PMCID: PMC7536551PMID: 33035643

Emergence and molecular mechanisms of SARS-CoV-2 and HIV to target host cells and potential therapeutics

Mansab Ali Saleemi,a Bilal Ahmad,a Khaled Benchoula,c Muhammad Sufyan Vohra,c Hing Jian Mea,a Pei Pei Chong,a Navindra Kumari Palanisamy,b and Eng Hwa Wongc,⁎

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7536551/

Abstract

The emergence of a new coronavirus, in around late December 2019 which had first been reported in Wuhan, China has now developed into a massive threat to global public health. The World Health Organization (WHO) has named the disease caused by the virus as COVID-19 and the virus which is the culprit was renamed from the initial novel respiratory 2019 coronavirus to SARS-CoV-2. The person-to-person transmission of this virus is ongoing despite drastic public health mitigation measures such as social distancing and movement restrictions implemented in most countries. Understanding the source of such an infectious pathogen is crucial to develop a means of avoiding transmission and further to develop therapeutic drugs and vaccines. To identify the etiological source of a novel human pathogen is a dynamic process that needs comprehensive and extensive scientific validations, such as observed in the Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), and human immunodeficiency virus (HIV) cases. In this context, this review is devoted to understanding the taxonomic characteristics of SARS-CoV-2 and HIV. Herein, we discuss the emergence and molecular mechanisms of both viral infections. Nevertheless, no vaccine or therapeutic drug is yet to be approved for the treatment of SARS-CoV-2, although it is highly likely that new effective medications that target the virus specifically will take years to establish. Therefore, this review reflects the latest repurpose of existing antiviral therapeutic drug choices available to combat SARS-CoV-2.

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7536551/

>>15578733

>Fred Hutch

(HUGE recipient of Gates Foundation $$)

$23.5M Granted to Fred Hutch Researchers to Defeat HIV

https://info.biotech-calendar.com/23.5m-granted-to-fred-hutch-researchers-to-defeat-hiv

DefeatHIV, an initiative based out of the Fred Hutchinson Cancer Research Center in Seattle, WA, has been researching potential cures for HIV over the past 5 years. Their research has focused on the use of blood cells genetically modified to be resistant to the HIV virus. It was recently announced that the National Institutes of Health (NIH) awarded the DefeatHIV team a new grant of $23.5 million that will continue to support their research on this potential cure for an additional 5 years.

With the new grant, the DefeatHIV team will focus on three key research areas which all involve studying the immune system and its potential to control, or eradicate, HIV. Seattle researchers will be collaborating with teams in Florida and Washington as part of the DefeatHIV research. (Image of the FHCRC courtesy of Ciar via Wikimedia Commons)

Dr. Keith-Jerome, a virologist in Seattle and co-director of DefeatHIV said that: “We’re excited and honored to be able to continue DefeatHIV’s work and keep Fred Hutch at the center of HIV cure research, particularly in the area of cell and gene therapy."

The Seattle-based Fred Hutchinson Cancer Research Center receives millions of dollars annually from private and public institutions and donors.In the 2015 fiscal year, the university received more than $232.6 million in life science funding from the National Institutes of Health(NIH). Funding given to the university is used to establish new research buildings and support vital life science research being undertaken at the institution. Learn more about the Fred Hutchinson Cancer Research Center:

The Fred Hutchinson Cancer Research Center is the only comprehensive cancer center in the Oregon and Washington area.

Fred Hutchinson has an annual research budget close to $400 million.

Fred Hutchinson Cancer Research Center receives more funding from the National Cancer Institute than any other research institution.

With so much funding from the NIH and other sources, researchers at Fred Hutch have the means to purchase many new lab products that will assist their research projects. Biotechnology Calendar, Inc. produces an annual BioResearch Product Faire™ event in Seattle that is a premiere opportunity for laboratory suppliers to market to life science researchers, and allows the researchers to find the best products and technologies for their work.

The 12th Annual BioResearch Product Faire™ Event in Seattle, WA will be held on Wednesday, October 11, 2017 and is expected to attract over 100 life scientists.

The three new approaches to curing HIV that the team will be focusing on are:

Using engineered HIV-resistant and anti-HIV T cells to target cells that carry HIV as a potential cure. This research area will take an approach that has been used to fight cancer, and transfer its method to combating HIV. Cancer researchers have been able to genetically modify T cells of patients by using chimeric antigen receptors (CARs), synthetic receptors, to kill certain cancer cells that contain a specific marker. The DefeatHIV team will study the possibility of engineering CARs that will be able to target markers found in cells that have HIV.

Using a genetically engineered synthetic antibody to to fight HIV. Researchers working on this approach will be led by Dr. Michael Farzan from the Scripps Research Institute in Jupiter, FL. Dr. Farzan created a molecule in 2015 that proved to be more powerful at fighting HIV than any naturally made antibody in humans. The team working with DefeatHIV will continue to study this engineered antibody and its potential to treat HIV.

Using a therapeutic vaccine to increase the immune system's response to HIV-resistant cells, like genetically modifies T cells. This portion of the research will be led by Dr. Jim Mullins from the University of Washington.

Dr. Hans-Peter Kiem, co-director of DefeatHIV in Seattle explained that: “We’ve learned that the immune response — the patient’s immune system — plays a critical role in controlling HIV, just like in cancer. It’s set the stage for the next generation of studies to further mobilize and harness the immune system to fight HIV.”