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WHAT'S NEW THIS SUNDAY: SIX ON HIV/AIDS

Thursday, 2nd of August 2012

• SIX ON HIV

 

• A WORLD WITHOUT AIDS, STILL WORLDS AWAY

 

By LAWRENCE K. ALTMAN, M.D.

The New York Times

Published: July 30, 2012

WASHINGTON — Is the world on the verge of ending the AIDS epidemic and creating an AIDS-free generation, even though a cure and a vaccine are still distant hopes?

Yes, roared enthusiasts among the nearly 24,000 participants at the 19th International AIDS Conference here last week. Their hopes are based on the extraordinary scientific gains made since the conference was last held in the United States, 22 years ago, when an AIDS diagnosis was a sure death sentence.

Among those gains: antiretroviral drug combinations for women to prevent infection of their newborns; drugs to treat and prevent infection with H.I.V., the virus that causes AIDS, among adults; and evidence that voluntary male circumcision can reduce the risk of female-to-male transmission by 50 to 60 percent.

Today, H.I.V. has become a chronic disease that, if treated appropriately, can be held at bay in a newly infected young adult for decades — if the patient adheres to the rigid daily drug regimen.

Michel Sidibé, the executive director of the United Nations AIDS agency, said that the opportunity to end AIDS will “evaporate” if governments do not show greater political will and increase investments to make gains available to millions more people.

“All that can stop us now is indecision and lack of courage,” he said.

Ending the AIDS epidemic is likely to be far more complicated than ending most other epidemics. The AIDS conferences assemble scientists and health workers from a wide range of disciplines, infected people, activists, protesters, journalists, elected and appointed officials, pharmaceutical representatives and others. The meetings, in part, boost morale and raise the aspirations of thousands of people fighting AIDS, a laudable goal.

 

But since they began, in 1985, they have become more like conventions than scientific meetings. Rhetoric is plentiful, and separating it from fact is sometimes a challenge. Activists disrupt scientific presentations and news conferences with loud demonstrations, creating a circuslike atmosphere. Lobbying for more AIDS money is a given.

Dr. Richard Horton, the editor of The Lancet, the medical journal that arguably focuses most on global health, said of the conference’s new sloganeering about turning back AIDS, “It’s a marketing strategy.” He added, “It’s one that could backfire.”

One obstacle is a failure to clearly define the epidemic or what it means to have an AIDS-free generation. While many speakers repeatedly admonished that AIDS policy must be based on scientific evidence, they missed this point. The importance of precise definitions for such hopeful words extends far beyond semantics.

Definitions of terms like these may help determine how many billions of dollars the world devotes to the battle against AIDS and how many millions of lives will be extended. A failure to meet ill-defined goals could lead to public misunderstandings that limit investments and the number of people who have access to the lifesaving antiretroviral drugs in the future.

And, as Sharonann Lynch, an AIDS policy adviser for Doctors Without Borders, said in an interview, “We do have to get concrete in terms of what it means, because otherwise we are not going to be able to hold governments accountable” for how they spend taxpayers’ money to achieve specified goals.

To begin with, defining the word “epidemic” is difficult. The term is flexible and subjective, and can mean different things to different experts. Even more elusive is determining what constitutes the end of an epidemic like this one.

AIDS makes people deathly ill from problems like severe weight loss, swollen lymph nodes and a loss of critical immune cells that increases a person’s vulnerability to myriad other infections. But H.I.V. infection can remain silent for several years before causing symptoms.

Some speakers defined an AIDS-free generation as the absence of people sick from the disease. But even if there is no one with AIDS, there will still be millions of H.I.V.-infected people with us for a very long time. In those terms, H.I.V. will likely be endemic until there is a cure.

Dr. Helen Rees, an AIDS expert at the University of the Witwatersrand in Johannesburg, said that while scientific advances provide “cause for optimism,” the fact is that if many infected people stop taking their drugs, even for brief periods, they could transmit H.I.V. to others — and those strains may well be drug-resistant.

This is not the end of an epidemic in any sense as we have understood it; an AIDS-free generation, if it arrives, will live in a world where H.I.V. very much remains a threat. Dr. Peter Piot, the United Nations AIDS program’s first director, from 1995 through 2008, said in an interview that he was “puzzled” by the apparent lack of attention to such distinctions at the conference.

“Which generation?” asked Dr. Piot, who is now the dean of the London School of Hygiene and Tropical Medicine in England. “Mine? Or the next one? Or my great-grandchildren’s?”

Bill Gates, whose foundation is spending billions on developing AIDS preventions, expressed skepticism that the world could soon end the AIDS epidemic by any conventional definition. “Unfortunately, we do not have the tools, and we need lots of new tools,” with a vaccine the ultimate preventive one, Mr. Gates told the conference.

He and others called for greater accountability from AIDS workers in identifying the measures that work so they can be stepped up and those that do not so they can be stopped. For example, in countries where young people are dying in excessive numbers, he said, health workers must learn “why they did not start treatment, and if they were on treatment, why did it not work?”

The AIDS epidemic is not unfolding uniformly across the globe. Speakers cited an undertaker in Lesotho who said he was going out of business because of poor coffin sales, as so many people with H.I.V. are staying alive.

But undertakers do a brisk business in other countries with a rising AIDS incidence. In some ways, this is not just one epidemic. Scientists often use the term “R0” as a statistical way to monitor an epidemic, with “R” standing for the reproductive number of an infectious disease agent.

When, on average, one infected person transmits an infection to more than one other person, R0 becomes greater than one, leading to sustained spread or epidemic spread of the agent. When R0 is less than one, epidemic spread does not occur, and the agent will become endemic or disappear.

In AIDS, R0 depends on a number of factors, like the prevalence of H.I.V. in a sexual network and the efficiency of H.I.V. transmission per sexual act. The R0 varies in the many different H.I.V. epidemics in the world.

“We talk about generalized epidemics and concentrated epidemics,” said Dr. Kevin M. De Cock, director of global health at the Centers for Disease Control and Prevention in Atlanta.

“As guidance, we say if the prevalence of H.I.V. is greater than 1 percent in a sentinel population like pregnant women, we call it a generalized epidemic,” he added. “That is terribly arbitrary, but useful for certain discussions.”

Because the conferences, held every two years, offer one of the biggest lobbying venues for AIDS workers, pleas for money from governments, foundations and other sources are standard. Indeed, the conference in South Africa in 2000 is credited with stimulating efforts to provide access to antiretroviral drugs for millions of people in poor countries who would have otherwise died.

Many participants were disappointed that President Obama did not appear. But a large number of administration officials, members of Congress and Bill Clinton did attend.

This conference came at a time of global recession, which has reduced the financial contributions used to provide treatment to those who need it. Of the 15 million infected with H.I.V. only five million are receiving the drugs they need, according to U.N.AIDS.

At the same time, participants raised questions about the ethics of providing uninfected Americans with drugs to prevent H.I.V. when poor people elsewhere with AIDS received none.

Many participants likened ending the AIDS epidemic to medicine’s successes against two other viral infections, smallpox and polio. Smallpox is the only naturally occurring human infection to have been eradicated, meaning that cases can no longer arise because the causative virus has been wiped out of nature.

The World Health Organization defines elimination of an infectious disease as bringing the number of cases below a predetermined amount, or reducing the number to zero in a specific region. Polio was eliminated from the Western Hemisphere, though it requires regular controlled public health efforts to maintain that, and it still is spread in Nigeria, Afghanistan and Pakistan.

The conference participants who spoke of eradicating or eliminating AIDS failed to recognize that a vaccine was required to succeed against smallpox and polio.

In saying that the United States is committed to achieving an AIDS-free generation, Secretary of State Hillary Rodham Clinton told the conference that her definition of the phrase means “virtually no child anywhere will be born with the virus” by 2015. People who become infected “will have access to treatment that helps prevent them from developing AIDS and passing the virus on to others.”

Under Mrs. Clinton’s definition, many people will continue to become H.I.V.-infected, but not go on to suffer the myriad other infections and devastation caused by AIDS. “The disease that H.I.V. causes need not be with us,” she said.

 

But even if that goal is reached, millions will be living with H.I.V. for a long time to come.

A version of this article appeared in print on July 31, 2012, on page D5 of the New York edition with the headline: A World Without AIDS, Still Worlds Away.

 

 

• THE LONG, UPHILL BATTLE AGAINST AIDS

The New York Times, Editorial,  28 July

The international AIDS conference in Washington has already made two points clear. There is no prospect that scientists will any time soon find the ultimate solutions to the AIDS epidemic, namely a vaccine that would prevent infection with the AIDS virus or a “cure” for people already infected with the virus. Even so, health care leaders already have many tools that have been shown in rigorous trials to prevent transmission of the virus, making it feasible to talk of controlling the epidemic within the foreseeable future. The only question is whether the nations of the world are willing to put up enough money and make the effort to do it.

An estimated 34.2 million people around the world are currently infected with H.I.V., the virus that causes AIDS. According to the United Nations agency that tracks the disease, some 23.5 million of these live in sub-Saharan Africa and another 4.2 million in India and Southeast Asia. About 1.1 million live in the United States.

This conference is the first in more than two decades to be held in the United States. It became possible only when a benighted policy that prohibited entry visas for people suffering from AIDS or infected with H.I.V. was finally overturned in 2009. It was “a bad policy, based on faulty science, that ran contrary to America’s deepest values,” Kathleen Sebelius, the secretary of health and human services, told the conference.

There has been optimistic talk at the conference about accelerating the search for a “cure” that would allow people to eventually stop taking the drugs that have prolonged many lives for decades — and about developing a truly effective vaccine. But Dr. Anthony Fauci, the American government’s top AIDS expert, made clear just how difficult those tasks will be. He told the conference that a cure was “way upstream” and depends on future research breakthroughs, and he called the most successful vaccine trial to date “humbling” because it showed only a modest degree of efficacy.

Instead of waiting for these future possibilities, Dr. Fauci and other health leaders are proposing the broad adoption of other available tools to reduce the spread of the virus so as to produce an “AIDS-free generation,” a goal enunciated last year by Secretary of State Hillary Rodham Clinton. In her talk at the conference this week, Mrs. Clinton anticipated a time when virtually no child anywhere would be born with the virus, teenagers and young adults would have much less risk of becoming infected and those that do become infected would have access to treatments to prevent them from developing full-fledged AIDS or passing the virus on to others.

She cited the importance of condoms, counseling and testing; voluntary circumcision to protect males from becoming infected by a female partner; treating mothers to prevent transmission to their babies; and treating infected people with antiviral drugs as early as possible to enhance their own health and lessen the likelihood they will spread the virus to others. Studies also show that people at high risk of infection can protect themselves by taking an antiviral pill daily.

All that will take money. There is a widespread misconception that donors from well-heeled international organizations, rich countries and charitable foundations are the main source of money to combat the global epidemic. The share provided by international donors has, in fact, stagnated while the share provided by low- and middle-income countries to fight the epidemic on their own turf has been growing rapidly. Last year, the poorer countries invested $8.6 billion of their own money while international financing remained at $8.2 billion, the 2008 level, according to a report from the United Nations AIDS agency. Both groups will need to expand their contributions to meet ambitious treatment and prevention goals set for coming years.

Mrs. Clinton announced additional financing for AIDS programs, but perhaps her most important pledge was that the United States will issue a blueprint by Dec. 1 setting forth a road map for how to achieve an AIDS-free generation. To be effective, it will need to set priorities and define specific health outcomes and coverage targets and require detailed annual reports on the progress being made. It is unacceptable that millions of people sick enough to need treatment are not getting it.

 

• MEASLES REVACCINATION OF HIV SEROPOSITIVES

‘Measles revaccination induced high rates of seroprotection and memory in children receiving HAART.’

J Infect Dis. (2012) 206 (4): 512-522. doi: 10.1093/infdis/jis386 First published online: June 12, 2012

Immunogenicity, Immunologic Memory, and Safety Following Measles Revaccination in HIV-Infected Children Receiving Highly Active Antiretroviral Therapy

Abstract below; full text available to JID subscribers

Mark J. Abzug1, Min Qin2, Myron J. Levin1, Terence Fenton2, Judy A. Beeler3, William J. Bellini4,

Susette Audet3, Sun Bae Sowers4, William Borkowsky5, Sharon A. Nachman6, Stephen I. Pelton7,

Howard M. Rosenblatt8,a

and for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1024 and P1061s Protocol Teams

+ Author Affiliations

1University of Colorado School of Medicine and Children's Hospital Colorado, Aurora

2Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts

3Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland

4Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

5New York University School of Medicine and Bellevue Hospital Center, New York

6State University of New York at Stony Brook, Stony Brook, New York

7Boston University School of Medicine and Boston Medical Center, Massachusetts

8Baylor College of Medicine and Texas Children's Hospital, Houston

Correspondence: Mark J. Abzug, MD, Pediatric Infectious Diseases, Box B055, Children's Hospital Colorado, 13123 East 16th Ave, Aurora, CO 80045 (mark.abzug@childrenscolorado.org).

Abstract

Background. Response rates and immunologic memory following measles vaccination are reduced in human immunodeficiency virus (HIV)–infected children in the absence of highly active antiretroviral therapy (HAART).

Methods. HIV-infected children 2 to <19 years old receiving HAART and with HIV loads <30 000 copies/mL, CD4% ≥15, and ≥1 prior measles-mumps-rubella vaccination (MMR) were given another MMR. Measles antibody concentrations before and 8, 32, and 80 weeks postvaccination were determined by plaque reduction neutralization (PRN). A subset was given another MMR 4–5 years later, and PRN antibody was measured before and 7 and 28 days later.

Results. At entry, 52% of 193 subjects were seroprotected (PRN ≥120 mIU/mL). Seroprotection increased to 89% 8 weeks postvaccination, and remained at 80% 80 weeks postvaccination. Of 65 subjects revaccinated 4–5 years later, 85% demonstrated memory based on seroprotection before or 7 days after vaccination. HIV load ≤400 copies/mL at initial study vaccination was associated with higher seroprotection rates, greater antibody concentrations, and memory. Grade 3 fever or fatigue occurred in 2% of subjects.

Conclusions. Measles revaccination induced high rates of seroprotection and memory in children receiving HAART. Both endpoints were associated with HIV viral load suppression.

• ANTIRETROVIRAL THERAPY  FOR TB PREVENTION IN HIV SEROPOSITIVE ADULTS

Editors' Summary below; full text is at http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001270

 

Background

Tuberculosis—a contagious bacterial infection— is a global public-health problem. In 2010, 8.8 million people developed active tuberculosis and 1.4 million people died from the disease. Tuberculosis can be cured by taking powerful antibiotics regularly for several months, and between 1995 and 2010, 46 million people with tuberculosis were successfully treated using DOTS—a directly observed antibiotic regimen designed by the World Health Organization (WHO). Now, though, the HIV epidemic is compromising global tuberculosis control efforts. HIV-positive people are very susceptible to tuberculosis because HIV, the virus that causes AIDS, destroys the immune system cells (including CD4 lymphocytes) that normally combat tuberculosis. In 2010, 1.1 million of the new (incident) cases of tuberculosis were among the 34 million people living with HIV, and 350,000 people died of HIV-associated tuberculosis, making tuberculosis the leading cause of death among HIV-positive people. To tackle HIV-associated tuberculosis, which occurs mainly in developing countries, WHO now recommends that HIV and tuberculosis programs use collaborative approaches such as the Three I's for HIV/TB strategy—intensified tuberculosis case-finding among HIV-positive people, isoniazid preventative therapy for HIV-positive people without active tuberculosis, and (tuberculosis) infection control in healthcare facilities, social settings, and households.

Why Was This Study Done?

Despite progress in scaling up the Three I's for HIV/TB strategy, complementary interventions are still needed to prevent tuberculosis in HIV-positive people. Antiretroviral therapy (ART) lowers the viral load of people infected with HIV and restores their immune system function and could, therefore, prevent HIVassociated tuberculosis, in addition to treating HIV infection. WHO recommends ART for all HIV-positive adults with a CD4 count of less than 350 cells/μl of blood and for all HIVpositive, tuberculosis-positive individuals irrespective of their CD4 count. However, the evidence for ART's preventative impact on tuberculosis has not been systematically examined. Here, the researchers undertake a systematic review (a search that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical method for combining the results of studies) to investigate the impact of ART initiated at various CD4 counts on the development of tuberculosis in HIV-positive adults in developing countries.

What Did the Researchers Do and Find?

The researchers found 11 studies that compared tuberculosis incidence by ART status in HIV-infected adults over periods longer than six months on average in developing countries and undertook meta-analyses of these studies based on four categories of CD4 count at ART initiation (less than 200 cells/μl, 200–350 cells/μl, greater than 350 cells/μl, and any CD4 count). For all these categories, ART was strongly associated with a reduction in the incidence of tuberculosis. For example, the meta-analysis of the two studies that reported on participants in whom ART was initiated at a CD4 count less than 200 cells/μl yielded a hazard ratio (HR) of 0.16. That is, study participants starting ART when their CD4 count was below 200 cells/μl were about one-sixth as likely to develop tuberculosis as participants not receiving ART. In the metaanalysis of all 11 studies, study participants receiving ART were about one-third as likely to develop tuberculosis as study participants receiving no ART, irrespective of their CD4 count (HR 0.35). Importantly, the CD4 count at which ART was initiated did not significantly alter the magnitude of ART's preventive effect on tuberculosis development.

What Do These Findings Mean?

These findings suggest that ART is strongly associated with a reduction in the incidence of tuberculosis in HIV-positive adults in developing countries, whatever the CD4 count at ART initiation. Because most of the studies in this meta-analysis were observational, these results do not show that ART causes a reduction in tuberculosis incidence—other unknown factors shared by the study participants who received ART may be responsible for their lower tuberculosis incidence. Moreover, factors such as variations in diagnostic methods among the studies included in this meta-analysis may have affected the accuracy of these findings. Nevertheless, the key finding that ART is associated with a significant reduction in tuberculosis cases among adults with CD4 counts greater than 350 cells//μl should be considered by healthcare providers, policymakers, and people living with HIV when weighing the benefits and risks of early ART initiation. It also suggests that early ART initiation (in combination with expanded HIV testing) could be a key component of future global and national strategies to control HIV-associated tuberculosis.

 

• HPV INFECTION AND INCREASED RISK OF HIV ACQUISITION: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract below and at http://pag.aids2012.org/abstracts.aspx?aid=16342

 

C.F. Houlihan^1,2, N.L. Larke¹, D. Watson-Jones^1,2, K.K. Smith-Mccune^3,4, S. Shiboski⁵, P.E. Gravitt⁶, J.S. Smith⁷, L. Kuhn^8,9, C. Wang¹⁰, R. Hayes<sup>1

1</sup>London School of Hygiene and Tropical Medicine, London, United Kingdom, ²Mwanza Intervention Trials Unit, Mwanza, United Republic of Tanzania, ³University of California San Francisco, Department of Obstetrics, Gynecology and Reproductive Sciences, San Francisco, United States, ⁴University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, United States, ⁵University of California San Francisco, Department of Epidemiology and Biostatistics, San Francisco, United States, ⁶Johns Hopkins University, Bloomberg School of Public Health, Baltimore, United States, ⁷University of North Carolina - Chapel Hill, North Carolina, United States, ⁸Columbia Mailman School of Public Health, Department of Epidemiology, New York, United States, ⁹Columbia University College of Physicians & Surgeons, Sergievsky Center, New York, United States, ¹⁰University of Cape Town, Department of Pathology, Cape Town, South Africa

 

Background: Human papillomavirus (HPV), one of the commonest sexually transmitted infections, may be a cofactor in HIV acquisition. We systematically reviewed the evidence for an association of HPV infection with HIV acquisition in women, heterosexual men and men who have sex with men (MSM).

Methods: Studies meeting inclusion criteria in Pubmed, Embase and conference abstracts up to 31/07/11 were identified. Random effects meta-analyses were performed to calculate summary hazard ratios (HR). Publication bias was formally tested using Begg's test and heterogeneity was assessed via the I² statistic. A components approach was used to evaluate bias within studies.

Results: Eight papers were included, with previously unpublished data received from five authors. Seven of the eight studies found an association between HPV infection and HIV acquisition. The risk of HIV acquisition in women doubled with prevalent HPV infection with any genotype (HR=2.06 (95%CI=1.44-2.94), I²=0%, n=3). Adjustment for confounders was often inadequate and the comparison group varied between studies. The effect seen was similar for high-risk (HR=1.99 (95%CI=1.54-2.56), I²=8.4%, n=5) and low-risk (HR=2.01 (95%CI=1.27-3.20), I²=0%, n=2) HPV genotypes with weak evidence of publication bias (p=0.06). In heterosexual men and MSM, penile and anal HPV infection, respectively, were associated with HIV acquisition. However, only two studies were identified and therefore meta-analysis was not performed.

Conclusions: Meta-analysis of studies in women showed an association between prevalent HPV infection and HIV acquisition, although included studies were at risk of bias and residual confounding. A similar association was seen in MSM and heterosexual men. If further studies validate this association, HPV vaccines may reduce HIV incidence in high-HPV prevalence populations, in addition to being highly effective in the primary prevention of cervical cancer. As HPV-vaccine programs are introduced, surveillance studies will be important to monitor the impact of HPV vaccination on HIV acquisition.

 

• STANFORD CHEMISTS SYNTHESIZE COMPOUND THAT FLUSHES OUT LATENT HIV

 

Stanford Report, July 16, 2012

 

A new collection of compounds, called "bryologs" – derived from a tiny marine organism – activate hidden reservoirs of the virus that currently make the disease nearly impossible to eradicate.

By Max McClure

Thanks to antiretrovirals, an AIDS diagnosis hasn't been a death sentence for nearly two decades. But highly active antiretroviral therapy, or HAART, is also not a cure.

Patients must adhere to a demandingly regular drug regimen that carries plenty of side effects. And while the therapy may be difficult to undergo in the United States, it is nearly impossible to scale to the AIDS crisis in the developing world.

The problem with HAART is that it doesn't address HIV's so-called proviral reservoirs – dormant forms of the virus that lurk within T-cells and other cell types. Even after all of the body's active HIV has been eliminated, a missed dose of antiretroviral drugs can allow the hibernating virus to emerge and ravage its host all over again.

"It's really a two-target problem," said Stanford chemistry Professor Paul Wender, "and no one has successfully targeted the latent virus."

But Wender's lab is getting closer, exciting many HIV patients hoping for a cure.

The lab has created a collection of "bryologs" designed after a naturally occurring, but difficult to obtain, molecule. The new compounds have been shown to activate latent HIV reservoirs with equal or greater potency than the original substance. The lab's work may give doctors a practical way to flush out the dormant virus.

The findings were published on July 15 in the journal Nature Chemistry.

Nature's medicine

The first attempts to reactivate latent HIV were inspired by observations of Samoan healers. When ethnobotanists examined the bark of Samoa's mamala tree, traditionally used by healers to treat hepatitis, they found a compound known as prostratin.

Prostratin binds to and activates protein kinase C, an enzyme that forms part of the signaling pathway that reactivates latent viruses. The discovery sparked interest in the enzyme as a potential therapeutic target, especially as it was discovered that prostratin isn't the only biomolecule to bind to the kinase.

The bryozoan Bugula neritina – a mossy, colonial marine organism – produces a protein kinase C-activating compound that is many times more potent than prostratin. The molecule, named bryostatin 1, was deemed to hold promise as a treatment, not only for HIV but for cancer and Alzheimer's disease as well.

The National Cancer Institute initiated a Phase II clinical trial for the compound in 2009 for the treatment of non-Hodgkin lymphoma. But the substance had a number of side effects and proved prohibitively difficult to produce.

"It took 14 tons of bryozoans to make 18 grams of bryostatin," said Wender. "They've stopped accrual in trials because, even if the trials worked, the compound cannot be currently supplied."

Patient enrollment was suspended until more accessible compounds came out of the Wender Group's lab.

A synthetic approach

Wender, who published the first practical synthesis of prostratin and its analogs in 2008, had set out to make a simpler, more effective synthetic analog of bryostatin.

"We can copy the molecule," he said, "or we can learn how it works and use that knowledge to create something that has never existed in nature and might be superior to it."

The seven resulting compounds, called bryologs, share two fundamental features with the original bryostatin: the recognition domain, which directly contacts protein kinase C, and the spacer domain, which allows the bryolog-protein kinase C complex to be inserted into the cell membrane.

The researchers tested the new compounds' ability to reactivate viral reservoirs in J-Lat cell lines, which contain latent HIV and begin to fluoresce when they express the virus.

In the J-Lat line, bryologs induced virus in as many or more cells than bryostatin at a variety of concentrations, and ranged from 25 to 1,000 times more potent than prostratin. The compounds showed no toxic effects.

Bryolog testing remains in the early stages – the researchers are currently conducting in vivo studies in animal models. But practical bryostatin substitutes may be the first step toward true HIV-eradication therapy.

"I receive letters on a regular basis from people who are aware of our work – who are not, so far as I know, scientifically trained, but do have the disease," said Wender. "The enthusiasm they express is pretty remarkable. That's the thing that keeps me up late and gets me up early."

The research was supported by the National Institutes of Health.

Primary authors are Stanford chemistry graduate student Brian Loy and doctoral students Brian DeChristopher and Adam Schrier, in collaboration with Professor Jerry Zack, co-director of the UCLA AIDS Center, and Dr. Matthew Marsden from the UCLA School of Medicine.

Abstract of Wender’s co-authored article, also at

http://www.nature.com/nchem/journal/vaop/ncurrent/full/nchem.1395.html

Nature Chemistry | Article

Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro

• Brian A. DeChristopher,^{1, 3} Brian A. Loy,^{1, 3} Matthew D. Marsden,^{2, 3} Adam J. Schrier,^{1, 3}

Jerome A. Zack² & Paul A. Wender¹

• ·Journal name:

Nature Chemistry, 2012Year published:

Abstract

Bryostatin is a unique lead in the development of potentially transformative therapies for cancer, Alzheimer's disease and the eradication of HIV/AIDS. However, the clinical use of bryostatin has been hampered by its limited supply, difficulties in accessing clinically relevant derivatives, and side effects. Here, we address these problems through the step-economical syntheses of seven members of a new family of designed bryostatin analogues using a highly convergent Prins-macrocyclization strategy. We also demonstrate for the first time that such analogues effectively induce latent HIV activation in vitro with potencies similar to or better than bryostatin. Significantly, these analogues are up to 1,000-fold more potent in inducing latent HIV expression than prostratin, the current clinical candidate for latent virus induction. This study provides the first demonstration that designed, synthetically accessible bryostatin analogues could serve as superior candidates for the eradication of HIV/AIDS through induction of latent viral reservoirs in conjunction with current antiretroviral therapy.

Figures at a glance

left

1.     Figure 1: Bryostatin, prostratin and synthetic analogues.

2.     Figure 2: Synthesis of analogues 1–4 via Prins-driven macrocyclization.

Reagents and conditions. a–f, Spacer domain synthesis. When X = H, TESCl, imidazole, CH₂Cl₂, 95% (a); CeCl₃·2LiCl, TMSCH₂MgCl, THF (b); silica gel, CH₂Cl₂, 85% over 2 steps (c); lithium naphthalenide, THF, 84% (d); TPAP (10 mol%), NMO, 4 Å MS, CH₂Cl₂ (e); NaClO₂, NaH₂PO_4, 2-methyl-2-butene, 2:1 t-BuOH:H₂O, 91% over 2 steps (f). When X = OTBS, conditions as before: >99% (a); 82% over 2 steps (b,c); 91% (d); 97% over 2 steps (e,f). g, Fragment coupling: 2,4,6-trichlorobenzoyl chloride, Et₃N, then DMAP, recognition domain 11, PhCH₃, rt. h, Prins macrocyclization: from 17 and 18, PPTS, EtOH, rt; from 19, i. PPTS, MeOH, rt, ii. TBSCl, imidazole, CH₂Cl₂. i–k, Analogue synthesis: from 20 and 21, HF·pyridine, THF, rt; from 19, i. PPTS, MeOH, rt, ii. HF·pyridine, THF, rt, iii. PPTS, 4:1 THF:H₂O (i); i. TESCl, imidazole, CH₂Cl₂, ii. Ac₂O, DMAP, pyridine, CH₂Cl₂ (j); HF·pyridine, THF (k).

3.     Figure 3: Synthesis of analogues 5–7 via ozonolysis followed by Horner–Wadsworth–Emmons olefination.

Reagents and conditions. a, O₃, CH₂Cl₂, –78 °C, then thiourea, MeOH:CH₂Cl₂. b, Trimethyl phosphonoacetate, NaHMDS, THF, 0 → 4 °C. c, From 26 or 27: HF·pyridine, THF, rt; from 28: i. HF·pyridine, THF, rt, then ii. PPTS, 4:1 THF:H₂O, rt. d, i. TESCl, imidazole, CH₂Cl₂, ii. Ac₂O, DMAP, pyridine, CH₂Cl₂. e, HF·pyridine, THF.

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