More evidence for possible link between cocaine use and HIV infection

 

New UCLA research offers further evidence that cocaine use disrupts the immune system, making people who use it more likely to become infected with HIV. In research published online June 18 in the peer-reviewed journal Scientific Reports, researchers with the UCLA AIDS Institute and Center for AIDS Research used an advanced form of humanized mice -- that is, immunodeficient mice engineered to have a human-like immune system -- to study the effects of cocaine. The findings suggest that using cocaine makes people significantly more susceptible to HIV infection. 'Substance use and abuse is a major issue, especially when it comes to HIV infection,' said Dimitrios Vatakis, the study's senior author and an assistant professor of medicine in the division of hematology/oncology at the David Geffen School of Medicine at UCLA. 'There has been a general attitude, especially in the scientific but also the general community, that risky behavior is the main reason for higher infections. This study shows that under the same transmission conditions, drug exposure enhances infection through a collective of biological changes.' This study builds on previous research by Vatakis and others on his team showing that a three-day exposure to cocaine appears to make a unique population of immune cells called quiescent CD4 T cells, which are resistant to HIV, more susceptible to infection by stimulating two receptors in the cells, called σ1 and D4. Those findings suggested that cocaine use increases the pool of CD4 T cells in the human body that can become infected by the virus. As a result, the odds for productive infection and a larger viral reservoir increase. That study, however, was based on in-vitro research -- that is, research done in a petri dish -- which could have skewed the results. The next step was to find the same effect in in-vivo studies -- that is, those conducted with living organisms, such as mice. This is what the current paper has done. For this study, Vatakis and his team used the most advanced humanized mouse model, called BLT. The name comes from the way the model is generated: mice are transplanted with human hematopoietic stem cells (B, for blood cells) and donor-matched liver (L) and thymus (T) tissues, resulting in the development of a functioning human immune system. 'This study is the first of its kind using this model,' said Vatakis, who also directs the UCLA/CFAR Virology Core Laboratory. 'The BLT has been used to study HIV latency, cancer immunotherapy and now drug abuse and HIV infection. It very closely resembles the human immune system and it is the most relevant.' The researchers separated the mice into two major groups. Half of the mice were injected with cocaine every day for five days, while the other half were injected with saline for comparison. After five days, half the mice in each group were injected with HIV-1. Then all of the mice were given saline or cocaine for two more weeks. The researchers then collected blood and tissue samples to measure infection levels and examine other effects of the cocaine. They found that the cocaine/HIV group had higher amounts of HIV than the saline/HIV mice. They also found that nine of the 19 saline/HIV mice had undetectable amounts of the virus, compared with only three of the 19 cocaine/HIV mice. The researchers were surprised to find that despite the cocaine-induced inflammation prior to infection, the CD4 T cells that HIV targets were not overtly activated. Also, CD8 T cells, which kill infected cells, were not functional, even though they appeared to be so. 'This points to cocaine blunting the potency of our body's defense against the virus,' Vatakis said. While these studies have shed further light on the effects of cocaine use and misuse on HIV infection, this small animal model, although it closely mimics human immunity, does not fully re-create real-life settings. In addition, the study used an acute -- or brief, uninterrupted -- cocaine exposure regimen, rather than a more clinically relevant chronic use model, which could affect the results. The next stages of research, using the same BLT model, will be to determine how cocaine abuse might affect HIV transmission in mucosal membranes such as vaginal and anal tissues; how pre- and post-exposure prophylaxis (that is, taking medication to reduce the risk of acquiring HIV) can be affected by cocaine exposure; how cocaine might affect viral latency, the process in which a virus lies dormant in a cell; and how cocaine alters the body's immune defenses and affects other viral infections. Story Source: The above post is reprinted from materials provided by University of California - Los Angeles Health Sciences. Note: Materials may be edited for content and length. Journal Reference: Sohn G. Kim, Emily L. Lowe, Dhaval Dixit, Cindy Seyeon Youn, Irene J. Kim, James B. Jung, Robert Rovner, Jerome A. Zack, Dimitrios N. Vatakis. Cocaine-mediated impact on HIV infection in humanized BLT mice. Scientific Reports, 2015; 5: 10010 DOI: 10.1038/srep10010

Research offers a new approach to improving HIV vaccines

 

In a scientific discovery that has significant implications for preventing HIV infections, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) have identified a protein that could improve the body's immune response to HIV vaccines and prevent transmission of the virus. The study shows how a protein called polyglutamine-binding protein 1 (PQBP1) acts as a front-line sensor and is critical to initiating an immune response to HIV. When the PQBP1 encounters the virus, it starts a program that triggers an overall protective environment against infection and enhances the production of virus-specific antibodies. The research, which identified PQBP1 as a target for improving HIV vaccines, was published June 4 online ahead of print in the journal Cell. 'Vaccines work by teaching the immune system to react by mimicking a natural infection,' said lead author Sunnie Yoh, Ph.D., a postdoctoral fellow in the lab of Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program at Sanford-Burnham. 'Designing a drug that mimics the interface between HIV and PQBP1 would allow an HIV vaccine to more effectively re-create an immune environment that mirrors real infection.' 'Current approaches to HIV vaccine development have thus far yielded little fruit, partly because of the lack of an effective vaccine adjuvant. Adjuvants promote a robust immune response to vaccines and are critical to eliciting long-lasting immunity,' said Chanda. 'Our study identifies a promising new target for a vaccine adjuvant that could advance the development of HIV vaccines and prevent infection.' How it works Although the major target of HIV infection is CD4+ T cells, dendritic cells are one of the first cell types to encounter HIV during sexual transmission. After HIV infects cells, its DNA forms an interface with PQBP1 in sentinel dendritic cells and initiates the immune response. Dendritic cells control the innate immune response -- a generic, non-specific defense against pathogens. These cells also activate the adaptive immune response that generates highly specific antibodies that provide protective, long-lasting immunity. Both the innate and adaptive immune systems are necessary to provide an optimal immune response to vaccines. 'PQBP1 acts as a sentry for innate immune response to HIV. The development of a highly effective HIV vaccine will likely depend on both combining the correct immunogens, which are viral proteins, and unlocking the innate response, to establish long-lived protection,' said Chanda. 'Now that we know the gatekeeper, it will be much easier to find a key.' Story Source: The above story is based on materials provided by Sanford-Burnham Medical Research Institute. The original article was written by Susan Gammon, Ph.D.. Note: Materials may be edited for content and length. Journal Reference: Sunnie M. Yoh, Monika Schneider, Janna Seifried, Stephen Soonthornvacharin, Rana E. Akleh, Kevin C. Olivieri, Paul D. De Jesus, Chunhai Ruan, Elisa de Castro, Pedro A. Ruiz, David Germanaud, Vincent des Portes, Adolfo García-Sastre, Renate König, Sumit K. Chanda. PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1. Cell, 2015; 161 (6): 1293 DOI: 10.1016/j.cell.2015.04.050

Latent HIV may lurk in 'quiet' immune cells, research suggests

 

Hide and seq: Lillian Cohn (above) and her colleagues sequenced the sites in the genomes of infected cells where the virus had integrated. This allowed them to determine whether or not an infected cell had previously been copied as part of an immune response. Drugs for HIV have become adept at suppressing infection, but they still can't eliminate it. That's because the medication in these pills doesn't touch the virus' hidden reserves, which lie dormant within infected white blood cells. Unlock the secrets of this pool of latent virus, scientists believe, and it may become possible to cure -- not just control -- HIV. In a study published in Cell, researchers lead by Zanvil A. Cohn and Ralph M. Steinman Professor Michel C. Nussenzweig at Rockefeller University and their collaborators describe new insights on which cells likely do, and do not, harbor this lurking threat. "It has recently been shown that infected white blood cells can proliferate over time, producing many clones, all containing HIV's genetic code. However, we found that these clones do not appear to harbor the latent reservoir of virus," says study author Lillian Cohn a graduate student in Nussenzweig's Laboratory of Molecular Immunology. "Instead our analysis points to cells that have never divided as the source of the latent reservoir." HIV belongs to a family of viruses that insert themselves directly into the host cell's genome where they can hide out quietly after the initial infection. HIV mostly targets CD4 T lymphocytes, a type of T cell involved in initiating an immune response. When HIV integrates itself into the genetic code of a CD4 T cell, it may produce an active infection, hijacking the cell to produce more copies of itself in order infect other cells, and killing it in the process. Antiretroviral drugs that suppress HIV infection work by disrupting this hijacking. But the virus may also fail to produce an active infection, remaining a quiet, tiny fragment of DNA tucked within the host cell's genome. If so, the drugs have nothing to disrupt, and the infection remains latent. Most often, however, what happens is actually something in between. While the virus does manage to get at least some of itself into the T cell's genome, problems with the process leave it incapable of hijacking the cell to replicate itself. But those few successful integrations still do damage, and the resulting depletion in the victim's immune system leaves him or her vulnerable to potentially fatal opportunistic infections years, or even decades, after the initial infection. "If a patient stops taking antiretrovirals, the infection rebounds. It is truly amazing that the virus can give rise to AIDS 20 years after the initial infection," Cohn says. Researchers think the reservoir of latent virus may be hiding out in a type of CD4 T cell: long-lived memory cells that help the immune system remember particular pathogens. When these cells encounter a pathogen they have previously seen, they spur the proliferation of T cells tuned to recognize it, in a process called clonal expansion. Prior research has suggested clonal expansion is crucial to maintaining HIV's latent reservoir. Following up on work initiated by Mila Jankovic, a senior research associate in the lab, Cohn and her colleagues examined cloned and unique CD4 T cells in blood samples from 13 people infected with HIV. An analytical computational technique developed by Israel Tojal da Silva, a research associate in the lab, made it possible to identify integration sites into which HIV had inserted itself within individual cells. "Given the size of the human genome, it is highly unlikely the virus would insert itself in exactly the same place more than once. So, if multiple cells contained virus with identical integration sites, we classified them as clones. Meanwhile if a cell had a unique integration site, one not shared with any other cell, then we assumed that cell was unique" Cohn says. The researchers tested 75 viral sequences taken from the expanded clones of cells to see if they had the potential to produce more of the virus. None could. "While we cannot rule out the possibility that a rare clone of cells may contain an active virus, it appears most likely that latent reservoir -- and the potential target for therapies meant to cure HIV -- resides in the more rare single cells containing unique integrations," Cohn says.

Hepatitis C ruled out as cause of mental impairment in HIV patients

 

December 11, 2014 Washington University in St. Louis Advances in treatment for human immunodeficiency virus (HIV) have made it possible for people with HIV to survive much longer. As they age, however, many experience impaired thinking, memory loss, mood swings and other evidence of impaired mental function. Secondary infection with the hepatitis C virus does not contribute to the mental impairments seen in many long-term survivors of HIV infection, a new study reveals. Advances in treatment for human immunodeficiency virus (HIV) have made it possible for people with HIV to survive much longer. As they age, however, many experience impaired thinking, memory loss, mood swings and other evidence of impaired mental function. To stop these changes, scientists have to learn what is causing them. One possibility researchers are considering is that long-term infections with other pathogens, common in HIV-positive patients, are affecting the brain. But a new study has eliminated one of their prime suspects: the hepatitis C virus, which infects about one in every three HIV-positive patients in the United States. The research, conducted by a team that includes scientists at Washington University School of Medicine in St. Louis, appeared Dec. 10 in Neurology. "Hepatitis C infection has serious long-term side effects, such as damage to the liver, but our research indicates that it does not affect the brain," said lead author David Clifford, MD, of Washington University. The research was conducted as part of the CNS HIV Anti-retroviral Therapy Effects (CHARTER) study, a multicenter collaborative that is examining the long-term neurological effects of HIV infection. Hepatitis C most commonly infects illicit-drug users who share needles used to inject the drugs. Drug abuse can harm the brain, making it difficult to determine whether hepatitis C or problems caused by drug use contribute to brain impairment in patients with both HIV and hepatitis C. To answer this question, Clifford and his colleagues studied 1,582 HIV patients, 408 of whom were also infected with hepatitis C. Each patient received a detailed neuropsychological exam devised by Clifford and other CHARTER researchers to detect signs of HIV-associated mental deficits. The exam takes two to 2 1/2 hours, and includes written examinations taken by the patient and physical exams given by medical professionals. Patients are tested for their ability to express themselves, to make decisions, to learn and retain new information using multiple types of memory, and to move the body and control muscles. "In all, we looked at seven domains of mental function," said Clifford, who is the Melba and Forest Seay Professor of Clinical Neuropharmacology in Neurology. "We studied their overall performance and looked at each domain individually and found no evidence that the group with hepatitis C performed worse." According to Clifford, this was particularly impressive because the participants in the group with hepatitis C were older, had less education and had lower scores on tests of reading, comprehension, spelling and math. With hepatitis C eliminated, Clifford and his colleagues are turning their attention to the immune responses triggered by HIV in the brain and the bowel during the initial stages of infection. He and others believe these early responses, which include bursts of inflammation, lead to chronic inflammation that adversely affects the brain. "If a hepatitis C infection gets to the point where it damages liver function, the resulting inflammation might well contribute to mental impairment," Clifford said. "Beyond that, though, it doesn't seem to be an active collaborator in the harm HIV does to the brain." Story Source: The above story is based on materials provided by Washington University in St. Louis. The original article was written by Michael C. Purdy. Note: Materials may be edited for content and length. Journal Reference: David B. Clifford, Florin Vaida, Yu-Ting Kao, Donald R. Franklin, Scott L. Letendre, Ann C. Collier, Christina M. Marra, Benjamin B. Gelman, Justin C. Mcarthur, Susan Morgello, David M. Simpson, Igor Grant, Robert K. Heaton. Absence of neurocognitive effect of hepatitis C infection in HIV-coinfected people. Neurology, December 2014 DOI: 10.1212/WNL.000000000000115

How to stop the spread of HIV in Africa

 

While Ebola has attracted much of the world's attention recently, a severe HIV epidemic rages on around the world and in sub-Saharan Africa in particular. Globally, more than 34 million people are infected with HIV; in sub-Saharan Africa alone, 3 million new infections occur annually. In an attempt to stop the spread of HIV, governments in the region are considering providing antiretroviral drugs to people who do not have the virus but are at risk for becoming infected. Such drugs are known as pre-exposure prophylaxis, or PrEP. Although the conventional strategy -- attempting to attempt to distribute the drugs to people in every city and village -- might seem logical and equitable, researchers at UCLA have devised a plan they say would be much more effective in reducing HIV transmission. The strategy, developed using a complex mathematical model, focuses on targeting "hot zones," areas where the risk of HIV infection is much higher than the national average. In South Africa, where 17 percent of the population is infected with HIV, the model predicted that targeting hot zones would prevent 40 percent more HIV infections than using the conventional strategy -- and would therefore be 40 percent more cost-effective. "Stopping the HIV pandemic is one of the greatest challenges facing the global community," said Sally Blower, the paper's senior author and the director of the Center for Biomedical Modeling at the UCLA Semel Institute for Neuroscience and Human Behavior. The report appears in the current online edition of Nature Communications. "Since results from clinical trials have shown that antiretroviral drugs are effective in protecting individuals against HIV, the big question now is how best to use them," said David Gerberry, the study's first author and a former UCLA postdoctoral fellow who now is an assistant professor in mathematics at Xavier University. To develop the strategy, UCLA researchers designed a computer model that calculated and mapped the incidence of HIV in South Africa and identified hot zones. The model featured three important components: the geographic dispersion of the population, the geographic variation in the severity of the HIV epidemic and the geographic variation in the level of risk behavior. The model revealed that two of South Africa's nine provinces are hot zones. The researchers then used the model to predict where, and how many, new HIV infections would occur based on using either the conventional strategy or a strategy targeting hot zones for distributing the drugs. "Our results are quite striking," Blower said. "Both strategies would provide PrEP to the same number of people, but using the hot zones plan would prevent 40 percent more HIV infections than using the conventional plan." Gerberry said the team's strategy could be applied to other nations as well. "The methods we developed can be used to find hot zones in any other sub-Saharan countries that have geographic variation in the severity of their HIV epidemic, such as Lesotho, Botswana, Nigeria and Uganda," he said. "Once the hot zones have been found in these countries, our spatial optimization algorithm can be used to identify the geographic targeting strategy that would be the most cost-effective." Blower said the study holds great significance for global health policy. "The findings show that, when interventions are rolled out, governments in sub-Saharan Africa will have to choose between maximizing equity in access to the drugs and minimizing transmission of HIV." Story Source: The above story is based on materials provided by University of California, Los Angeles (UCLA), Health Sciences. Note: Materials may be edited for content and length. Journal Reference: David J. Gerberry, Bradley G. Wagner, J. Gerardo Garcia-Lerma, Walid Heneine, Sally Blower. Using geospatial modelling to optimize the rollout of antiretroviral-based pre-exposure HIV interventions in Sub-Saharan Africa. Nature Communications, 2014; 5: 5454 DOI: 10.1038/ncomms6454

MEDIA AVAILABILITYNIH-Led Scientists Discover HIV Antibody that Binds to Novel Target on Virus

 

​WHAT:
An NIH-led team of scientists has discovered a new vulnerability in the armor of HIV that a vaccine, other preventive regimen or treatment could exploit. The site straddles two proteins, gp41 and gp120, that jut out of the virus and augments other known places where broadly neutralizing antibodies (bNAbs) bind to HIV. This newly identified site on the viral spike is where a new antibody found by the scientists in an HIV-infected person binds to the virus. Called 35O22, the antibody prevents 62 percent of known HIV strains from infecting cells in the laboratory and is extremely potent, meaning even a relatively small amount of it can neutralize the virus.

Following their discoveries, the scientists found that 35O22-like antibodies were common in a group of HIV-infected people whose blood contained antibodies that potently neutralized a broad array of HIV strains. According to the researchers, this suggests that it might be easier for a vaccine to elicit 35O22 than some other known bNAbs, which are less common. 

Since 35O22 binds only to forms of the viral spike that closely resemble those that naturally appear on HIV, the scientists believe a vaccine that elicits 35O22-like antibodies would need to mimic the natural shape of the spike as closely as possible. This would require a different approach than that used in many previous experimental HIV vaccines, which have included just parts of the viral spike rather than a structure that looks like the entire native viral spike.

In addition, the researchers report, the HIV strains that 35O22 neutralizes complement strains neutralized by other bNAbs. This suggests that eliciting or combining 35O22 with a few other bNAbs in a vaccine or a prevention or treatment regimen could likely neutralize the vast majority of HIV strains found around the globe, according to the scientists.

ARTICLE:
J Huang et al. Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-120 interface. Nature DOI: 10.1038/nature13601 (2014).

WHO:
Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, part of NIH, is available for comment. Mark Connors, M.D., chief of the HIV-Specific Immunity Section of the NIAID Laboratory of Immunoregulation and the principal investigator of the study, also is available for interviews.

CONTACT:
To schedule interviews, please contact Laura S. Leifman, (301) 402-1663, niaidnews@niaid.nih.gov.

New approach to HIV vaccine explored by scientists

 

May 29, 2014

University of Nebraska-Lincoln

A promising new approach to a live attenuated HIV-1 vaccine is being pursued by scientists, using a genetically modified form of the HIV virus. The new method involves manipulating the virus' codons -- a sequence of three nucleotides that form genetic code -- to rely on an unnatural amino acid for proper protein translation, which allows it to replicate. Because this amino acid is foreign to the human body, the virus cannot continue to reproduce, researchers report.

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Qingsheng Li (left), Wei Niu and Jiantao Guo.

Using a genetically modified form of the HIV virus, a team of University of Nebraska-Lincoln scientists has developed a promising new approach that could someday lead to a more effective HIV vaccine.

The team, led by chemist Jiantao Guo, virologist Qingsheng Li and synthetic biologist Wei Niu, has successfully tested the novel approach for vaccine development in vitro and has published findings in the international edition of the German journal Angewandte Chemie.

With the new approach, the UNL team is able to use an attenuated -- or weakened -- HIV virus in the vaccine. The new method involves manipulating the virus' codons -- a sequence of three nucleotides that form genetic code -- to rely on an unnatural amino acid for proper protein translation, which allows it to replicate. Because this amino acid is foreign to the human body, the virus cannot continue to reproduce, Guo said.

Adaptive immunity is developed when the body's immune system develops antibodies that attack the virus. The virus is then shut off from replicating by removing the amino acid.

"Since the unnatural amino acid is not present in humans, the virus cannot further replicate and cause disease once a desirable protection is achieved," Guo said.

On June 1, they will begin the next phase of development through a four-year, $1.9 million grant from the National Institutes of Healthand the National Institute of Allergy and Infectious Diseases. The grant will allow further research involving the genetically modified virus and lead to animal trials of the vaccine.

Since the HIV/AIDS pandemic began in the 1980s, an estimated 36 million people have died from the disease. Today, more than 35 million people live with the virus and 2.5 million new infections are recorded each year. No universal cure or vaccine exists, mainly because of the virus' persistent replication and evolution.

The most successful vaccination attempt in humans -- a trial in Thailand in the middle of the last decade -- had a roughly 31 percent efficacy rate. But that vaccine used engineered versions of HIV genes and proteins, rather than the actual virus.

"The science tells us a live-attenuated vaccine would work best to stop the pandemic and possibly eradicate the disease," Li said. "But, using a live virus in a human trial has safety concerns."

Using an attenuated virus in a vaccine has not been accomplished before because HIV -- even a weakened form of the virus -- replicates rapidly, which allows it to evolve quickly and regain is virulence and disease-causing ability.

With the funds from the grant, Guo, assistant professor of chemistry, and Li, associate professor of biology, along with Niu, research assistant professor in chemistry, will perfect the technology and begin new trials.

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Story Source:

The above story is based on materials provided by University of Nebraska-Lincoln. Note: Materials may be edited for content and length.

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Journal Reference:

1. Nanxi Wang, Yue Li, Wei Niu, Ming Sun, Ronald Cerny, Qingsheng Li, Jiantao Guo. Construction of a Live-Attenuated HIV-1 Vaccine through Genetic Code Expansion. Angewandte Chemie International Edition, 2014; 53 (19): 4867 DOI: 10.1002/anie.201402092