Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Giving HIV the Silent Treatment and Other Strategies Examined at Conference

Giving HIV the Silent Treatment and Other Strategies Examined at Conference Boston—A process to "silence" genes might be harnessed to treat HIV infection, say scientists who are currently exploring the technique in laboratory and animal studies. While the research is in its infancy, a new study has already demonstrated that the technique protected animals in an experimental model of hepatitis. These findings, as well as research exploring other therapeutic strategies, were reported here at the 10th Conference on Retroviruses and Opportunistic Infections. Rna interference: "shoot" the messenger Rna interference: "shoot" the messenger RNA generally has had a lower profile compared with its genetic sibling, DNA; DNA was respected as the message, while RNA was considered to be merely the messenger. But RNA's role in human health and disease is becoming the focus of intense interest among many biomedical scientists, thanks in part to a new technique called RNA interference (RNAi). HIV researchers are no exception and are exploring RNAi as a possible therapy for HIV infection. Rna interference: "shoot" the messenger As a technique used to silence individual genes, RNAi involves an engineered version of a natural process that scientists believe protects cells against viruses and other elements, such as transposons (pieces of DNA that move from one place in a genome to another), that could cause harm. Scientists believe that small snippets of double-stranded RNA called small interfering RNAs (siRNAs) are picked up by an enzyme complex in the cell. This enzyme complex then uses the genetic sequence of the siRNAs to recognize and destroy messenger RNA that has a complementary genetic sequence. Since the function of messenger RNA is to carry a gene's instructions for making a protein to the cell's protein-making machinery, selectively destroying messenger RNA can "silence" a gene or decrease its expression. Rna interference: "shoot" the messenger Researchers realized that they might be able to harness this process to silence genes for therapeutic purposes. They reasoned that by introducing into cells minute synthetic siRNAs that corresponded to the messenger RNAs of specific genes, they could silence a key gene in a pathogen or a mutant disease-causing human gene. Rna interference: "shoot" the messenger But there are some challenges that scientists will have to address before RNAi can be used for therapy. High on the list is a hurdle faced by gene therapy researchers: how to deliver the genetic material to cells. Rna interference: "shoot" the messenger "It's a major hurdle to deliver nucleic acids to cells," Mario Stevenson, PhD, of the University of Massachusetts Medical School, Worcester, remarked in a press briefing. Rna interference: "shoot" the messenger However, Judy Lieberman, MD, PhD, of the Center for Blood Research and Harvard Medical School, Boston, reported the first demonstration that RNAi can prevent liver injury and death in a mouse model of hepatitis, and that vectors may not always be necessary to ferry the siRNA into cells. The findings also were released on the Nature Medicine Web site on February 10 and were published in the journal's March issue (http://www.nature.com/nm/). Liver scarring (left) from inflammation is seen in mice given a placebo treatment for hepatitis, while animals that received a "gene-silencing" treatment were protected (right). (Photo courtesy of Judy Lieberman, MD, PhD, Center for Blood Research, reprinted from Nature Medicine.) Rna interference: "shoot" the messenger The investigators used RNAi to silence a gene called Fas that has been associated with liver disease, including autoimmune and viral hepatitis, explained Lieberman. They discovered that when they infused massive amounts of siRNA targeting Fas into mice, up to 90% of the liver cells took up the synthetic genetic material. Rna interference: "shoot" the messenger Mice that received siRNA targeting Fas were protected against liver damage when they were injected the following day with an antibody that normally activates Fas. More than 80% (33/40) of the treated mice survived and remained free of severe liver damage, while all 40 control mice died of acute liver failure within days. Rna interference: "shoot" the messenger Lieberman also described "proof-of-principle" in vitro studies examining whether RNAi targeting the CCR5 receptor and p24 (a core HIV protein) could interfere with HIV's ability to invade and replicate in human cells. Rna interference: "shoot" the messenger "We found that combinations of siRNAs targeting both cellular and viral genes can completely abrogate HIV-1 infection in macrophages," she said. Lieberman and her team also discovered that a single application of siRNAs provided protection for these nondividing cells for up to 3 weeks and that HIV replication in already-infected cells could also be suppressed. Rna interference: "shoot" the messenger While studies of RNAi as a potential approach to treating HIV infection are in their infancy, the work is an exciting first step, said Lieberman. Rna interference: "shoot" the messenger "It's a burgeoning area," said Stevenson. "Hopefully, something useful will come out of this." A helpful virus? A helpful virus? In another report, researchers described new insights into a virus that slows HIV disease progression in people coinfected with HIV. A helpful virus? Since 1998, several studies have found that an innocuous virus called GB virus C (GBV-C) that was discovered in the mid-1990s seemed to benefit people who were also infected by HIV. However, the biological mechanism underlying such protection was unclear, and some people theorized that GBV-C infection was merely an indicator of some other factor that blunted the effects of HIV infection. A helpful virus? Now scientists not only have more evidence supporting the link between GBV-C and less aggressive HIV infection but also have a clue regarding GBV-C's beneficial effects. A helpful virus? Transmission of GBV-C occurs mainly through blood or sexual contact. Studies indicate that about 1% to 2% of all blood donors have active GBV-C infection and that another 13% to 18% have antibodies that indicate a previous infection. A helpful virus? In a study presented by researchers from the National Institute of Allergy and Infectious Diseases (NIAID), the University of Iowa, and other institutions, the investigators tested stored blood samples for GBV-C infection from participants in the ongoing Multicenter AIDS Cohort Study (MACS) that began in 1984. Tests of serum samples from 271 participants collected an average of 12 to 18 months after HIV diagnosis (designated the "early visit") revealed that nearly 40% had an active GBV-C infection and about half had an antibody (anti-E2 antibody) to GBV-C, indicating they had been infected at one time but had cleared the virus. A helpful virus? The researchers also tested serum samples collected about 5 to 6 years after the initial diagnosis (designated the "late visit") and examined 1995 medical records of MACS participants (about 11 years after HIV diagnosis). They found that men who did not have active GBV-C infection at either the early or late visit were more than twice as likely to die than men who had a persistent GBV-C infection at both visits, a statistically significant difference, explained Carolyn Williams, PhD, an epidemiologist in NIAID's Division of AIDS. Moreover, those who had active GBV-C infection at the early visit and cleared the virus by the late visit, were nearly six times more likely to die than men who were persistently infected with GBV-C, also a statistically significant difference. A helpful virus? In another report, researchers led by Jack Stapleton, MD, of the University of Iowa, Iowa City, infected cell cultures with HIV and GBV-C in search of clues to the latter's protective effect for people infected with HIV. They found a plausible reason for GBV-C's beneficial effects: it appears to result in fewer copies of CCR5, a receptor on the surface of T lymphocytes that some HIV strains use to gain entry. A helpful virus? Such an effect by GBV-C would not prevent HIV infection, because it doesn't eliminate all CCR5 receptors, nor does it eliminate the possibility that HIV will use an alternative receptor, CXCR4. "But it slows replication," said Stapleton. Infection with GBV-C also boosts the production of various proteins called chemokines that mobilize and activate immune cells to fight infection, he said. A helpful virus? Intentionally infecting HIV-infected patients with GBV-C in the hopes that it will confer a beneficial effect is worth considering, especially for people with multidrug-resistant HIV who have no remaining treatment options, said Stapleton. Even so, such an attempt would be problematic. For one thing, HIV-infected individuals who are coinfected with GBV-C and subsequently clear the latter virus from their systems not only lose the purported benefit but may fare worse than patients who were never coinfected with the two viruses in the first place. A helpful virus? But if other studies indicate that GBV-C substantially slows progression of HIV, scientists may try to develop drugs that mimic its effects. "Understanding the mechanisms for the interaction between GBV-C and HIV may provide insights into ways to control HIV disease progression," the researchers noted. Targeting hiv entry Targeting hiv entry Foiling HIV entry into cells by making CCR5 and other receptors on target cells inaccessible to the virus is an ongoing focus of research, and researchers described work in progress on this front, including findings from early studies in humans of a monoclonal antibody called TNX-355 (formerly called HU548). This peptide recognizes the CD4 receptor, one of the coreceptors (along with CCR5 or CXCR4) that HIV uses to invade human cells. The antibody is a humanized version of a mouse monoclonal antibody that "coats" the CD4 receptor in such a way that it inhibits the process of cell entry by HIV without interfering with the CD4 receptor's natural function as a chemokine receptor. Targeting hiv entry In early trials involving 30 patients with HIV infection (all of whom had been treated with many different HIV drugs and in two thirds of whom highly active antiretroviral therapy was failing), high doses of the antibody caused a more than 90% reduction of HIV levels in the blood, and was safe and well tolerated, reported Daniel R. Kuritzkes, MD, of Harvard Medical School, Boston. Targeting hiv entry Because the mechanism of action for the peptide differs from that of currently available antiretroviral drugs, it could offer an alternative for patients with HIV that is resistant to currently available drugs. Because the CD4 coating persisted for up to 27 days at the highest dose, it also might be possible to administer the drug infrequently, perhaps every week or two. Targeting hiv entry One possible limitation might be the development of antibodies to TNX-355 itself, which could blunt or eliminate the drug's activity, noted Kuritzkes. Studies with macaques that had received several doses of the peptide did develop such antibodies, but chimpanzees—which are more closely related to humans—did not. A multiple-dose study is currently under way, he said. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Giving HIV the Silent Treatment and Other Strategies Examined at Conference

Stephenson, Joan
JAMA , Volume 289 (12) – Mar 26, 2003
Download PDF
2 pages

Loading next page...
 
/lp/american-medical-association/giving-hiv-the-silent-treatment-and-other-strategies-examined-at-J0E04nRHy7

References (0)

References for this paper are not available at this time. We will be adding them shortly, thank you for your patience.

Publisher
American Medical Association
Copyright
Copyright © 2003 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.289.12.1494
Publisher site
See Article on Publisher Site

Abstract

Boston—A process to "silence" genes might be harnessed to treat HIV infection, say scientists who are currently exploring the technique in laboratory and animal studies. While the research is in its infancy, a new study has already demonstrated that the technique protected animals in an experimental model of hepatitis. These findings, as well as research exploring other therapeutic strategies, were reported here at the 10th Conference on Retroviruses and Opportunistic Infections. Rna interference: "shoot" the messenger Rna interference: "shoot" the messenger RNA generally has had a lower profile compared with its genetic sibling, DNA; DNA was respected as the message, while RNA was considered to be merely the messenger. But RNA's role in human health and disease is becoming the focus of intense interest among many biomedical scientists, thanks in part to a new technique called RNA interference (RNAi). HIV researchers are no exception and are exploring RNAi as a possible therapy for HIV infection. Rna interference: "shoot" the messenger As a technique used to silence individual genes, RNAi involves an engineered version of a natural process that scientists believe protects cells against viruses and other elements, such as transposons (pieces of DNA that move from one place in a genome to another), that could cause harm. Scientists believe that small snippets of double-stranded RNA called small interfering RNAs (siRNAs) are picked up by an enzyme complex in the cell. This enzyme complex then uses the genetic sequence of the siRNAs to recognize and destroy messenger RNA that has a complementary genetic sequence. Since the function of messenger RNA is to carry a gene's instructions for making a protein to the cell's protein-making machinery, selectively destroying messenger RNA can "silence" a gene or decrease its expression. Rna interference: "shoot" the messenger Researchers realized that they might be able to harness this process to silence genes for therapeutic purposes. They reasoned that by introducing into cells minute synthetic siRNAs that corresponded to the messenger RNAs of specific genes, they could silence a key gene in a pathogen or a mutant disease-causing human gene. Rna interference: "shoot" the messenger But there are some challenges that scientists will have to address before RNAi can be used for therapy. High on the list is a hurdle faced by gene therapy researchers: how to deliver the genetic material to cells. Rna interference: "shoot" the messenger "It's a major hurdle to deliver nucleic acids to cells," Mario Stevenson, PhD, of the University of Massachusetts Medical School, Worcester, remarked in a press briefing. Rna interference: "shoot" the messenger However, Judy Lieberman, MD, PhD, of the Center for Blood Research and Harvard Medical School, Boston, reported the first demonstration that RNAi can prevent liver injury and death in a mouse model of hepatitis, and that vectors may not always be necessary to ferry the siRNA into cells. The findings also were released on the Nature Medicine Web site on February 10 and were published in the journal's March issue (http://www.nature.com/nm/). Liver scarring (left) from inflammation is seen in mice given a placebo treatment for hepatitis, while animals that received a "gene-silencing" treatment were protected (right). (Photo courtesy of Judy Lieberman, MD, PhD, Center for Blood Research, reprinted from Nature Medicine.) Rna interference: "shoot" the messenger The investigators used RNAi to silence a gene called Fas that has been associated with liver disease, including autoimmune and viral hepatitis, explained Lieberman. They discovered that when they infused massive amounts of siRNA targeting Fas into mice, up to 90% of the liver cells took up the synthetic genetic material. Rna interference: "shoot" the messenger Mice that received siRNA targeting Fas were protected against liver damage when they were injected the following day with an antibody that normally activates Fas. More than 80% (33/40) of the treated mice survived and remained free of severe liver damage, while all 40 control mice died of acute liver failure within days. Rna interference: "shoot" the messenger Lieberman also described "proof-of-principle" in vitro studies examining whether RNAi targeting the CCR5 receptor and p24 (a core HIV protein) could interfere with HIV's ability to invade and replicate in human cells. Rna interference: "shoot" the messenger "We found that combinations of siRNAs targeting both cellular and viral genes can completely abrogate HIV-1 infection in macrophages," she said. Lieberman and her team also discovered that a single application of siRNAs provided protection for these nondividing cells for up to 3 weeks and that HIV replication in already-infected cells could also be suppressed. Rna interference: "shoot" the messenger While studies of RNAi as a potential approach to treating HIV infection are in their infancy, the work is an exciting first step, said Lieberman. Rna interference: "shoot" the messenger "It's a burgeoning area," said Stevenson. "Hopefully, something useful will come out of this." A helpful virus? A helpful virus? In another report, researchers described new insights into a virus that slows HIV disease progression in people coinfected with HIV. A helpful virus? Since 1998, several studies have found that an innocuous virus called GB virus C (GBV-C) that was discovered in the mid-1990s seemed to benefit people who were also infected by HIV. However, the biological mechanism underlying such protection was unclear, and some people theorized that GBV-C infection was merely an indicator of some other factor that blunted the effects of HIV infection. A helpful virus? Now scientists not only have more evidence supporting the link between GBV-C and less aggressive HIV infection but also have a clue regarding GBV-C's beneficial effects. A helpful virus? Transmission of GBV-C occurs mainly through blood or sexual contact. Studies indicate that about 1% to 2% of all blood donors have active GBV-C infection and that another 13% to 18% have antibodies that indicate a previous infection. A helpful virus? In a study presented by researchers from the National Institute of Allergy and Infectious Diseases (NIAID), the University of Iowa, and other institutions, the investigators tested stored blood samples for GBV-C infection from participants in the ongoing Multicenter AIDS Cohort Study (MACS) that began in 1984. Tests of serum samples from 271 participants collected an average of 12 to 18 months after HIV diagnosis (designated the "early visit") revealed that nearly 40% had an active GBV-C infection and about half had an antibody (anti-E2 antibody) to GBV-C, indicating they had been infected at one time but had cleared the virus. A helpful virus? The researchers also tested serum samples collected about 5 to 6 years after the initial diagnosis (designated the "late visit") and examined 1995 medical records of MACS participants (about 11 years after HIV diagnosis). They found that men who did not have active GBV-C infection at either the early or late visit were more than twice as likely to die than men who had a persistent GBV-C infection at both visits, a statistically significant difference, explained Carolyn Williams, PhD, an epidemiologist in NIAID's Division of AIDS. Moreover, those who had active GBV-C infection at the early visit and cleared the virus by the late visit, were nearly six times more likely to die than men who were persistently infected with GBV-C, also a statistically significant difference. A helpful virus? In another report, researchers led by Jack Stapleton, MD, of the University of Iowa, Iowa City, infected cell cultures with HIV and GBV-C in search of clues to the latter's protective effect for people infected with HIV. They found a plausible reason for GBV-C's beneficial effects: it appears to result in fewer copies of CCR5, a receptor on the surface of T lymphocytes that some HIV strains use to gain entry. A helpful virus? Such an effect by GBV-C would not prevent HIV infection, because it doesn't eliminate all CCR5 receptors, nor does it eliminate the possibility that HIV will use an alternative receptor, CXCR4. "But it slows replication," said Stapleton. Infection with GBV-C also boosts the production of various proteins called chemokines that mobilize and activate immune cells to fight infection, he said. A helpful virus? Intentionally infecting HIV-infected patients with GBV-C in the hopes that it will confer a beneficial effect is worth considering, especially for people with multidrug-resistant HIV who have no remaining treatment options, said Stapleton. Even so, such an attempt would be problematic. For one thing, HIV-infected individuals who are coinfected with GBV-C and subsequently clear the latter virus from their systems not only lose the purported benefit but may fare worse than patients who were never coinfected with the two viruses in the first place. A helpful virus? But if other studies indicate that GBV-C substantially slows progression of HIV, scientists may try to develop drugs that mimic its effects. "Understanding the mechanisms for the interaction between GBV-C and HIV may provide insights into ways to control HIV disease progression," the researchers noted. Targeting hiv entry Targeting hiv entry Foiling HIV entry into cells by making CCR5 and other receptors on target cells inaccessible to the virus is an ongoing focus of research, and researchers described work in progress on this front, including findings from early studies in humans of a monoclonal antibody called TNX-355 (formerly called HU548). This peptide recognizes the CD4 receptor, one of the coreceptors (along with CCR5 or CXCR4) that HIV uses to invade human cells. The antibody is a humanized version of a mouse monoclonal antibody that "coats" the CD4 receptor in such a way that it inhibits the process of cell entry by HIV without interfering with the CD4 receptor's natural function as a chemokine receptor. Targeting hiv entry In early trials involving 30 patients with HIV infection (all of whom had been treated with many different HIV drugs and in two thirds of whom highly active antiretroviral therapy was failing), high doses of the antibody caused a more than 90% reduction of HIV levels in the blood, and was safe and well tolerated, reported Daniel R. Kuritzkes, MD, of Harvard Medical School, Boston. Targeting hiv entry Because the mechanism of action for the peptide differs from that of currently available antiretroviral drugs, it could offer an alternative for patients with HIV that is resistant to currently available drugs. Because the CD4 coating persisted for up to 27 days at the highest dose, it also might be possible to administer the drug infrequently, perhaps every week or two. Targeting hiv entry One possible limitation might be the development of antibodies to TNX-355 itself, which could blunt or eliminate the drug's activity, noted Kuritzkes. Studies with macaques that had received several doses of the peptide did develop such antibodies, but chimpanzees—which are more closely related to humans—did not. A multiple-dose study is currently under way, he said.

Journal

JAMA – American Medical Association

Published: Mar 26, 2003

Keywords: hiv,hiv infections

There are no references for this article.