Studies Examine Effect Of Male Circumcision On Sexual Behavior, Breast-Feeding Interventions For HIV-Positive Women

The following highlights recently released journal articles on HIV/AIDS.

Male Circumcision in Siaya and Bondo Districts, Kenya: Prospective Cohort Study To Assess Behavioral Disinhibition Following Circumcision," Journal of Acquired Immune Deficiency Syndromes: Kawango Agot -- project coordinator of a collaborative research project among the University of Nairobi, University of Illinois and the University of Manitoba -- and colleagues conducted the study among 324 recently circumcised men and 324 uncircumcised men to determine the effect of circumcision on sexual behavior. The researchers compared the two groups' sexual behaviors at one, three, six, nine and 12 months following circumcision or study enrollment. They found that during the first month following circumcision, men were 63% less likely to report having 0 to 0.5 risky sexual acts weekly than uncircumcised men. The researchers also found that during the first month following circumcision, men were 61% less likely to report having more than 0.5 risky sexual acts weekly than uncircumcised men. The differences in sexual behavior disappeared during the remainder of the follow-up period, and similar results were seen for risky unprotected sexual acts, number of at-risk sexual partners and condom use, according to the researchers. The researchers concluded that during the first year following circumcision, men did not report an increased number of risky sexual acts compared with uncircumcised men -- indicating that "any protective effect of male circumcision on HIV acquisition is unlikely to be offset by an adverse behavioral impact" (Kawango et al., Journal of Acquired Immune Deficiency Syndromes, 1/1).

Two-Year Morbidity-Mortality and Alternatives to Prolonged Breast-Feeding Among Children Born to HIV-Infected Mothers in Cote d'Ivoire," PLoS Medicine: Renaud Becquet of the Institut National de la Sante et de la Recherche Medicale Unite in France and colleagues conducted the study from 2001 through 2005 among 557 infants born to HIV-positive women in Abidjan, Cote d'Ivoire. After their infants were born, the women, who underwent prenatal antiretroviral prophylaxis, either received breastmilk substitutes or exclusively breast-fed for four months. Nutritional counseling and clinical management were provided for two years, and breastmilk substitutes were provided at no cost. Thirty-four percent of the 262 infants who were breast-fed for an average of four months during the two-year follow-up period did not experience any adverse health outcomes -- which the researchers defined as diarrhea, acute respiratory infections or malnutrition -- compared with 37% of the infants who received breastmilk substitutes. The two-year probability of presenting with a severe health event -- which the researchers defined as hospitalization or death -- was 14% among the breastmilk substitute group, compared with 15% among the breast-fed infants. The researchers concluded that breastmilk substitutes and short-term breast-feeding can be safe interventions aimed at preventing mother-to-child HIV transmission in urban African settings where adequate nutritional counseling and care, access to clean water and breastmilk substitutes are available (Becquet et al., PLoS Medicine, January 2007). In a related opinion piece, Grace John-Stewart of the University of Washington writes that the researchers "provide good data to suggest that with appropriate provisos, replacement feeding can be a safe option to consider" for HIV-positive women in urban African settings (John-Stewart, PLoS Medicine, January 2007).

"Reprinted with permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Engineered Immune Cells And AIDS

Twenty years after its introduction, gene therapy still holds great promise as a way to harness the insidious power of viruses such as human immunodeficiency syndrome (HIV). But scientists have yet to solve a vexing problem: developing an efficient transport system that is capable of delivering therapeutic payloads to specific cells.

As challenging as the problem has been, researchers in the USC Viterbi School of Engineering may be turning a corner. With support from a $13.9 million grant from the Bill and Melinda Gates Foundation, a multi-institutional team of scientists, including Pin Wang of the USC Mork Family Department of Chemical Engineering and Materials Science, is exploring a completely new way of manipulating the body's natural defense system.

"Rather than focusing on conventional vaccines that boost the immune system, we are experimenting with a way to help the immune system produce antibodies that can neutralize the virus," says Wang. "If we can design a modified virus that will deliver these antibodies to chosen cells, we will be able to insert DNA that will help rather than harm cells."

Viruses are efficient carriers or transport vehicles in the body because they are naturally able to penetrate cells, inserting the genetic material they contain into their new host. By itself, a virus cannot reproduce; it must infect a cell and take control of the host's machinery to make copies.

HIV also possesses an unusual structure and a keen ability to hide from antibodies in a sugar-coated shield. The shield has very few open spaces on its surface, Wang says, which makes it virtually impossible to penetrate. And because the virus also has an uncanny ability to hide, HIV often goes virtually unnoticed by neutralizing antibodies that are roaming the body in search of foreign invaders.

Faced with such a clever adversary, Wang wants to synthetically alter the HIV invaders and use their hollow shells as delivery vehicles to insert DNA that will counteract the infection.

The "Cadillac" of this gene delivery system is an HIV-based "lentiviral vector," a type of retrovirus that uses the backbone of a virus to infect both dividing and nondividing cells. Wang says lentiviral vectors are very efficient delivery vehicles for human cells.

Collaborators on his project are targeting hematopoietic stem cells -- the bone marrow cells that form blood cells - to create B lymphocytes. The researchers want to reprogram these bone marrow cells by adding genes that will instruct the cells to produce rare antibodies such as B12, 4E10, 2G12 and 2F5. Wang says these antibodies are known to neutralize the virus.

"In laboratory tests, we remove harmful genes coding for the HIV virus and engineer the backbone, or spine, of virus so that it is no longer replicable " he says. "Once manufactured recombinantly, this modified virus - the lentiviral vector -- becomes a natural delivery system that can transport useful genes into cells without causing illness."

Although the gene delivery technique looks promising, researchers are still working on ways to manipulate these elusive bone marrow cells and get them to generate "designer immune cells." Another problem seems to be making sure lentiviral vectors target only hematopoietic stem cells, and not other types of cells, to achieve the desired targeted delivery.

With a group of USC biomedical engineering students and Caltech biologists, Wang is experimenting with CD20 as a target antigen for human B cells. His strategy, published in the August 1, 2006 issue of Proceedings of the National Academy of Sciences, targets the human B cells only. After two years of experimentation, the team has been able to demonstrate that they can specifically target human B cells in mice.

"Possibly the most important implication of the work is that gene therapy could now be carried out as an inexpensive procedure, able to be considered even in the less-developed world," Wang and his coauthors wrote.

That's good news for the World Aids Foundation, which announced on World AIDS Day (Dec. 1, 2006) that the disease is on the rise again. More than 39 million people around the world are now infected with HIV, the foundation reported.

"I think we are finally on the right track," Wang says. "If scientists can find a way to genetically engineer immune cells to neutralize HIV, we may be able to develop immunotherapy for HIV-Infected people, as well as find ways to prevent it all together."

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Wang's research is part of the Gates Foundation's Grand Challenges in Global Health initiative, which was launched in 2003 to create "deliverable health tools" that were "not only effective, but also inexpensive to produce, easy to distribute and simple to use in developing countries."

Collaborators on the five-year project, titled "Engineering Immunity Against HIV and Other Dangerous Pathogens," include principal investigator David Baltimore of Caltech, co-principal investigators Pamela Bjorkman of Caltech and Wang of USC. The USC student researchers working on the project are Leslie Bailey, Taehoon Cho, Haiguang Yang and Alex Lei. All four are third-year Viterbi School graduate students majoring in chemical engineering.

Contact: Diane Ainsworth
University of Southern California

China Considering Evidence That Male Circumcision Could Reduce Risk Of HIV Infection, Unlikely To Launch Campaign, Health Official Says

China is considering evidence that routine male circumcision could reduce a man's risk of HIV infection but likely will not implement such a campaign nationwide, Ru Xiaomei, deputy director general of China's National Population and Family Planning Commission, said on Friday, Reuters U.K. reports (Blanchard, Reuters U.K., 1/19). Data from two studies conducted in Kenya and Uganda released last month by NIH indicate that routine male circumcision could reduce a man's HIV infection risk through heterosexual sex by about 50%. According to researchers, male circumcision eliminates the cells most vulnerable to HIV. In addition, a circumcised penis develops thicker skin that is resistant to HIV infection. The results of the Uganda and Kenya studies were similar to the results of a study conducted in South Africa in 2005 (Kaiser Daily HIV/AIDS Report, 12/14/06).

Comments
According to Ru, Chinese officials have seen the results of the studies conducted in Africa, but the "AIDS situation in China has not yet reached such a large scale (as in Africa)." She added, "I'm not yet totally certain about the evidence for circumcision. We should exercise caution." According to Reuters U.K., the number of circumcisions performed in China is low compared with some Asian countries, including South Korea, Japan and Indonesia. In addition, a wide-scale male circumcision campaign might encounter resistance from China's non-Muslim majority, according to Ru. She added that the cost of such a campaign might present an issue because of China's 1.3 billion population. "It would be a big deal," she said, adding, "It's much more reasonable to get people to use condoms" (Reuters U.K., 1/19). <

"Reprinted with permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

A Spoonful Of Sugar Makes The Medicine Work

There will soon be no more bitter pills to swallow, thanks to new research by University of Leeds scientists (UK): a spoonful of sugar will be all we need for our bodies to make their own medicine.

Professor Simon Carding of Leeds' Faculty of Biological Sciences has adapted a bacteria in our own bodies to make it produce a treatment for Inflammatory Bowel Disease (IBD). Bacteria and viruses have been used before to deliver drugs in this way, but Professor Carding has solved the major problem with this kind of treatment: he uses a sugar to 'switch' the bacteria on and off. By eating the sugar, a patient will set the medicine to work and then can end the treatment simply by stopping consumption of the sugar.

"Current bacteria and virus delivery systems produce their drugs non-stop, but for many treatments there is a narrow concentration range at which drugs are beneficial," said Professor Carding. "Outside of this, the treatment can be counterproductive and make the condition worse. It's vitally important to be able to control when and how much of the drug is administered and we believe our discovery will provide that control."

Professor Carding has modified one of the trillions of bacteria in the human gut so that it will produce human growth factors which help repair the layer of cells lining the colon, so reducing inflammation caused by IBD. But he's also adapted the bacteria so it only activates in the presence of a plant sugar called xylan that is found in tree bark. Xylan is naturally present in food in low concentrations, so by taking it in higher quantities, a patient will be able to produce their own medicine as and when they need it.

"The human gut has a huge number of bacteria, and this treatment simply adapts what's there naturally to treat the disease," said Professor Carding. "We're already looking at using the same technique for colorectal cancer, as we believe we could modify the bacteria to produce factors that will reduce tumour growth. Treatment of diseases elsewhere in the body might also be possible as most things present in the gut can get taken into the blood stream."

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The discovery has been patented - and is being developed further with support from the University's technology transfer partner, Techtran Group Ltd - part of the IP Group plc - and the Medical Research Council. The technique has been shown to work in vitro, but the researchers will be testing the treatment over the next twelve months in preparation for clinical trials.

Contact: Jo Kelly
University of Leeds

Cbl-b Resists Pseudomonas Aeruginosa Infection

Infection with Pseudomonas aeruginosa is a major problem for patients in hospital, who are at increased risk of infection because they often have a weakened immune system, as well as individuals with cystic fibrosis. One of the things that makes P. aeruginosa so virulent is the expression of a number of proteins that function as a type III secretion system. In a study that appears online on January 18 in advance of publication in the February print issue of the Journal of Clinical Investigation, researchers from the University of California at San Francisco, have identified Cbl-b as a protein that helps protect mice from infection with P. aeruginosa by targeting one of the components of the type III secretion system, ExoT.

Joanne Engel and colleagues found that in cultured human cells, ExoT was targeted for destruction by the host protein Cbl-b. More importantly, ExoT was shown to be important for bacterial dissemination in mice infected with P. aeruginosa and mice lacking Cbl-b were more susceptible to both intranasal and systemic infection with P. aeruginosa than wild-type mice. This study therefore identifies Cbl-b as a component of early host defense against infection with P. aeruginosa, an observation that could help develop new strategies for the treatment of individuals infected with this major opportunistic pathogen.

TITLE: The ubiquitin ligase Cbl-b limits Pseudomonas aeruginosa exotoxin T-mediated virulence

AUTHOR CONTACT:

Joanne Engel
University of California at San Francisco, San Francisco, California, USA.

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JCI table of contents: Jan. 18, 2007

Contact: Karen Honey
Journal of Clinical Investigation