Abstract
Compounds Attack Tuberculosis Through Essential Enzyme
Researchers at Johns Hopkins University School of Medicine screened 175,000 small chemical compounds to find a group that that selectively slows an essential protein necessary for tuberculosis (TB) to grow. The class of compounds attacks the methionine aminopeptidase (MetAP) activity. This is an essential enzyme found in organisms ranging from bacteria to humans. Its role is to ensure the proper manufacture of proteins.
According to the researches, MetAP inhibitors work in the following manner. Proteins are folded in unique 3-D shapes, with the amino acid in every string being methionine. The methionine ultimately must be removed for the protein to mature and fold correctly. Its removal is the job of enzymes called methionine aminopeptidases, or MetAPs. Eliminate this enzyme in TB, and the bacteria will not survive.
After screening thousands of compounds, the researchers found a potent class called 2,3-dichloro-1,4-naphthoquinone that inhibits this enzyme. They accomplished this by using large-scale, high-throughput screening of 175,000 compounds and measuring the potencies of a dozen related hits against the enzyme. After this, the team tested the MetAP inhibitors on TB bacteria in culture to see if it had any effect on bacteria growth.
In the future, the hope is that one of these compounds can be added to existing TB therapies to enhance their efficacy. One of the MetAP inhibitors is probably not potent enough to work alone as a therapeutic agent.
The study was published in the journal Chemistry & Biology, 2010;17:86–97.
MRSA Infection Six Times Higher in HIV Patients
A new study has found that patients with HIV infection are at increased risk of acquiring community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections. Specifically, researchers at John H. Stroger, Jr., Hospital of Cook County and Rush University Medical Center found the incidence of CA-MRSA in the Chicago area was sixfold higher among HIV-infected patients than it was among HIV-negative patients.
At one time, MRSA infections were normally found in patients in hospitals and long-term care facilities. More recently, however, transmission of MRSA has emerged in community environments outside of these institutions. As a result, people without prior health-care facility exposure are picking up these infections in the community setting. The traditional risk factors for CA-MRSA include close person-to-person contact, such as children in daycare facilities, and those who are prisoners, athletes and military personnel.
Most of these MRSA infections involve minor skin and soft-tissue infections. They are usually treated with antibiotic therapy and drainage of the infection. Complications can occur, such as necrotizing pneumonia, fasciitis, and bacteremia.
In their study, the researchers retrospectively studied HIV-infected patients with CA-MRSA who received medical care during the period from 2000 to 2007 in the regional Cook County Health and Hospitals System. Patients' zip codes were used to determine where the cases were distributed geographically.
Overall, the incidence of CA-MRSA increased significantly for all populations in Cook County from the first period (2000–2003) to the second period (2004–2007). The incidence increased fourfold from 61 cases to 253 cases per 100,000 HIV-negative patients and nearly fourfold from 411 cases to 1,474 cases per 100,000 HIV-infected patients, respectively.
The most significant predictors associated with CA-MRSA infection included living in zip codes with a high prevalence of former prison inmates, and living in alternative housing, such as a substance-abuse treatment facilities, shelters, or subsidized housing. When the epidemic first started, it was clustered in certain zip codes. During the first period, 10% of the zip codes in Cook County had a high rate of MRSA among HIV-infected patients. By the second time period, that percentage had jumped to 21% of zip codes.
Now that an association has been established between HIV and CA-MRSA, the researchers plan to find out what might be causing these infections in the community. They speculate that the risk among people with HIV infection may be increased because of overlapping community-based social networks.
The study was published in the April 1 issue of the journal Clinical Infectious Diseases, 2010;50:979–987.
Therapeutic Vaccine Trial Begins Enrollment
The AIDS Research Consortium of Atlanta (ARCA) has received approval to begin enrollment of the first therapeutic trial ever conducted by using a promising HIV vaccine candidate developed by GeoVax, Inc., a biotechnology company in Atlanta, Georgia. This is the first study using the company's vaccine products for treatment of persons who already have HIV infection. ARCA will be the only site for this trial.
ARCA worked together with GeoVax to design the protocol for the Phase I clinical trial. The trial is based on the achievement of excellent postvaccine viral control in animal studies conducted in recently infected nonhuman primates at the Yerkes National Primate Research Center, affiliated with Emory University.
Persons eligible for the trial must have a negative HIV test followed by a positive test ≤6 months later. They should also have started antiretroviral drugs within 6 months of being diagnosed. The study will last up to 77 weeks. All patients will be followed up closely for safety and for the ability of the vaccine to elicit protective immune responses in vaccinated participants. Patients will be compensated for their participation in the study. Only 10 to 12 persons are expected to enroll and be selected.
Individuals interested in learning more about the trial can contact ARCA at
Faith-based Program May Help Reduce Risky Sexual Behaviors
A researcher at the University of Illinois at Chicago is developing and evaluating a faith-based, HIV-prevention program for African-American mothers and their daughters. The $795,000 funding for the initiative is being provided by the National Institute of Mental Health.
Dr. Chisina Kapungu is an assistant professor of obstetrics and gynecology and a clinical psychologist who has worked on HIV-prevention programs, conducted research on the multisystemic factors of HIV risk in African-American adolescents, and counseled HIV-infected women and children. Her new project will work with two Chicago churches to pilot a faith-based HIV-prevention program for community-based educators to administer to women and their daughters, ages 13 to 16 years.
According to Kapungu, a major collaborative aspect will be part of the program. It is based on principles of community-based participatory research. Throughout the initiative, decision making will be shared among those involved. The intervention is based on two existing HIV-prevention programs. One has been developed by the Religious Coalition for Reproductive Choice in Washington. The second is an evidenced-based program, “Sisters Informing, Healing, Living, and Empowering,” recommended by the U.S. Centers for Disease Control and Prevention (CDC) and proven effective among African-American women and girls. Kapungu plans to integrate the two programs and customize the curriculum based on the needs of the community, to include information about parental monitoring, assertive communication, and negotiating safe sexual practices. It will not focus on condom use.
Drug-Resistant TB Being Studied in South Africa
Researchers at Albert Einstein College of Medicine of Yeshiva University are studying how extensively drug-resistant tuberculosis (XDR-TB) is transmitted in rural South Africa. The findings could alter public health approaches for controlling the XDR-TB epidemic in the developing world. Their work is being funded by a 5-year, $3.9 million grant from the National Institutes of Health (NIH).
The research team will prospectively interview and analyze the medical records of 400 patients with XDR-TB to determine how many new cases develop because of person-to-person transmission compared with new cases of amplified resistance. The study will take place in the area of Tugela Ferry in the KwaZulu-Natal district of South Africa, which has exceedingly high rates of XDR-TB. Many TB patients in this area are coinfected with HIV.
Efforts to curb the growing XDR-TB epidemic currently focus primarily on preventing amplified resistance through directly observed therapy. If person-to-person transmission is found to be the major source of drug-resistant TB, public health agencies will have to adjust their XDR-TB control efforts by emphasizing measures that prevent people from infecting others. This will include earlier diagnosis and treatment and more-rigorous infection-control measures. The findings would be applicable throughout sub-Saharan Africa, where the TB epidemic follows patterns similar to those in Tugela Ferry.
The researchers will try to determine how person-to-person XDR-TB transmission is most likely to occur. This may be within families, among co-workers, or perhaps among people admitted to the hospital at the same time. They will combine classic contact investigation methods with advanced epidemiologic techniques (including molecular genotyping) and social-network analysis. Molecular genotyping will allow the researchers to identify clusters of particular strains of XDR-TB. The goal will be to determine how individuals in these clusters are linked.
Prevention Campaigns Must Take Sexual Trends into Account
HIV-prevention campaigns must take into account changing sexual trends and social norms. When they do, they are more effective than campaigns that ignore them. The finding comes from a series of surveys conducted in France by researchers at the Institut National de la Sante et de la Recherche Medicale (INSERM) in Paris
The study outlines the changes in sexual behavior and norms as revealed by a series of three random probability surveys conducted in 1970, 1992, and 2006. Over the last few decades, the average age at first intercourse has decreased by 4 years for women, from 22.0 years in the 1930s to 17.6 years in the 2000s, and one year for men, from 18.1 years to 17.2 years. The average number of sexual partners a women has during her lifetime has more than doubled since the 1970s, from 1.8 to 4.4 in 2006, whereas the average for men has remained largely unchanged, from 11.8 to 11.6. At the same time, the proportion of respondents, especially women, who reported nonpenetrative sexual practices and considered sexual intercourse essential to well-being was increasing.
According to the researchers, these changes are due to an increase in women's social status during the 20th century. They also observed a marked increase in condom use after the first HIV-prevention campaigns in the 1980s in France and elsewhere around the world, where prevention policies aimed at harm limitation, rather than at abstinence, appear to have agreed with secular trends. Public health interventions that are synergistic with changing trends in social norms are likely to be more effective than are those that run counter to them.
The findings will be published in the May 15 issue of AIDS, 2010;24:1185–1191.
False-Positive TB Diagnosis Linked to Higher Mortality
HIV-infected patients with a false diagnosis of tuberculosis (TB) from rapid testing have higher rates of mortality than do those who are correctly diagnosed with the disease. The interesting finding comes from a study conducted by researchers at the University of California-San Francisco and Makerere University-Kampala.
In this study, the researchers evaluated the outcomes of 600 HIV-infected patients who were treated at Mulago Hospital in Kampala, Uganda, including patients who were incorrectly diagnosed with TB after rapid testing. Poorer outcomes are likely attributable to the fact that patients who are misdiagnosed are treated erroneously for TB, while the actual underlying condition remains untreated. Because physicians believe that TB is the culprit, any search for the real underlying disease is delayed. As a result, so is proper treatment.
The findings should serve as a cautionary note to physicians, who should continue to monitor patients diagnosed with TB. By closely monitoring them, the physician can ensure that treatment is working. If the patient does not improve with treatment, then the diagnosis should be reassessed.
According to the researchers, the findings suggest that rapid diagnostic tests for TB should be refined further. Such tests are not always sensitive or specific in their ability to diagnose TB. Better tests are needed with more sensitivity and specificity that are affordable for poor countries to use effectively.
The study was presented at the American Thoracic Society International Conference, May 14–19, New Orleans, LA; Abstract 1654.