The AIDS virus inserts its genetic material into the genome of the infected cell. Scientists of the German Cancer Research Center have now shown for the first time that the virus almost entirely spares particular sites in the human genetic material in this process. This finding may be useful for developing new, specific AIDS drugs.

Like all retroviruses, the AIDS virus (HIV) integrates its DNA into the genome of the infected cell. As integration sites, HIV usually prefers active genes that are transcribed frequently. This is advantageous for the virus, because this is where it finds large amounts of enzymes which are responsible for transcription. The virus abuses this cellular equipment for its own replication.

At DKFZ, Associate Professor (PD) Dr. Stephanie Laufs and Dr. Frank Giordano are trying to find out whether AIDS viruses can be used as gene delivery vehicles in gene therapy. Therefore, it is crucial for them to know where exactly HIV integrates into the genetic material of the host cell. This is a critical step in gene therapy, because depending on the position, this process can result in permanent activation of oncogenes or other damage. Therefore, the researchers took a very close look by starting an analysis of more than 46,000 known integration sites of HIV-based gene delivery vehicles that were determined in various gene therapy studies or are available in gene databases.

Up to now, researchers have been convinced that both HIV and HIV gene delivery vehicles have a particular preference for sites where gene transcription starts. At these sites there is an abundance of those enzymes which the viruses need. However, the database analysis produced an entirely different picture. While many HIV do really integrate close to transcription start sites, the investigators found hardly any such start points in the closest, immediate vicinity of the HIV integration sites, i.e. only 1,000 DNA building blocks “to the left” and “to the right” of them.

“For the first time we have very precisely defined areas in the human genome where HIV hardly ever integrates,” Giordano explains. The scientists are electrified by the result, because there must be a reason why HIV evades these sites. “We assume that there is a particular mechanism at work which blocks the way for the virus,” says Giordano. “On the other hand, it is also possible that some factor that HIV needs for its integration is missing at these sites.” The researchers even know already that this access barrier cannot be an unspecific one: “Other retroviruses even prefer to insert their genetic material exactly at the transcription start sites,” Laufs explains. “Therefore, we assume that the mechanism protecting the transcription start sites of active genes from HIV genome integration very specifically prevents HIV integration.” For example, this mechanism might block the work of an enzyme called integrase, which is responsible for integrating the viral DNA into the DNA of the infected cell.

This enzyme is currently in the focus of the search for an improved AIDS therapy. The highly active treatment available today attacks the virus from several different angles using different drugs: Reverse transcriptase inhibitors prevent the viral genome from being copied. Protease inhibitors block the maturation of new viral proteins. Scientists agree, however, that the best way of fighting the severe immune deficiency is to prevent integration of the viral genetic material into the DNA of the host cells. Substances preventing this, called integrase inhibitors, have been used in recent years, but the viruses have already started evading their effect through mutations. Therefore, virologists are urgently searching for new approaches to blocking this key enzyme of the virus. The mechanism that prevents HIV from integrating at the transcription start site might be a molecular model for developing such substances.

Credit: Professor Dr. Hanswalter Zentgraf, German Cancer Research Center


Legend: HIV particles at a cellular membrane


Frank A. Giordano, Jens-Uwe Appelt, Manuela Zucknick, Mohammed Abba, W. Jens Zeller, Stefan Fruehauf, Heike Allgayer and Stephanie Laufs: Cold spots in hot spots: transcription start sites of active genes are spared from HIV vector integration. AIDS 2009, DOI: 10.1097/QAD.0b013e3283336432

Source: Dr. Sibylle Kohlstaedt

Helmholtz Association of German Research Centres

World AIDS Day 2009 will be marked with both grim and hopeful data: more than 25 million people have died of AIDS worldwide since 1981; 33 million are living with HIV/AIDS. While potent, effective medications have changed an HIV diagnosis from death sentence to manageable chronic illness in resource rich countries, global rates of infection still outstrip prevention and treatment capacity. And, increasingly, past “knowns” don’t apply. Half of all people with HIV worldwide are now women. This and other shifts in HIV/AIDS prevalence, incidence, and demographics have Johns Hopkins University School of Nursing (JHUSON) faculty exploring avenues to more effective, community-based prevention and treatment of HIV.

Women: The Multiplying Faces of HIV/AIDS-Today, HIV is a women’s issue. Young African-American women are contracting HIV at rates exceeding those of all other groups. Women in sub-Saharan Africa are dying of AIDS at three times the rate of their male counterparts. JHUSON faculty are working to unravel risk and protective factors for HIV among women, to discern women at greatest risk for HIV, and to prevent HIV transmission. Professor and domestic violence researcher Jacquel
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yn Campbell, PhD, RN, FAAN, leads the way. Her meticulous community-based work in the U.S. and South Africa highlights the central role intimate partner violence (IPV) and other forms of sexual violence play in the transmission of HIV to women. She has found these types of violence increase women’s risks of contracting and dying from HIV/AIDS, whether in countries where HIV is readily diagnosed and treated, like the U.S., or in nations with significantly fewer health resources, such as South Africa.

Joining in the quest for knowledge about the relationship between IPV and HIV is Campbell’s frequent collaborator, associate professor Nancy E. Glass, PhD, MPH, RN, FAAN. Glass, whose work primarily focuses on IPV, has broadened her focus to explore issues at the intersection of HIV and violence in a study of women exposed to HIV as the result of rape in war-torn areas of the eastern Democratic Republic of the Congo (formerly Zaire). When it comes to preventing HIV, Campbell observes, “If you’re being beaten up and raped, it’s hard to negotiate for condom use by an HIV-infected partner. And, as we know from our work in IPV, it’s also hard for women to admit sexual or other abuse and walk away from it. It’s all about relationships.”

Those relationships are at the heart of research conducted by professor Phyllis Sharps, PhD, RN, CNE, FAAN. An expert in racial and ethnic health disparities, especially in maternal and child health, Sharps was struck by the high HIV rates among women of color in their childbearing years and wondered what could be learned from HIV positive women to improve interventions, assessments, and prevention. Her findings from over 55 in-depth interviews have powerful implications, particularly for prevention. Simply put, women need more knowledge about HIV presented in ways that engage them, enlighten them, and empower them. Sharps observes “Many young women become HIV positive from one or two episodes of unprotected sex. Some don’t think to ask about HIV and condoms; some don’t know how to ask.” She has found that talking at young women doesn’t work. Reaching them means reaching into the very fabric of their lives by “finding interventions that can serve as models and adapt them for use in the inner cities and the rural hills. HIV isn’t about ‘those women’ any more; it’s about all women.”

The trio agrees that nurses can meet the challenge of HIV in women by helping women disclose IPV and other risk factors for HIV transmission such as unprotected sex and drug use. Campbell is “feeling increasingly hopeful. Public policymakers are starting to recognize the changing face of HIV. They can help us advance a public health agenda that promotes culturally appropriate prevention and intervention for women at risk for HIV.”

Infection Control and TB: Combating the Other Face of HIV-Assistant professor Jason Farley, PHD, MPH, CRNP, is an infection fighter working to halt the spread of resistant infections in hospitals, prisons, and other community settings. He’s now turned his research to the growing number of individuals with both HIV and drug-resistant infections at home and abroad to assess how the two problems affect each other. With co-occurring HIV and multi-drug-resistant tuberculosis (MDR-TB) affecting as many as 75% of patients with HIV in South Africa, Farley has just completed a study that evaluated treatment outcomes of MDR-TB before the widespread availability of anti-retroviral therapy for patients with HIV was available in that nation. Among the study’s large cohort, mortality among persons with both MDR-TB and HIV was twice as high as among patients with only MDR-TB. At home, Farley is evaluating the prevalence of multi-drug-resistant staph infections (MRSA) in patients with HIV and their sexual partners. He also hopes to evaluate the risk factors for harboring MRSA and pro
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tective factors for avoiding colonization. Farley notes, “This HIV-related research reminds practitioners that we can’t treat HIV in a vacuum. We need to approach HIV from a holistic perspective that can assess the presence of other problems such as co-occurring illnesses that can complicate care and treatment regimens for both.” In 2010, Farley will team up with the Institute for Johns Hopkins Nursing (IJHN) to give practicing nurses a refresher and update on HIV science and clinical practice. According to IJHN executive director Jane Shivnan, RN, MScN, AOCN, “This program couldn’t be coming at a better time since it responds to the recent rapid changes in who is affected by HIV/AIDS and how the illness is best managed.”

Public Health Nurse Education: A New Face in East Africa-Assistant professor Sara Groves, DrPH, APHN, BC, is a hands-on health problem solver whose nursing knowledge and researcher’s enquiring mind have been put to extensive use in her travels as a public health nurse. She’s worked to prevent maternal mortality in rural Haiti and to improve maternal and child health in Brazil. Now, she’s landed in Uganda as part of a partnership between the Johns Hopkins University schools of Nursing, Public Health and Medicine, and Makerere University funded by the Bill and Melinda Gates Foundation. Groves is working to help change ‘what is” to “what could be” in healthcare education, research, and practice in Uganda and elsewhere in East Africa, in part to reduce the incidence and transmission of HIV (and its fellow-traveler, tuberculosis) in the region. The program is expanding HIV/AIDS clinical services in war-torn northern Uganda, promoting hospital births to reduce mother-to-child HIV transmission and maternal mortality, and advancing circumcision and condom use to help decrease HIV spread. Working to buttress the skills of local nursing students, Groves also is emphasizing public health and primary care in rural areas, particularly when it comes to reducing the spread of HIV and its co-occurrence with TB. Groves says her work, both in Uganda and at home, is “guided by the knowledge that nurses can create change to move people out of poverty and provide real opportunity for health worldwide.”

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Johns Hopkins University School of Nursing

HIV and sexual health charity Terrence Higgins Trust has welcomed the announcement by the Department of Health that all new nurses will be educated to degree level from 2013.

Terrence Higgins Trust (THT) currently employs nurses who work in Chlamydia screening programmes for young people, HIV testing clinics and clinics that offer contraception services and screening for sexually transmitted infections.

Jason Warriner, Clinical Director at Terrence Higgins Trust said “As our clinical services continue to grow, nurses will be pivotal in ensuring high quality services can be delivered in a variety of community settings. Degree level education will guarantee nurses have the right mix of clinical experience, clinical skills and expert knowledge, which can only benefit people using our services.”

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Terrence Higgins Trust