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GLOBAL NEWS

The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) recently issued recommendations saying that adult male circumcision should be recognized internationally as an important intervention to reduce HIV transmission. The recommendations also advise countries with high HIV prevalence and low rates of male circumcision to consider rapidly and dramatically increasing access to this surgical procedure to men at risk of heterosexual transmission of HIV. The organizations released these guidelines following an international consultation with various governments, researchers, human rights advocates, funding agencies, and civil society members that was held from March 6-8 in Switzerland. According to the guidelines, circumcision should now be included broadly as part of a comprehensive strategy to prevent HIV transmission, along with the use of condoms, voluntary counseling and testing services, and the treatment of other sexually transmitted diseases. Many individual countries are also in the process of establishing national guidelines on the introduction of male circumcision programs.

The decision to recommend male circumcision as an HIV prevention tool comes on the heels of the results from three randomized, controlled clinical trials that have shown circumcision can reduce the risk of heterosexual transmission of HIV infection by as much as 60% in men. These trials were conducted in Kisumu, Kenya; Rakai District, Uganda; and Orange Farm, South Africa. Studies to predict the impact of different prevention technologies on the course of the epidemic suggest that implementation of circumcision programs in sub-Saharan Africa could prevent 5.7 million new HIV infections over the next 20 years.

The WHO/UNAIDS guidelines recommend that more research be conducted on how male circumcision may impact HIV transmission to women, as well as the risks and benefits of performing circumcision in men who are already HIV infected. An ongoing study sponsored by the Bill & Melinda Gates Foundation is looking at how male circumcision affects HIV transmission to female partners. Limited data from studies already conducted suggests that HIV transmission between recently circumcised HIV-infected men and their female partners may be increased if they engage in sexual activity before their surgical wound is completely healed, and this process may take longer in HIV-infected men.

One concern shared by WHO/UNAIDS and organizations that will be implementing circumcision programs in developing countries is ensuring access to safe services, which requires training providers to conduct the procedure, providing sanitary settings and properly sanitized instruments, and then closely monitoring and evaluating circumcision programs once they begin to ensure that the circumcisions are being performed properly. The recommendations also suggest that men seeking circumcision be offered counseling services to prevent them from having the false perception that they are completely protected against HIV infection and therefore able to engage in high-risk behaviors, an idea known as behavioral disinhibition.

In Uganda, researchers are planning to establish a limited number of sites to serve as centers of excellence for adult male circumcision. The site in Kisumu where the clinical trial of male circumcision was conducted has received funding from the US President's Emergency Plan for AIDS Relief (PEPFAR) to serve as a center of excellence in the region.

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All articles written by Kristen Jill Kresge

PRIMER

What are the major scientific obstacles to the development of an effective AIDS vaccine?

Over the past several years there has been significant scientific progress in understanding HIV infection and how the virus interacts with the human immune system. There has also been renewed political and financial commitment to the global effort to combat HIV/AIDS and there are now more than 30 ongoing clinical trials evaluating different AIDS vaccine candidates. Despite these advances, HIV is a difficult virus to target and developing a safe and effective vaccine that protects people against infection will involve overcoming several of the remaining scientific obstacles.

Genetic diversity

One reason AIDS vaccine development is so complex is because HIV replicates, or makes copies of itself, extremely rapidly within an infected individual. Once HIV infects a CD4+ T cell it quickly produces more viruses that can subsequently infect more immune cells, setting off a cycle of destruction that allows HIV to overwhelm and eventually destroy the immune system. But this replication process is imperfect and each time HIV copies its genetic material it makes mistakes. This results in a huge number of viruses, each having a slightly different genetic makeup, circulating within a single individual, as well as within the overall population.

HIV's extraordinary genetic diversity makes development of an effective AIDS vaccine much more difficult because it will have to protect against so many different virus strains. The vaccine against influenza provides a sobering example. Although the influenza virus varies substantially less than HIV, the vaccine still must be reformulated each year to be effective against the predominant strain of virus in circulation.

Natural infection

Most licensed vaccines against other diseases are thought to work because they induce virus-specific neutralizing antibodies (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). But even though several HIV-specific neutralizing antibodies have already been discovered in infected individuals, it is still not known how much of a role they play in controlling HIV infection. The antibody responses generated against HIV naturally by the immune system are insufficient to clear an infection because there has never been a documented case of a person who was able to clear an established HIV infection.

In many long-term nonprogressors whose immune systems can control HIV infection for much longer than the typical decade, researchers do not often observe significant neutralizing antibody responses directed against HIV (see VAXSeptember 2006 Primer on Understanding Long-term Nonprogressors). And even when neutralizing antibodies are generated against HIV, they are sometimes incapable of protecting against other closely-related strains of the virus. There are several confirmed cases of superinfection, where HIV-infected individuals are infected with a second strain of HIV despite having antibodies toward the strain they were already infected with.

Even though antibodies may not play a critical role in controlling HIV in infected individuals, researchers speculate that vaccine-induced HIV-specific antibodies would still be important, even necessary, in protecting someone against infection. This presents a significant challenge to AIDS vaccine researchers who have to discover new ways to induce immune responses—both antibodies and cellular immune responses (CD4+ and CD8+ T cells)—that are even more effective than those produced during natural infection.

Immune system under attack

Part of the reason that it is more difficult to clear an HIV infection is that the virus's primary target is the immune system itself. This is one of the main challenges to developing a vaccine that could control HIV infection, rather than completely prevent it. HIV preferentially attacks CD4+ T cells, a particular subset of immune cells that help orchestrate all of the other types of immune responses against pathogens. During HIV infection, many of these cells are damaged and can't function properly. As more and more of the CD4+ T cells are eventually killed, the immune system becomes incapable of fighting off HIV, as well as other viral and bacterial infections, and AIDS onset occurs. A partially-effective AIDS vaccine that could help bolster the immune response against HIV before too many CD4+ T cells are damaged might help preserve some of the critical immune cells early in the course of infection and significantly slow disease progression. Such a vaccine may also reduce the likelihood of an infected individual transmitting HIV to others.

Imperfect animal model

Another way to gather useful information about the types of immune responses that protect against infection is to study the virus in an animal model. But HIV does not infect any other animals so AIDS vaccine researchers must instead study a related virus, simian immunodeficiency virus (SIV). This virus infects some species of non-human primates, including rhesus macaques (see VAX October 2006 Primer on Understanding AIDS Vaccine Pre-clinical Development). This is not a perfect model for human infection since it is a different virus and any vaccine candidates that are tested in non-human primates must be based on SIV and not HIV.

Immunogen design

The key to inducing strong antibody and cellular immune responses with a vaccine is selecting the right immunogen or antigen—either whole HIV proteins or pieces of protein—that will stimulate the immune system to induce the desired type and amount of responses. Designing immunogens to include in AIDS vaccines is very difficult and only incremental progress has been made in this area. Currently several different immunogens are being evaluated in both pre-clinical and clinical trials. These immunogens are being tested in combination with several different viral vectors (see VAX September 2004 Primer on Understanding Viral Vectors) and adjuvants (see VAX October 2004Primer on Understanding Vaccine Adjuvants) to try to increase the level of immune responses that are generated. Other approaches to improve the immunogenicity of vaccine candidates can also be tried, including alternative delivery methods—such as intravenous, oral, or intra-nasal administration.