In advance of World AIDS Day, which was observed on December 1, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) released a report detailing updated global and regional estimates of the number of people newly HIV infected in 2006 (UNAIDS/WHO AIDS Epidemic Update: December 2006). Twenty-five years after the first cases of AIDS were reported the epidemic is still spreading relentlessly around the globe. In 2006 alone, 4.3 million people were newly infected with HIV, bringing the total number of people living with HIV/AIDS to 39.5 million.

Since 2004 the number of people living with HIV increased in every region of the world. In some regions these new infections are disproportionately occurring in young people. In the Russian Federation, 80% of HIV-infected individuals are younger than 30 years old. The primary route of transmission in the countries of Eastern Europe and Central Asia is still injection drug use and 67% of HIV infections in 2005 were a result of people injecting drugs with contaminated needles and syringes (see Spotlight article).

However, in eight African countries where sufficient data was available, HIV prevalence has declined among young people since 2000/2001. This trend is attributed to the success of HIV prevention messages targeting this age group that encourage young people to avoid behaviors that place them at risk of HIV infection. Throughout the world women are also continuing to bear the brunt of the HIV epidemic. In sub-Saharan Africa 59% of the people living with HIV/AIDS are now women.

Despite promising advancements in the availability of HIV treatment in developing countries, 2.9 million people died from AIDS in 2006—the highest number ever reported for a single year. The vast majority of these deaths (72%) occurred in sub-Saharan Africa where the epidemic is still having the greatest impact, but worldwide AIDS is now the leading cause of death in people between the ages of 15 and 59.

The theme of this year's World AIDS Day was accountability and Kofi Annan, secretary-general of the United Nations, said in a USA Today editorial that, "as the number of infections continues unabated, we need to mobilize political will as never before." He called on every prime minister, president, parliamentarian, and politician to strengthen protections for vulnerable groups, including people living with HIV, young people, commercial sex workers, injection drug users (IDUs), or men who have sex with men. Both UNAIDS and WHO emphasize the need to increase and improve prevention efforts that target people who are at greatest risk of HIV infection.

Results from two randomized, controlled clinical trials show that circumcision of male adults reduced their risk of acquiring HIV by approximately 50%. These results were released on December 12, 2006 after an independent committee of clinical research experts, statisticians, ethicists, and community representatives reviewed the interim data collected in these trials. Based on the substantial benefit offered by circumcision, male volunteers in the control group will now also be offered the surgical procedure. Researchers will continue to monitor the HIV infection rates among all volunteers and will also study how the procedure affects their behaviors.

Both of these trials, one which took place in Rakai, Uganda, and the other in Kisumu, Kenya, were sponsored by the US National Institute of Allergies and Infectious Diseases (NIAID), part of the National Institutes of Health. They confirmed the results of a previous circumcision study conducted in South Africa, which was the first to show that removal of the foreskin offered some protection against HIV infection (see VAX August 2005 Spotlight article, A comprehensive response). According to NIAID, studies in Africa have found that circumcision is an accepted practice, with 50-86% of those surveyed saying they would either have the procedure or want their partner to undergo circumcision if it was known to be safe, affordable, and have minimal side effects.

Organizations like UNAIDS and WHO are currently working on recommendations for the implementation of adult male circumcision in countries where sexual transmission of HIV predominates. Another study sponsored by US-based Johns Hopkins University is still ongoing to determine if male circumcision reduces HIV transmission from men to women. However, public health experts agree that any intervention that reduces HIV rates in men by 50% will also benefit women.

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All articles written by Kristen Jill Kresge.
Spotlight article was adapted from an article by Catherine Zandonella (IAVI Report, 10, 4, 2006)

How can animal models be used to identify the correlates of protection for an AIDS vaccine?

Using animal models to study HIV infection and the progressive development of AIDS is an important way for researchers to analyze how the virus behaves in humans (see VAX October 2006 Primer on Understanding AIDS Vaccine Pre-clinical Development). Despite its limitations, the non-human primate model is immensely useful to researchers. Studying the related simian immunodeficiency virus (SIV) in non-human primates, typically rhesus macaques, provides important information about HIV, even though these studies involve a different virus. Many discoveries about how SIV interacts with the immune system and causes disease, a principle known as pathogenesis, in macaques have later been shown to also be true for HIV in humans. For example, the finding that HIV preferentially kills CD4+ T cells, a critical subset of immune cells, at the mucosal surfaces of the intestine or gut early in the course of infection was first observed with SIV infection in rhesus macaques (see VAX April 2006 Primer on Understanding the Early Stages of HIV Infection).

Non-human primate studies are also an important tool for researchers who are studying the immune correlates of protection so that they can design improved AIDS vaccine candidates (see VAX November 2006 Primer onUnderstanding Immune Correlates of Protection). If they can successfully identify the specific types of immune responses (antibodies, CD4+ or CD8+ T-cell responses, other natural immune responses, or some combination of these) that protect rhesus macaques from SIV infection, it will most likely provide vital clues about the types of responses that would be protective against HIV infection in humans.

Sterilizing protection

Working with non-human primates also allows researchers to conduct studies that would be impossible to do in humans. Due to safety concerns, researchers have not tested any AIDS vaccine candidates in humans that contain either a killed version of HIV or a live but weakened version of the virus. However, researchers are able to test live-attenuated SIV vaccine candidates in rhesus macaques and then try to infect or challenge them with SIV and see if they are protected. These challenge studies would never be conducted with human volunteers, but the results of these animal studies may be important in the identification of the correlates of protection.

When rhesus macaques are given a live-attenuated SIV vaccine and then challenged with exactly the same viral strain, the majority of animals are protected from SIV infection. So far this is the only model where researchers have been able to induce sterilizing immunity against the virus.

This indicates that there is an immune response, or a combination of responses, which are capable of protecting macaques. Now researchers have to identify the exact immune responses that are responsible for this protection. Work in this area is ongoing and researchers, many of whom are working as part of larger scientific consortia, are now studying this question. Researchers have already identified an antibody that is directed to the envelope protein on the surface of the specific SIV strain used in these experiments. This antibody is capable of neutralizing the virus and therefore is correlated with protection, but it is still unknown if this response is actually responsible for the protection.

Researchers are also studying other immune responses induced at specific sites, like the intestine, and the genetic makeup of the macaques to see if these factors are also contributing to protection. Defining the precise correlates of protection is an incredibly difficult and time-consuming task. Since many different laboratories are working in this area, it is also important that researchers use the same tests or assays to evaluate the immune responses so that their data can be compared.

Mechanism of protection

Even after researchers identify the antibodies or cellular immune responses that correlate with protection there are still many other questions. These responses are still just correlated or associated with protection and often researchers don't know specifically how these immune responses interact with HIV. Pinpointing the precise method by which these immune molecules and cells kill the virus and block HIV infection is also an important area of research. This mechanism of protection can be particularly instructive when researchers are considering how to induce these responses with vaccination.

There are several complications with determining the mechanism of action between these immune responses and the virus. In some cases the immune responses that researchers identify as the correlate of protection may only be masking another antibody or cellular immune response that is actually the one responsible for protection. It is also possible that another genetic factor not related to the immune system provides protection.

Relevance

If researchers are able to define the correlates of protection in non-human primate models, developing an AIDS vaccine candidate that can provide sterilizing immunity in humans will still be a complex process. It may be difficult to stimulate similar immune responses without using a live-attenuated AIDS vaccine candidate, and it is unlikely that this approach will ever be tested in humans.

Most of the vaccine candidates that are currently in clinical trials trigger primarily cellular immune responses and specifying the correlates of protection with these types of vaccines will be even more difficult, in both animals and humans. Some researchers think it is possible that different vaccine candidates may even stimulate different CD4+ or CD8+ T cell responses, and therefore have different correlates of protection.

Despite these challenges, working with non-human primates is still the best model available to AIDS vaccine researchers and it is likely to provide them with critical clues that will help improve the design of novel candidates.