Understanding mucosal immune responses is critical to developing effective AIDS vaccines, but progress has been slow
By Alix Morris, contributing writer
In December 2006, the US National Institutes of Health halted two clinical trials in Kenya and Uganda after study results indicated that male circumcision cut a man’s risk of contracting HIV by more than half (see VAX December 2006 Global News). These studies confirmed results from a previous randomized, controlled trial of adult male circumcision conducted in South Africa. Soon after, the World Health Organization (WHO) issued guidelines urging countries to consider adding male circumcision to their existing HIV/AIDS prevention strategies (see VAX April 2007Global News). Last year, the US-based news magazine Time ranked circumcision as the number one medical breakthrough of 2007 because of its potential to slow the spread of HIV. But to date, only a handful of health ministries in sub-Saharan Africa, the region most severely affected by HIV/AIDS, have started developing national policies on circumcision, and even fewer have established actual programs. This has spurred some public health officials to question the delay.
In an editorial published in the January issue of the journal Future HIV Therapy, Daniel Halperin, senior research scientist at Harvard University, and colleagues emphasized the benefits of male circumcision and called upon countries, international leaders, and donor agencies to introduce safe circumcision practices. Halperin says that in response to the WHO guidelines, approximately nine African governments conducted consultations with the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the WHO. I think in every case, after doing the consultation, they decided that they wanted to have a circumcision program or circumcision policy,he says. But so far few policies have been enacted. A lot of these countries are on their way, but only Kenya and Rwanda have actual policies as far as I know.
This month Rwanda launched a voluntary national circumcision campaign aimed at reducing the risk of HIV transmission. The campaign prioritizes circumcision for male soldiers, policemen, and students. In September of 2007, Kenya’s Ministry of Health published its national policy on male circumcision. The Kenyan policy stipulates that safe, voluntary male circumcision should be promoted in conjunction with other HIV prevention strategies, and delineates the roles of the Ministry of Health, the National AIDS Control Council, and other partner organizations in coordinating these programs. But there is no indication when circumcision programs will be implemented.
Providing circumcision services in areas with high HIV prevalence could have a considerable effect on reducing the number of new infections. Surgically removing the foreskin eliminates a site with a high concentration of cells that are targets for HIV (see Primer, this issue). Computer modeling studies conducted by the WHO and other health agencies to determine the impact circumcision could have on the course of the HIV epidemic suggest that if all males in sub-Saharan Africa were circumcised, two million HIV infections could be averted over the next 10 years. Using this same model, an additional 3.7 million new infections could be prevented over the following 10 years.
Evidence for the potential impact of circumcision programs can already be seen on the population level, says Halperin. It’s not just about modeling. We can actually see the real-world impact. For example, in Cameroon, a country where male circumcision is common practice, the adult HIV prevalence rate is only 5%, whereas in Botswana and Swaziland, countries where the majority of men are uncircumcised, adult HIV prevalence rates are up to five times higher.
If more males were circumcised there would also be a herd immunity effect although only men directly benefit from the procedure, reducing the level of HIV in the population would also result in fewer new infections among women.
Many challenges have contributed to delays in introducing male circumcision programs, including cultural hurdles, a shortage of trained professionals, and financial constraints. While the US President’s Emergency Plan for AIDS Relief (PEPFAR) has agreed to fund circumcision programs, the governments and health ministries need to specifically request this support. Once they ask for it, it’s like anything else, it takes a while for the money to come down, says Halperin. It’s going to vary in different places but I’m sure there will be a lag before things really get going.
What events lead to the sexual transmission of HIV and how can mucosal immune responses protect against infection?
Most infectious agents, including viruses and bacteria, enter the body through mucosal surfaces. These surfaces, or membranes, are the moist tissues that line the body’s internal cavities, such as the lungs, nose, intestine, and genitals. HIV is most commonly transmitted from person to person through sexual contact—researchers estimate that 85% of infections are sexually transmitted. HIV transmission can also occur from direct blood-to-blood contact, which occurs primarily when injection-drug users share needles, or through mother-to-child transmission, either during delivery or from tainted breast milk.
Since the majority of infections are due to sexual transmission, immune responses induced at these mucosal surfaces are the first line of defense against HIV and are critical to stopping the virus in its tracks. Researchers have attempted to develop HIV prevention methods, including microbicides, which could block the virus at the mucosal surfaces of the genitals or rectum, where exposure to the virus first occurs.
In recent years researchers have also focused on developing AIDS vaccine candidates capable of inducing potent immune responses at mucosal surfaces (see Spotlight article, this issue). Scientists are studying different types of immunization strategies, as well as ways to measure mucosal immune responses in clinical trials (see VAXDecember 2005 Primer on Understanding Mucosal Immunity). They have also been closely studying the events leading up to sexual transmission using animal models to better understand the type of mucosal immune responses that would be necessary to thwart HIV infection in humans.
Crossing the barrier
HIV preferentially infects CD4+ T cells, which are a subset of immune cells that are vital to the functioning of the human immune system. These cells are located throughout the body but certain compartments, such as the mucosal tissues lining the intestine or gut, contain the greatest number of CD4+ T cells. For this reason, the intestine is one of the main breeding grounds for HIV during the early stages of infection (see VAX April 2006 Primer on Understanding the Early Stages of HIV Infection).
But before HIV reaches cells in the intestine or other areas of the body, it must first get beyond the genital or rectal mucosal tissues. These tissues are often referred to as the mucosal barrier because viruses have difficulty penetrating the outer layer of cells, known as the epithelium. This is one method the immune system uses to fend off infectious agents.
The mucosal barrier is actually quite effective at blocking HIV—researchers estimate that only one successful HIV infection occurs for every 1,000 times a person is exposed to the virus during vaginal intercourse. There are relatively few target cells in the vaginal mucosal tissues that are susceptible to HIV, which makes it more difficult for HIV to reproduce. If a vaccine or microbicide induces potent immune responses against HIV at these surfaces, it may make it even more of a struggle for HIV to establish an infection, especially in the vaginal tissues. Researchers have observed that in studies with non-human primates, transmission of a related monkey virus known as simian immunodeficiency virus (SIV) occurs more easily rectally than vaginally, and therefore HIV infection may also be more difficult to block at rectal tissues.
It is much easier for HIV to establish an infection at mucosal sites if these tissues are damaged in some way. For example, other sexually-transmitted infections can cause inflammation and irritation, or even ulceration, of the mucosal tissues. This attracts more immune cells to the site, increasing the total number of target cells for HIV and making it easier for the virus to establish an infection. For this reason, infection with other STIs is thought to increase an individual’s risk of contracting HIV. During sexual intercourse, small tears or scrapes are often created in the mucosal surface and researchers think this too can compromise the mucosal barrier effect.
The speed with which HIV spreads makes it impractical to study transmission and the earliest stages of infection in human volunteers. Instead, researchers conduct studies with nonhuman primates, mostly rhesus macaques, using SIV. After SIV crosses the mucosal barrier, research suggests that the virus first establishes a small, localized infection in the genital mucosal tissues. After that, it begins to spread rapidly and is quickly dispersed to other areas of the body through the blood. Results from some animal studies suggest that within one week, and sometimes even within a day, SIV can spread to and be detected at different sites throughout the animal’s body.
If HIV is disseminated as quickly, mucosal immune responses (antibodies and/or cellular immune responses) induced by an AIDS vaccine candidate would have to be induced very rapidly to completely prevent an HIV infection. Typically, immune responses elicited by vaccines take between three and five days to become active. Once HIV begins spreading to other regions of the body that are rich with target cells, such as the mucosal lining of the intestine, research has shown that the virus reproduces explosively and destroys large populations of CD4+ T cells. This is referred to as the acute stage of HIV infection. The quick and often irreversible loss of these immune cells further weakens the immune system’s ability to fight the virus.
Even at this stage, mucosal immune responses can play an important role in helping to limit or control HIV infection. An AIDS vaccine candidate capable of inducing immune responses at mucosal sites, including the intestine, could help prevent some damage to CD4+ T cells and therefore preserve the immune system’s defenses. Systemic or more generalized immune responses would also help control the progression of HIV infection at this stage. -Kristen Jill Kresge