Epidemic becomes more diverse
An important theme of July’s International AIDS Conference in Bangkok was the genetic diversity of HIV infection. Populations in some parts of the world show a very high level of co-infection. Co-infection is when an individual is infected with more than one genetic form of HIV; this can mean infection with two or even three different genetic versions of HIV. This can occur when a person is originally infected with more than one genetic form of HIV. It also can occur when a person who is already infected with HIV becomes infected with a new viral strain, which is called “superinfection.” These genetically different viruses can recombine within an infected person, meaning that the two viruses can swap parts of their genetic material to form a new virus (it is still HIV, but slightly altered). This leads to what are called “unique recombinant forms,” or URFs, within a single person. These could be spread to other people, leading to “circulating recombinant forms” (CRFs). A recombinant form is an HIV that has genetic characteristics of two or more different subtypes.
HIV-1 is divided into three distinct genetic groups, M, N, and O. The M group is responsible for almost all of the HIV infections in the world. It originally came from the simian immunodeficiency virus (SIV) that is found in chimpanzees. Scientists think that HIV-1 jumped into humans from chimpanzees several different times, most likely through eating “bushmeat.” This is when chimpanzees are slaughtered for food, and it is thought that the virus was passed from chimpanzees to humans either through a bite or a cut during butchering. Since these first events, over time additional genetic diversity has developed within each group. These regional subgroups are called clades or genetic subtypes.
In the past, it was thought to be sufficient to look at small parts of the HIV genetic material to be able to tell what subtype the virus was and where it was likely to have come from. But with increasing amounts of recombination seen, it is going to be necessary to do more extensive genetic studies. For example, Francine McCutchan and colleagues from the Henry M. Jackson Foundation found that in a group of high-risk, HIV-infected women in Tanzania, subtype C was the major single subtype found among women infected with one HIV subtype only. But 43% of the women carried recombinant forms of HIV. Furthermore, some of the women were infected with two or more different, unmixed subtypes at the same time. McCutchan and colleagues found that the subtypes and recombinant forms identified in the coinfected women differed at different points in time. Although the women remained co-infected, sometimes one form of the virus was found in study participants and other times other forms were found. “People who are co-infected are the source of many, many recombinant forms that presumably they can pass along,” says McCutchan, “and they’re continuously generated in those people over time.”
But recombinant forms of HIV are not new. Marcia Kalish and colleagues at the US Centers for Disease Control and Prevention (CDC), the National Institute of Health (NIH) and Project SIDA in Kinshasa, analyzed blood samples collected in western Zaire in the mid-1980s, during the early years of the epidemic. They found that the samples also have recombinant forms of HIV in them. Samples collected in 1986 in Burkina Faso in west Africa had two recombinant forms of HIV and less genetic diversity. This suggests that in 1986, the Burkina Faso epidemic was more recent in origin than the one in western Zaire. Older epidemics will likely have more recombinants than newer ones because the viruses circulating in that population have had more opportunity to infect the same person and then recombine.
One of the major difficulties in obtaining a complete picture of the HIV epidemic is tracking the movement of the various viral types and subtypes throughout infected populations. Furthermore, a large amount of genetic research is required to get a full picture of where these viral subtypes are prevalent. This type of research requires much more intensive sampling and sequencing of the genetic material of the various HIV subtypes found. Researchers also need to know which subtypes are more likely to combine to create recombinants. All of this will help scientists understand the HIV epidemic so that they will be better able to develop vaccines to prevent it.
Recombinant forms may be a problem in developing an AIDS vaccine since many vaccine candidates in development are designed against only one subtype of HIV. If many recombinant forms are found in infected people, then protecting against one subtype may not be effective. Researchers are hoping that an immune response against one HIV subtype may also protect against another HIV subtype, so having a clearer picture of the subtypes and recombinants that are circulating in populations is important.
The presence of these recombinant subtypes makes it even more important that health care workers and governments stress HIV prevention and treatment, especially for those people who are most at risk of becoming infected.
Improving DNA vaccines
For a number of years, vaccine researchers have discussed the potential of naked DNA vaccines. These vaccines would contain a piece of the HIV genetic material in the form of DNA. But there are several hurdles for naked DNA vaccines. First, the DNA vaccine must find its way into the vaccinated person’s cells. To do that they have to get through the outer covering of the cell, the cell membrane. Although viruses are able to do this when they attach to receptors on the host cell’s membrane, pieces of DNA cannot do this easily. So researchers are looking at new ways to deliver the naked DNA into the cell. Once this DNA is delivered to human cells this genetic material is converted to some of the HIV proteins. It is hoped that these HIV proteins will then cause an immune response that can act against the whole virus if a person is exposed later through high-risk behavior.
Researchers from Yiming Shao’s group at China’s National Center for AIDS/STD Control and Prevention had some success in delivering DNA into a cell by adding genetic material from a monkey virus called SV40 to portions of naked HIV DNA. They tested the naked DNA in mice and got some encouraging results; the vaccine stimulated an immune response against HIV. The scientists’ next step is to test this potential vaccine in humans to see if it has the same effect as it does in mice.
A group of researchers led by George Pavlakis at the US National Cancer Institute is studying naked DNA that carries two HIV genes and an adjuvant. Researchers hope that this kind of vaccine could be used to prevent HIV transmission or to lower the amount of HIV in people who are already infected. Some preliminary studies show that these vaccines did not prevent SIV infection in monkeys that were later given SIV. However, the vaccines were successful in keeping the amount of circulating SIV low in these monkeys after they became infected. It is hoped that such a vaccine could possibly protect a person who is already infected with HIV from becoming sick with AIDS. The scientists are continuing their studies of this type of vaccine.
Two live-attenuated vaccinia AIDS vaccine candidates
Two vaccines based on vaccinia viruses were able to stimulate immune responses in Phase I studies in humans, but the responses were not as strong as had been hoped. (Phase I trials enroll small numbers of people who are at low risk for contracting HIV, mainly to test the safety of a vaccine candidate. For more information on trial design seePrimer, August 2003).
Guiseppe Pantaleo and colleagues from the EuroVacc consortium reported on a Phase I trial of a NYVAC vector vaccine. This vaccine carries proteins from four different genes from a subtype C HIV. NYVAC is an altered vaccinia virus, related to the virus that is used in smallpox vaccine. It is highly weakened or “attenuated” and is not infectious in humans (see Primer, this issue). Nearly half the trial participants showed responses to one of the HIV proteins. Responses to two of the other HIV proteins were less common, and there were no responses to the fourth protein. EuroVacc is also looking at using other vectors, such as modified vaccinia Ankara (MVA), with the same proteins as used with NYVAC.
Researchers from the German company, Bavarian Nordic, gave early data on their Phase I trial of an MVA vector that carries one of the HIV proteins. The immune response directed against the MVA vector itself was good, with T cells responding specifically to the vector. But response to the HIV protein was not as impressive. Studies are continuing.
All articles written by contributing author Myrna Watanabe, PhD