Special Coverage: 11th Retroviruses Conference

Novel approaches to HIV vaccine are being studied

One possibility is vaccine that slows disease

Dozens of potential HIV vaccine candidates have been studied since the late 1980s, and many of the latest additions to this field of research include novel strategies to elicit HIV antibodies and cytotoxic T-cells, as well as some that may help slow disease progression among those who subsequently become infected.

Research presented at the 11th Conference on Retroviruses and Opportunistic Infections, held in February in San Francisco, offered a look at some of the more interesting and promising vaccine research that is under way across the world.

For instance, investigators at Case Western Reserve University in Cleveland and the National Institutes of Health presented a study that discussed the development of an HIV-1 vaccine using the human parainfluenza virus as a novel viral vector to induce mucosal immunity.1

So far, the approach works, but the next step will be to try the vaccine on nonhuman primates, says Michael Cho, PhD, an assistant professor in the Department of Medicine at Case Western Reserve University.

"We wanted to develop vaccines that can respond faster so that the immune system is able to control HIV-1 at an earlier stage of infection," he explains. "The idea is to elicit immunity at the mucosal surface where most virus infections start."

Recombinant viral vectors work by expressing HIV-1 proteins and inducing immune responses against them, Cho says.

"However, viral vectors themselves are nonpathogenic," he adds. "So far, we’ve shown that the recombinant viruses we generated are attenuated compared to wild type, and so we could try them directly in humans."

Cho theorizes that this vaccine approach using only the parainfluenza virus may not be enough to thwart HIV, so he and co-investigators also are exploring the possibility of combining this approach with other viral vectors and subunit proteins.

"We’re generating a novel set of viral vectors based on a vaccinia virus," he says. "Many of the studies in the past have utilized the vaccinia virus because it can encode a large amount of HIV-1 proteins, and it does a very good job of eliciting immune responses."

The point is that rather than using a single viral vector or a single HIV-1 protein, researchers may have to use multiple viral vectors and multiple viral proteins to elicit cellular immune response and then still have to overcome the problem of eliciting broadly reactive neutralizing antibodies, Cho explains.

"When you immunize with a viral vector, you not only elicit immune responses against HIV-1 proteins, but also against the viral vector," he says. "Subsequent uses of the same vector diminish the boosting capability."

But by using different vectors that encode the same proteins, strong immune responses could be generated against the target HIV-1 proteins, Cho points out.

Based on the time needed to evaluate new candidates and for other reasons, Cho says he is not optimistic that there will be an effective HIV vaccine within the next decade.

Although the AIDSVAX vaccine had no impact on the vaccine efficacy and disease progression endpoints, there could be others that will be successful on both realms.

"Some of the vaccines being tested may have beneficial effects both to prevent infection and to control viral load," says Peter B. Gilbert, PhD, associate member of the Fred Hutchinson Cancer Research Center in Seattle. "It’s even conceivable that a pure t-cell vaccine might have effects on infection and viral load."

The problem many vaccine investigators are experiencing is that it’s difficult to find a vaccine that broadly neutralizes the many HIV strains, he says.

"But once a person is exposed to the virus and acquires the virus, the fact that the vaccine has been there to prime the immune system will allow their immune responses to give it a head start to suppress the viremia, keeping it at lower levels," Gilbert notes. "The key endpoint in these trials will be the initiation of antiretroviral therapy."

A vaccine that successfully slows disease progression, even if it did not prevent infection, could be of great public health benefit and save treatment resources, he adds.

"It could also cut transmission, because if a person’s virus stays pretty low, then there are good data suggesting that it would translate into a reduced probability of transmission to others," Gilbert says.

"I think people say they’re going for both prevention and slowing disease progression, but I think many of us may be are a bit more optimistic that we’ll get something that controls viral load before we get something that prevents infection," he states.

Among the vaccine research presented at the recent retroviruses conference, were these studies:

  • Foamy viruses as potential vectors.

    Investigators from Atlanta and Los Angeles presented findings about the use foamy viruses, which are retroviruses endemic in nonhuman primates, as vectors. Their study concluded that foamy viruses can successfully transfer HIV-1 gag in a variety of cells, and so further study is warranted.2

  • Therapeutic HIV vaccination regimens.

    Investigators from the United Kingdom, Switzerland, Sweden, Australia, and France studied the hypothesis that a therapeutic vaccination of antiretroviral-treated primary HIV infection subjects could suppress plasma HIV-1 RNA for the long-term following medication discontinuation. Their double-blind, randomized study did not find any significant benefit of vaccination with ALVAC-HIV over placebo.3

  • Broad HIV-1 sensitivity to neutralization with vaccine sera.

    Investigators with ViroLogic Inc. in South San Francisco tested more than 50 viruses for sensitivity to various immunologic reagents and defined three categories of isolates. They concluded that HIV-1 isolates that are broadly sensitive to neutralization with many immunologic reagents also have pan-sensitivity to monoclonal antibodies directed against diverse regions across gp160.4

References

1. Han D, Kim Y, Skiadopoulos M, et al. Developing HIV-1 vaccine using human parainfluenza virus. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract: 265.

2. Hardy WD, Liu C, Xie Y, et al. Foamy viruses as potential vectors for HIV vaccine and gene therapy applications. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract: 262.

3. Kinloch S, Perrin L, Hoen B, et al. Evaluation of 2 therapeutic HIV vaccination regimens in HAART-treated primary HIV infection subjects following analytical treatment interruption: QUEST PROB3005, a randomized, placebo-controlled study. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract: 168.

4. Wrin T, Chappey C, Huang W, Petropoulos C. Broad HIV-1 sensitivity to neutralization with vaccine sera, monoclonal antibodies, and HIV+ plasma and sera is a pan-gp160 phenomenon associated with high fusion activity and shortened V1/V2 regions. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract: 165.