Quest for effective HIV vaccines present new possibilities, challenges

A vaccine that prevents HIV infection remains an important goal in the fight against AIDS, but the current top HIV vaccine candidates may not work in this way, say scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).

Rather, the first successful preventive HIV vaccines, if administered prior to HIV infection, may reduce HIV levels in the body, thereby delaying the progression to AIDS and the need to start antiretroviral drugs. These vaccines may also reduce the chance that a person infected with HIV would pass the virus on to other people, according to NIAID Director Anthony S. Fauci, M.D., and Margaret I. Johnston, Ph.D., director of NIAID's Vaccine Research Program in the Division of AIDS.

In a review article in the May 17 issue of the New England Journal of Medicine, Drs. Johnston and Fauci examine the daunting challenges posed by HIV, the evolution of HIV vaccine research, the role T cells may play in HIV vaccine effectiveness, and how the first successful HIV vaccine may fit into a comprehensive HIV/AIDS prevention effort.

Vaccines typically work by mimicking the effects of natural exposure to a specific microbe. Because of initial exposure, the immune system develops the ability to recognize the specific microbe and can protect the human body against it if it reappears. HIV, however, has thwarted scientists efforts thus far to develop a classic preventive vaccine for the virus because of its ability to integrate into target cells and evade clearance by the immune system. The interaction between HIV and the immune system is complex, and how different HIV-specific immune responses help to control infection is only partially understood.

"The development of an HIV vaccine is a complex research challenge because the virus is unusually well-equipped to elude immune defenses," says Dr. Fauci. "Much progress has been made; however, we must continue research efforts to improve our understanding of HIV and how it evades the immune system, to design new vaccine candidates and to assess the most promising ones in clinical trials."

Dr. Johnston adds, "An important research challenge is to determine if these so-called T-cell vaccines that primarily induce a cellular immune response can have a beneficial effect by reducing viral levels and preserving critical cells needed to control infection. There will be a tremendous public health challenge as well, in an HIV vaccine that does not completely prevent the virus from establishing itself in the body."

Once HIV enters the body, it infects crucial CD4+ T cells, replicates, spreads throughout the body and establishes HIV reservoirs in lymphatic tissues. Within weeks of exposure, virus levels peak and then decline to levels that may remain low for months or years. It is believed that CD8+ T cells--so-called killer T-cells--are responsible for this reduction in HIV levels; however, their ability to continue to suppress the virus declines over time as the virus mutates and the immune system is progressively destroyed.

The infection of CD4+ T cells occurs very early in HIV disease, and virus persists indefinitely. Other viruses also replicate robustly but, unlike HIV, most do not establish a permanent reservoir of infected cells in the body. The window of opportunity to prevent long-term HIV infection may close permanently once a pool of latently infected cells is in place, Drs. Johnston and Fauci note. Neutralizing antibodies, which can attach to and eliminate free virus, only appear after HIV levels have declined substantially. Further, the effectiveness of these antibodies is stymied because of the rapid genetic changes that occur in HIV's outer envelope protein, which allow the virus to escape detection.

While early efforts to develop an HIV vaccine focused on the viral envelope, an improved understanding of how HIV causes disease has brought increased attention to the role that T cells could play in an HIV vaccine by spurring cellular immunity. Numerous animal and human studies have confirmed how important cellular immunity is in the early and later stages of HIV infection, even though the virus is never completely eliminated. Vaccines that induce strong cellular immune responses may have some benefits, say the authors. In non-human primate models of HIV infection, T-cell vaccines have reportedly decreased the total amount of virus produced during early infection, caused a reduction in virus levels following the acute stage of infection, or produced some combination of these effects. In many of these animals, disease progression was also delayed.

Based on the scientific evidence, several questions remain, say Drs. Johnston and Fauci: Can a vaccine that does not prevent HIV infection but reduces virus levels and preserves a segment of uninfected CD4+ T cells from destruction benefit the immunized individual" Might people immunized with T-cell vaccines before HIV exposure remain disease-free for a prolonged period once they are infected"

Additionally, T-cell vaccines may reduce secondary HIV transmission if they can help the immune system keep viral replication at a very low level for a long time. Studies have suggested that people with high levels of virus--namely those in the early and late stages of infection--are most likely to infect their sexual partners. A preventive vaccine given before exposure to HIV might stifle the initial burst of virus, better control virus levels and potentially reduce that person's ability to infect other people, Drs. Johnston and Fauci assert.

Vaccines of this type present several complications, however. T-cell-mediated control of HIV infection may not stave off disease forever. Additional human studies would be needed to determine if the vaccine also reduces the spread of HIV. Finally, an HIV vaccine that delays but does not completely prevent disease could not stand alone as a preventive measure; the public health community would need to include it as part of a broader HIV prevention program, so that recipients would minimize, or ideally, not engage in high-risk behaviors, according to the authors.

Currently, several vaccines that induce primarily T-cell responses are in or will soon enter expanded human clinical trials to determine if they impact HIV infection. Researchers also continue to give high priority to creating an HIV vaccine that induces broadly neutralizing antibodies, which might prevent the establishment of HIV infection. Although rare, such antibodies do exist, giving hope to scientists that a vaccine to induce such antibodies can be designed.

Drs. Johnston and Fauci conclude that a vaccine that prevents HIV infection by clearing the virus before cells become latently infected remains the goal. In addition, they believe that even a vaccine that does not prevent infection could prove beneficial if it prolongs the disease-free period and possibly even reduces virus transmission. If such a vaccine is shown to be successful and is eventually licensed, it would need to be delivered as part of a comprehensive, multifaceted HIV prevention program.