A study by a research team based at the Massachusetts General Hospital (MGH) suggests that it may be possible to develop an AIDS vaccine that will be effective against the different versions of the virus found around the world. As reported in the November issue of the Journal of Virology, the researchers found that the immune system's killer cells, called cytotoxic T-lymphocytes (CTLs), are capable of recognizing different strains, or clades, of the human immunodeficiency virus (HIV). In the past it has been feared that the prevalence of different HIV strains in different parts of the world would require developing different vaccines targeted to each strain.
CTLs have become the focus of HIV vaccine research in recent years, as earlier vaccine strategies based on the activity of antibodies have not proven successful. The immune system teaches these killer cells to target a specific type of virus, bacteria or other foreign material. Cells targeted to a specific virus seek out and destroy virally infected cells by recognizing peptides -- small fragments of the proteins that make up that virus -- that are displayed on cell surfaces.
CTLs are not infected by HIV and usually mount a defense against the virus soon after the initial infection. In most patients, however, the levels of CTLs eventually decrease, allowing HIV levels to rise and AIDS symptoms to develop.
Recent research has produced evidence that CTL activity is likely to be be a key immune response against HIV. High CTL levels have been seen in long-term nonprogressors -- individuals who remain healthy despite being infected for many years -- and CTLs that target the virus have been found in people who remain uninfected despite many exposures to HIV. In addition, CTLs seem to play an important role in the immune response against other viral disease, like cytomegalovirus and Epstein-Barr virus.
"There really is a growing consensus in the field that generating a strong, virus-specific CTL response will be important in developing any successful vaccine against HIV," says Bruce Walker, MD, director of the Partners AIDS Research Center based at the MGH and senior author of the report. "Since those parts of world most affected by this disease do not have the resouces to take full advantage of current therapies, a vaccine is the only way we're going to be able to eliminate AIDS globally."
Most HIV-infected individuals in the United States and Europe are infected with clade B, while several other clades -- the most common are A, C, D and E -- predominate in Africa and Asia. The researchers tested CTLs taken from individuals infected with clade B HIV and tested whether they would recognize viral peptides from all of the major clades. All of the tested CTLs recognized peptides from at least one non-B clade virus, and most reacted against peptides from all clades tested. The team also tested CTLs from 14 infected individuals from Senegal, 10 of whom were infected with clade A virus, three with clade G and one with clade C. CTLs from all 14 individuals reacted against proteins from clade B viruses.
"We were very surprised to see this striking amount of CTL cross-reactivity," says Walker. "But this result is supported by previous observations that people infected with one strain seem be protected against other strains of HIV."
Walker notes that CTL-based vaccines are just beginning to be tested in human volunteers, and many questions remain to be answered. For instance, it is far from certain whether CTL activity alone would be sufficient to protect against either HIV infection or progression to AIDS. Future studies are needed to define exactly which immune system responses will be most important for protection against HIV.
Walker's coauthors include Huyen Cao, MD, first author, and Spyros Kalams, MD, from the MGH; Phyllis Kanki, DVM, Jean-Louis Sankale, MD, and Abdoulaye Dieng-Sarr, of the Department of Cancer Biology at Harvard School of Public Health; Gail Mazzara, PhD, of Therion Biologic Corporation in Cambridge; Bette Korber, PhD, of the Los Alamos National Laboratory in New Mexico; and Souleymane Mboup, MD, of University Cheikh Anto Diop in Dakar, Senegal. The research was supported by grants from the National Institutes of Health.
Journal
Journal of Virology