October 26, 2002
This complex but important study won an award for outstanding contribution by a young investigator. As we all know, there are some people with HIV who seem to be able to control the disease well without therapy. Understanding why this happens is key to designing therapeutic vaccines and other strategies that may boost the body's ability to control HIV. Previous studies have identified the cytotoxic CD8 cell response, chemokine receptor variations such as the CCR5 delta 32 mutation and certain HLA types as predictors.
In the past, those termed "long-term non-progressors" were defined so by surviving a substantially longer period than expected without developing low CD4 counts or AIDS. However, the definition has varied among investigators.
In this study, a somewhat different approach was taken. The investigators from Bruce Walker's lab at Harvard, led by Dr. Addo, assembled a group of patients based on their ability to control their viral load at less than 1,000 copies, rather than focusing on long-term outcome. This study was a comprehensive attempt to look at the predictors of controlling viral load without therapy.
The investigators hypothesized that "controllers" would have a CD8 cytotoxic T-lymphocyte (CTL) response that targeted specific regions of the HIV genome and that the response would be "broader" than that of "progressors." A broader response is one that recognizes a greater range of specific peptide sequences, or epitopes, within HIV genes. They used elispot assays and intracellular staining for cytokine production to measure the CTL response. They also looked at other possible predictors, including the presence of mutations in the CCR5 receptor and the CCR2 receptor, HLA type and the presence of infection with GB-virus C. GB virus-C was initially identified as a positive hepatitis virus, but does not appear to cause much hepatitis. However, several studies have found lower rates of HIV progression among people who are also infected with GB virus-C.
The results were a bit surprising. There was no difference in the overall breadth or magnitude of CTL response among the virus controllers compared to the progressors. There were three specific epitopes in gag and nef that were more likely to be recognized by the controllers. There was a difference, however, in the markers of the type of HIV-specific CD8 CTL cells. The cells from the virus controllers were more likely to be of an "effector" phenotype, meaning they were the type of cell that can kill infected cells. This suggests that in progressors there may be a block in the functional maturation of the immune cells directed against HIV.
In addition, 55 percent of the controllers had an HLA allele that was of a type associated with non progression. About 16 percent were heterozygous for CCR5 delta 32 and 20 percent had mutations in the CCR2 receptor. Significantly more controllers were infected with GB-virus C.
Control of virus therefore seems to be a complex mix of factors. This study contributes to our understanding by looking at many of these factors in a fairly large group of people who manage to control the virus. Understanding the mix of factors -- and especially how they interact -- may help develop new immune therapies and gene therapies. Perhaps as important, it may help avoid blind alleys in vaccine development. Much work remains to be done, but this is another important contribution from Dr. Walker's lab.