August 11, 2008
In light of the recent cancellation of two major HIV vaccine studies, unique ideas are desperately needed to help solve the global AIDS crisis. The answer to this scientific riddle may lie in a group of people with HIV who naturally control the infection on their own, without help from HIV therapy. These elite controllers, or long-term non-progressors (LTNPs), represent less than 1% of all people living with HIV.
Science has not studied LTNPs all that much compared to other areas of HIV research. However, more intense research is starting to be discussed and implemented. Thursday's session at the International AIDS Conference in Mexico City, Elite Controllers and Long Term Non Progressors, presented results from several studies that may help explain why LTNPs resist HIV disease progression.
A Spanish study followed 10 LTNPs over 4 years. The LTNPs were HIV-positive for more than 10 years, had more than 500 CD4 cells, and had never been on HIV therapy. The researchers examined the effects of 2 HIV proteins, Gag and Nef, on the type of immune response by CD8 cells. They studied 3 chemicals (MIP, TNF, IL2) produced by CD8s.
Over the 4 years, average CD4 counts and viral loads remained stable. The results showed that the 3 chemicals were produced in different amounts at different times. Overall, there was an increase from 10 to 50% of the 3 chemicals in response to the Gag protein. However, the CD8 response to Nef showed a decrease from 40 to 20%.
This suggests that an LTNP's immune response may evolve over time and may be able to function in different ways in order to control HIV infection. Though this response has been noticed in other studies, there's very little information about how stable it is over time. This four-year study helps contribute more information to understanding this response, and may help lead to an immune therapy for HIV infection.
Another Spanish study used new technology to examine how certain immune genes behave during HIV infection. The study included 16 LTNPs (HIV-positive for more than 15 years with no HIV therapy) and compared them to 17 others with more typical HIV disease: positive for less than 5 years, a loss of more than 50 CD4 cells each year, also with no HIV therapy.
The study showed 146 genes in LTNPs were active while 315 were active in the comparison group. The active genes in LTNPs were mainly involved at the cells' walls and in how they communicated with each other. In contrast, the genes in the non-LTNP group were mainly involved inside the cells with their cell regulation and division.
This difference may point to why LTNPs are successful in controlling their HIV infection, perhaps due to focusing more on cell signals rather than cell regulation and division. This finding will need to be confirmed in larger studies, but could help deepen our understanding of the immunologic differences between LTNPs and others living with HIV.
An Italian study sought to examine if the immune chemical IL-15 has an effect on HIV replication. The researchers collected blood samples from 13 LTNPs, 9 with HIV disease never on therapy, and 9 HIV-negative people. They used the chemical, interferon-gamma (IFN-g), to stimulate IL-15 and to compare the three groups both before and after using IFN-g.
The results showed that LTNPs have a significantly higher percentage of IL-15 than progressors, both in the walls of and inside immune cells. After using IFN-g, the levels of IL-15 significantly increased in LTNPs while it was nearly absent in progressors. In the HIV-negative samples, their capacity to respond to IFN-g was present, though not significantly. These results support the role of highly active and functional CD8 cells in LTNPs, which may be more able to use IL-15 as an immune therapy to control HIV progression.
A US study looked at what role a person's gene pair, called HLA B*57, has on HIV infection in LTNPs. (This is similar to research that discovered that people with the HLA B*5701 gene pair are more likely to react to abacavir, resulting in a hypersensitivity reaction.) This study collected blood samples from 52 LTNPs and 41 progressors. It compared HIV's ability to reproduce, called replication capacity or RC, in each group as well as its RC against various gene pairs, like B*57.
Not surprisingly, the results showed a lower RC among LTNPs than for the other group. The study also found that B*57 lowered RC more than other gene pairs. However, different RC between the groups were also noticed for those who did not have B*57. Further, two other common gene pairs -- A*02 and B*07, common in North America -- showed higher rates of RC. So, although B*57 was significantly related to lower RC, other gene pairs were also likely involved. This may one day lead to a gene therapy to alter HIV's replication capacity.
Another US study looked at the roles that telomeres and shelterin genes have in HIV infection. A telomere is a gene that "caps" and protects the end of a human chromosome. (In Greek, telo = end and mere = part.) Shelterin genes are a group of proteins that protects telomeres. Together they help chromosomes maintain all their information when cells divide.
This study took blood samples from LTNPs (viral loads below 50, not on HIV therapy) and from progressors (viral loads above 30,000). It looked at 5 telomeres and 6 shelterin genes as they related to the control of HIV infection by CD8 cells. The results showed certain telomeres and shelterin genes have some relation to CD8 cells being able to function and control HIV infection. This information may be able to help identify new targets for gene therapy of CD8 cells.
These fascinating studies and others like them are just beginning to unwrap some of the various genetic reasons how LTNPs may control their HIV infection. Though this field of investigation is truly in its infancy, it could some day yield information to help design gene, immune or other therapy that would eliminate the need for HIV therapy.
In each of these cases, a great deal more study needs to be done. Most studies were done in the lab from blood samples, so the results may be quite different than when studied in animals or humans. However, taken collectively, these results show great promise into further understanding the intricacies of our immune systems, and may result in contributing to the eventual cure for HIV disease.