Vaccine and Infectious Disease Division

Escape from regulation by HIV-protective cytotoxic T cells

Among individuals with HIV-1 infection, there are a rare few who are able to successfully control the virus for many years, maintaining very low viral loads and high CD4+ T cell counts without the need for therapeutic interventions.  These long-term non-progressors have been the subject of much research in the quest to identify immune factors capable of effectively controlling HIV.  Two Human Leukocyte Antigen (HLA) alleles, HLA-B*27 and HLA-B*57, are more common in this population than in the HIV-infected population as a whole.  These proteins are involved in the presentation of small pieces of foreign protein to immune cells.  When a cytotoxic T lymphocyte (CTL) with the appropriate receptor encounters such an antigen, it becomes activated and releases cytotoxic compounds, thereby killing the presenting cell and thus the pathogen.  Activated CTLs express surface proteins including Tim-3 that interact with receptors on regulatory T cells (Tregs), which patrol the immune system and eventually suppress the activated CTLs.  In most situations this is beneficial because an active immune response is only needed for a brief time to eliminate a pathogen, and suppression regulates the cytotoxic response and maintains tolerance, prevents autoimmune disease and limits chronic inflammation.  In chronic infection, however, suppression of the immune response could be detrimental. For example, in most HIV-infected individuals, HIV-specific CTLs become dysfunctional and exhausted, and this exhaustion correlates with progressive disease.  It is thought that Tregs play an important role in this exhaustion, but the mechanism remains unidentified.

Researchers from the laboratory of VIDD affiliate investigator Helen Horton, along with VIDD co-director Julie McElrath, VIDD staff scientist Kerry Laing, and VIDD affiliate investigator David Koelle, investigated the mechanism for this sustained protective CTL response in long-term non-progressors.  They found that CTLs restricted by HLA-B*27 and B*57 are capable of proliferating and secreting cytokines even in the presence of Tregs, whereas HIV-specific CTLs restricted by other HLA alleles, even those from the same people, are dysfunctional and highly regulated.  They found that B*27 and B*57 CTLs express much less Tim-3 than other CTLs, and the Tim-3 interaction is necessary for Treg-mediated suppression.  Lastly, they demonstrated that B*27 and B*57 CTLs are able to kill Treg cells they encounter by secreting the protein Granzyme B, which also helps to maintain their functional ability.  Interestingly, CTLs from long-term non-progressors who eventually succumb to progressive HIV disease lose this ability to escape regulation and behave similarly to CTLs from regular HIV-infected individuals, implying that there are complex nuances to the immune response that remain to be identified.  Improved knowledge about how effective cytotoxic responses to HIV-1 can be sustained long-term could be of great benefit for the development of new classes of therapeutic interventions for all HIV positive people, regardless of their HLA types.

Elahi S, Dinges WL, Lejarcegui N, Laing KJ, Collier AC, Koelle DM, McElrath MJ, Horton H.  Protective HIV-specific CD8(+) T cells evade T(reg) cell suppression.  Nat Med. 2011 Jul 17;17(8):989-95.