Naturally occurring examples of immune system-mediated HIV control provide encouragement for the ultimate development of effective vaccines and immunotherapies that would limit HIV replication.. Identification of the components, targets, and magnitude of an effective immune response to HIV are important steps toward the development of effective vaccines or immunotherapies. Although patients with normal CD4+ T cell counts and low levels of plasma virus are a heterogeneous group, a small subgroup of patients with truly non-progressive HIV infection and restriction of virus replication likely holds important clues to the basis of an effective immune response to HIV. A small subpopulation (fewer than 0.8% of HIV infected individuals) shows no signs of progression over a 10-year period. We have assembled a stringently defined cohort of such patients, termed long-term nonprogressors (LTNPs) or elite controllers. Many of these patients have been infected for 20 years with no CD4+ T cell decline without taking antiretroviral therapy, and maintain plasma viral RNA below 50 copies per milliliter. Cells from these patients are being used to systematically dissect the mechanisms of immune-mediated restriction of virus replication. HIV-specific T-cell responses of these patients have been studied in extreme detail. Through this project, extraordinary progress has been made in understanding the basis of immunologic control of HIV. Our prior work indicates a dramatic association with the HLA B*5701 allele and that the immune response is highly focused on peptides restricted by this allele. This result established a host genetic and functional link between immunologic control and the CD8+ T-cell response of these patients. More recently we have found that this focus is specific to HIV, and is not found in the response to other pathogens such as Hepatitis C virus or Cytomegalovirus. LTNP patients do not differ in the frequency of HIV-specific T cells or in the ability to recognize the autologous virus, when compared to progressors. The finding of high frequencies of CD8+ T cells specific for the patients virus in both LTNPs and progressors strongly suggests that differences between responses of these patient groups are not quantitative, but rather qualitative in nature. One important qualitative difference in the HIV-specific immune response that distinguishes LTNPs from progressors is the maintenance of HIV-specific CD8+ T cells with a high proliferative capacity. This proliferation parallels perforin expression required for effective killing of HIV-infected CD4+ T cells. In 2009 we established the properties of the HIV-specific CD8+ T-cell response that are tightly associated with the LTNP phenotype. Although the HIV-specific CD8+ T cells of LTNPs have a greater capacity to proliferate and produce molecules responsible for killing HIV infected cells, the mechanism(s) by which these properties translate into effective immunologic control of HIV has remained unknown. Most current assays are not sufficiently powerful to establish if differences in HIV-specific CD8+ T-cell function are determined by frequency, CD8+ T cell proliferation, preferential target or effector cell death, or the mechanism of HIV-infected cell elimination. To better understand the mechanisms of immunologic control, we recently devised a method to measure HIV-infected cell elimination on a per-cell basis. Measured on a per-cell basis, HIV-specific CD8+ T cells of LTNPs efficiently eliminated primary autologous HIV-infected CD4+ T cells. This effective killing was clearly distinguishable from responses of progressors over a very broad range of effectors to HIV-infected targets. Progressors cells did not mediate effective killing even at high effector to target ratios. Defective cytotoxicity of progressor effectors could be restored in vitro. These results establish an effector function and mechanism that clearly segregate with immunologic control of HIV. A deeper understanding of the basis of immunologic control in LTNPs and the loss of immunologic control in progressors is likely to provide information that is critical for development of immunotherapies or prophylactic vaccines for HIV. In future work we seek to understand the molecular basis of the difference in killing capacity between LTNPs and progressors. We are also working to understand the mechanism by which such responses arise in LTNP patients, and determine whether they may be exploited in an HIV vaccine.
Showing the most recent 10 out of 32 publications
