The Institute for Medical Biology seeks to answer the underlying questions that remain in HIV immunology and vaccine development. By asking the more difficult questions, Dr. Streeck’s laboratory continues to add invaluable knowledge to the field and further shape how scientists view the multitude of interactions that occur during infection. Please see below for a list of written publications describing the institute’s contributed work to date, the conferences Dr. Hendrik Streeck and his faculty have attended and presented at, along with various pieces of literature that Dr. Streeck has written.
Aug 1, 2015
CD4(+) T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4(+) T cell functions beyond helper effects have been described, and a role for cytolytic CD4(+) T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4(+) T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4(+) T cells revealed a distinct transcriptional signature compared to Th1 CD4(+) cells but shared similar features with HIV-specific cytolytic CD8(+) T cells. Furthermore, HIV-specific cytolytic CD4(+) T cells showed comparable killing activity relative to HIV-specific CD8(+) T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4(+) T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4(+) T cells as an independent subset distinct from Th1 cells that show combined activity with CD8(+) T cells in the long-term control of HIV infection.
Feb 5, 2015
A study of SIV-infected rhesus macaques suggests that T follicular helper (TFH) cells, a specialized CD4+ T cell subset within the B cell follicles, are a sanctuary for SIV that is largely inaccessible to CD8+ T cells. These findings may open new avenues for research aimed at eradicating HIV.
Emergence of individual HIV-specific CD8 T cell responses during primary HIV-1 infection can determine long-term disease outcome
Events during primary HIV-1 infection have been shown to be critical for the subsequent rate of disease progression. Early control of viral replication, resolution of clinical symptoms and development of a viral set point have been associated with the emergence of HIV-specific CD8 T cell responses. Here we assessed which particular HIV-specific CD8 T cell responses contribute to long-term control of HIV-1. A total of 620 individuals with primary HIV-1 infection were screened by gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay for HLA class I-restricted, epitope-specific CD8 T cell responses using optimally defined epitopes approximately 2 months after initial presentation. The cohort was predominantly male (97%) and Caucasian (83%) (Fiebig stages II/III [n = 157], IV [n= 64], V [n = 286], and VI [n = 88] and Fiebig stage not determined [n = 25]). Longitudinal viral loads, CD4 count, and time to ART were collected for all patients. We observed strong associations between viral load at baseline (initial viremia) and the established early viral set points (P < 0.0001). Both were significantly associated with HLA class I genotypes (P = 0.0009). While neither the breadth nor the magnitude of HIV-specific CD8 T cell responses showed an influence on the early viral set point, a broader HIV-specific CD8 T cell response targeting epitopes within HIV-1 Gag during primary HIV-1 infection was associated with slower disease progression. Moreover, the induction of certain HIV-specific CD8 T cell responses—but not others—significantly influenced the time to ART initiation. Individual epitope-specific CD8 T cell responses contribute significantly to HIV-1 disease control, demonstrating that the specificity of the initial HIV-specific CD8 T cell response rather than the restricting HLA class I molecule alone is a critical determinant of antiviral function.
Independent evolution of Fc- and Fab-mediated HIV-1-specific antiviral antibody activity following acute infection.
Fc-related antibody activities, such as antibody-dependent cellular cytotoxicity (ADCC), or more broadly, antibody-mediated cellular viral inhibition (ADCVI), play a role in curbing early SIV viral replication, are enriched in human long-term infected nonprogressors, and could potentially contribute to protection from infection. However, little is known about the mechanism by which such humoral immune responses are naturally induced following infection. Here, we focused on the early evolution of the functional antibody response, largely driven by the Fc portion of the antibody, in the context of the evolving binding and neutralizing antibody response, which is driven mainly by the antibody-binding fragment (Fab). We show that ADCVI/ADCC-inducing responses in humans are rapidly generated following acute HIV-1 infection, peak at approximately 6 months postinfection, but decay rapidly in the setting of persistent immune activation, as Fab-related activities persistently increase. Moreover, the loss of Fc activity occurred in synchrony with a loss of HIV-specific IgG3 responses. Our data strongly suggest that Fc- and Fab-related antibody functions are modulated in a distinct manner following acute HIV infection. Vaccination strategies intended to optimally induce both sets of antiviral antibody activities may, therefore, require a fine tuning of the inflammatory response.