A new paper from Joseph Casazza and colleagues at the NIH’s Vaccine Research Center reports that some memory CD4 T cells can shield themselves against HIV infection by releasing beta chemokines. The researchers were following up on prior studies showing that CD4 T cells targeting HIV antigens are preferentially infected with the virus compared to CD4 T cells of other specificities (such as those targeting CMV).
Looking at CMV-specific CD4 T cells in detail, they found that release of the chemokines MIP-1 alpha and MIP-1 beta is significantly correlated with resistance to HIV infection. These chemokines can inhibit HIV infection, both by blocking virus interactions with the CCR5 co-receptor and causing CCR5 downregulation from the cell surface. The researchers also report that the ability of CMV-specific CD4 T cells to make beta chemokines is linked to the maturational status of the cells; more mature CD4 T cells produce more chemokines. Maturation refers to the progressive acquisition of functions that occurs after a CD4 T cell is initially stimulated. This process is also referred to as differentiation and it typically progresses as CD4 T cells divide.
In contrast with CMV-specific cells, the study found that HIV-specific CD4 T cells rarely produce beta chemokines and are significantly less differentiated. This suggests that HIV infection inhibits the maturation of HIV-specific CD4 T cells, and is consistent with a study of acutely infected individuals which reported that the vast preponderance of HIV DNA is found in HIV-specific CD4 T cells that would normally be expected to mature into functional “memory” cells (these developing memory cells can be identified based on expression of the receptor for IL-7).
Casazza et al note that this research lays the groundwork for the development of strategies aiming to induce CD4 T cell responses against HIV that can self-protect against infection. The next step is to evaluate whether specific types of immunization can bias the virus-specific CD4 T cell response toward the production of the beta chemokines MIP-1 alpha and MIP-1 beta. If a successful approach can be discovered, it could conceivably be very useful for both preventive and therapeutic vaccine development.
PLoS Pathog 5(10): e1000646. doi:10.1371/journal.ppat.1000646
Autocrine Production of β-Chemokines Protects CMV-Specific CD4+ T Cells from HIV Infection
Joseph P. Casazza1*, Jason M. Brenchley2, Brenna J. Hill2, Ribka Ayana1, David Ambrozak1, Mario Roederer3, Daniel C. Douek4, Michael R. Betts5, Richard A. Koup1
1 Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America, 2 Immunopathogenesis Unit, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, United States of America, 3 ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America, 4 Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America, 5 Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
Abstract Top
Induction of a functional subset of HIV-specific CD4+ T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease progression. CMV-specific CD4+ T cells, which are less frequently infected than HIV-specific CD4+ T cells, are a model for such an effect. To determine the mechanism of this protection, we compared the functional response of HIV gag-specific and CMV pp65-specific CD4+ T cells in individuals co-infected with CMV and HIV. We found that CMV-specific CD4+ T cells rapidly up-regulated production of MIP-1α and MIP-1β mRNA, resulting in a rapid increase in production of MIP-1α and MIP-1β after cognate antigen stimulation. Production of β-chemokines was associated with maturational phenotype and was rarely seen in HIV-specific CD4+ T cells. To test whether production of β-chemokines by CD4+ T cells lowers their susceptibility to HIV infection, we measured cell-associated Gag DNA to assess the in vivo infection history of CMV-specific CD4+ T cells. We found that CMV-specific CD4+ T cells which produced MIP-1β contained 10 times less Gag DNA than did those which failed to produce MIP-1β. These data suggest that CD4+ T cells which produce MIP-1α and MIP-1β bind these chemokines in an autocrine fashion which decreases the risk of in vivo HIV infection.
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