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.
Leave a Reply