Modulation of Susceptibility to HIV-1 Infection by the Cytotoxic T Lymphocyte Antigen 4 Costimulatory Molecule

Abstract

CD4 T cells activated in vitro by anti-CD3/28–coated beads are resistant to infection by CC chemokine receptor 5 (CCR5)-dependent HIV-1 isolates. In vivo, antigen-presenting cells (APCs) activate CD4 T cells in part by signaling through the T cell receptor and CD28, yet cells stimulated in this manner are susceptible to HIV-1 infection. We show that cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement counteracts the CD28 antiviral effects, and that the ratio of CTLA-4 to CD28 engagement determines the susceptibility of HIV-1 infection. Furthermore, unopposed CTLA-4 signaling provided by CD28 blockade promotes vigorous HIV-1 replication, despite minimal T cell proliferation. Finally, CTLA-4 antibodies decrease the susceptibility of antigen-activated CD4 T cells to HIV, suggesting a potential approach to prevent or limit viral spread in HIV-1–infected individuals.

ICOS Costimulation Requires IL-2 and Can Be Prevented by CTLA-4 Engagement

“…However, we and others have found it to be useful system for analyzing the interplay between different costimulatory molecules due to the ease in which signal strengths can be manipulated (11,13,14). Using this system, we show that CTLA-4 ligation can block ICOS-mediated costimulation by preventing up-regulation of ICOS on the T cell surface and interfering with ICOS signal transduction.…”

“…Alternatively, cells were stimulated with 5 g/ml PHA (Sigma, St. Louis, MO) and 300 U/ml IL-2. Cells were cultured at 1 ϫ 10 6 /ml as previously described (14). Cell proliferation assays were conducted in 96-well plates using 1 ϫ 10 5 cells.…”

“…RNA was purified and reverse transcribed as described previously (14). Primers and probes to detect IL-2, IL-4, IL-10, IL-13, and 28S rRNA were designed using Primer Express software (Applied Biosytems, Foster City, CA), and their sequences are available upon request.…”

“…In vitro, microspheres coated with Abs against CD3, CD28, and CTLA-4 have been useful tools for studying the roles these molecules play in the immune response in both human and murine models (11,12). Using this approach, we have shown that CTLA-4 could block CD28-mediated proliferation, IL-2 production, and CCR5 down-regulation but not Bcl-x L induction (13,14).…”

HIV-Specific TGF-β-Positive CD4+T Cells Do Not Express Regulatory Surface Markers and Are Regulated by CTLA-4

“…16 Increased CTLA-4 expression correlates with markers of HIV disease progression. [17][18][19] Upregulation of CTLA-4 also increases CCR5 expression and enhances susceptibility of CD4 þ T cells to HIV infection, 20 and in vitro blockade of CTLA-4 augments HIV-specific CD4 þ T cell functions. 17 TGF-b is an antiinflammatory cytokine and its increased production leads to suppression of T cell function.…”