Abstract
CD4+ CCR6+ T cells are highly susceptible to HIV infection, and a high cytokine producing CCR6+ T cell subset is selectively lost during HIV infection. The CCR6 chemokine MIP-3α (CCL20) is produced at sites of infection in SIV animal models. Recently, we have shown that MIP-3α inhibits HIV replication. This inhibition of HIV infection is mediated by CCR6 signaling and eventuates in increased APOBEC3G expression. Since there are few existing reports on the role of MIP-3α in health or disease, we studied its production by PBMCs from HIV-seronegative and HIV+ subjects. We evaluated the ability of PBMCs to produce MIP-3α in response to antigen stimulation using cells obtained from two groups: one composed of HIV-seronegative subjects (n = 16) and the other composed of HIV+ subjects (n = 58), some asymptomatic and some with clinically defined AIDS. Antigens included fragment C of the tetanus toxin, Candida albicans, whole-inactivated HIV, and HIV p24. MIP-3α was detected by ELISA in tissue culture supernatants of antigen-stimulated PBMCs. MIP-3α production by antigen-stimulated PBMCs was readily measured for HIV-negative subjects and for HIV-seropositive asymptomatic subjects, but not for patients with AIDS. These results suggest that subversion of the MIP-3α-CCR6 axis by HIV during the course of infection contributes to the loss of immune function that eventually leads to AIDS.
Highlights
Chemokine receptors play an important role in HIV immunopathogenesis and immune antiviral response. [1,2]
We have shown that MIP-3α possesses antiviral activity when added post-infection and that the CCR6 ligands MIP-3α and human β-defensin 2 induce the expression of the host restriction factor APOBEC3G in both unstimulated and PHA-stimulated PBMCs and CD4+ T cells [26]
Since CCR5 and CCR6 are often coexpressed in CD4+ T memory cells [59], we investigated whether MIP-3α is produced upon antigen stimulation
Summary
Chemokine receptors play an important role in HIV immunopathogenesis and immune antiviral response. [1,2]. Chemokine receptors play an important role in HIV immunopathogenesis and immune antiviral response. We demonstrated that CCR5 ligands are potent and specific inhibitors of certain isolates of HIV-1 [3]. Studies on HIV and SIV immunopathogenesis have highlighted the role played by the MIP-3α-CCR6 axis [14,15,16,17,18,19,20,21,22,23,24,25,26]. We reported that CCR6 mediates the HIV inhibitory activity of its ligands, MIP-3α and hBD2 [26]. CCR6 is expressed on activated and memory CD4+ T cells, especially on lymphocytes that infiltrate inflamed mucosa [37]
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