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Blocking CXCL9 Decreases HIV-1 Replication and Enhances the Activity of Prophylactic Antiretrovirals in Human
Sherrill L Macura1, Melissa J Lathrop, Jiang Gui
1*Research Service, V. A. Medical Center, White River Junction, VT; †Center for Devices and Radiological Health, Food and Drug Administration, Office of Device Evaluation, Silver Spring, MD; ‡Division of Select Agents and Toxins, Centers for Disease Control and Prevention, Atlanta, GA; §Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH; ‖CONRAD, Eastern Virginia Medical School, Norfolk, VA; ¶Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH; and #Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH.
Objectives:
The interferon-gamma-induced chemokine CXCL9 is expressed in a wide range of inflammatory conditions including those affecting the female genital tract. CXCL9 promotes immune cell recruitment, activation, and proliferation. The role of CXCL9 in modulating HIV-1 infection of cervicovaginal tissues, a main portal of viral entry, however, has not been established. We report a link between CXCL9 and HIV-1 replication in human cervical tissues and propose CXCL9 as a potential target to enhance the anti-HIV-1 activity of prophylactic antiretrovirals.
Design:
Using ex vivo infection of human cervical tissues as a model of mucosal HIV-1 acquisition, we described the effect of CXCL9 neutralization on HIV-1 gene expression and mucosal CD4 T-cell activation. The anti-HIV-1 activity of tenofovir, the leading mucosal pre-exposure prophylactic microbicide, alone or in combination with CXCL9 neutralization was also studied.
Methods:
HIV-1 replication was evaluated by p24 ELISA. HIV-1 DNA and RNA, and CD4, CCR5, and CD38 transcription were evaluated by quantitative real-time polymerase chain reaction. Frequency of activated cervical CD4 T cells was quantified using fluorescence-activated cell sorting.
Results:
Antibody blocking of CXCL9 reduced HIV-1 replication by decreasing mucosal CD4 T-cell activation. CXCL9 neutralization in combination with suboptimal concentrations of tenofovir, possibly present in the cervicovaginal tissues of women using the drug inconsistently, demonstrated an earlier and greater decrease in HIV-1 replication compared with tissues treated with tenofovir alone.
Conclusions:
CXCL9 neutralization reduces HIV-1 replication and may be an effective target to enhance the efficacy of prophylactic antiretrovirals.
