IL-4 downregulates gap junction protein connexin 26 to promote HIV-1 infection in macrophages

Macrophages and dendritic cells (DCs) are important targets for HIV-1 replication in vivo. Myeloid cells are collectively more resistant to HIV-1 infection than CD4⁺ T lymphocytes, but interleukin (IL)-4 has been observed to promote macrophage susceptibility to HIV-1 infection. However, the mechanism remains unclear. Herein, we found that IL-4 enhanced HIV-1 infection in myeloid lineage macrophages by downregulating the novel antiviral factor gap junction protein beta 2 (GJB2) located on the cell membrane. In the absence of GJB2, the IL-4-mediated enhancement of HIV-1 replication was largely impaired in primary macrophages. Conversely, IL-6-mediated enhancement of HIV-1 infection was unaffected by GJB2 depletion. GJB2 was constitutively expressed in myeloid cells but not in CD4⁺ T cells, and GJB2 silencing enhanced HIV-1 transmission in macrophages and DCs. Additionally, GJB2 required Ca2⁺ to exert its antiviral activity by interfering with HIV-1 attachment to target cells. Because IL-4 downregulated GJB2 expression to enhance HIV-1 infection in macrophages, GJB2 may be a novel target for the treatment of HIV-1 infection.

HIV-1 primarily targets two groups of cells in vivo: CD4⁺ T lymphocytes and myeloid lineage cells, such as macrophages and dendritic cells. Although myeloid cells are more resistant to HIV-1 infection than CD4⁺ T cells, some cytokines, including interleukin (IL)-4 and IL-6, promote myeloid cell infection. Gap junction protein beta 2 (GJB2) is particularly relevant in the field of auditory science. Here, we identified GJB2 as a novel antiviral factor by demonstrating that IL-4-mediated reduction in GJB2 levels enhanced HIV-1 infection in myeloid cells. Interestingly, GJB2 expression was regulated by IL-4 but not by interferons. The reduction in GJB2 levels was inversely correlated with increased HIV-1 infection levels, suggesting the potential of GJB2 for combating HIV/AIDS.