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

## TL;DR

This study shows that IL-4 promotes HIV-1 infection in macrophages by reducing levels of a protein called GJB2, which normally protects against the virus.

## Contribution

The study identifies GJB2 as a novel antiviral factor downregulated by IL-4 to enhance HIV-1 infection in myeloid cells.

## Key findings

- IL-4 enhances HIV-1 infection in macrophages by downregulating GJB2.
- GJB2 depletion impairs IL-4-mediated HIV-1 replication but not IL-6-mediated infection.
- GJB2 requires calcium to block HIV-1 attachment to cells.

## Abstract

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.