Background:  Interactions of HIV-1 with other microbes (co-pathogens) is an important factor in HIV disease progression. Innate response is the first line of the host defense to an incoming infection. Toll-like receptors (TLR) are one of the key elements in this response. Their engagement by microbial ligands leads to the induction of a variety of cellular factors that interfere with the life cycle of the pathogen. Any other, present or incoming, pathogen may be also affected by these factors.

Methods:  To investigate how the co-pathogens-induced engagement of TLR affects HIV-1 replication, we studied the effect of ligands specific for TLR-2, -3, -4, -5, -7, -8, and -9 on HIV-1 replication in human lymphoid tissue ex vivo. Replication of CCR5-tropic (SF162) and CXCR4-tropic (LAI.04) HIV-1 viral strains was measured by p24 enzyme-linked immunosorbent assay (ELISA). Cell activation (CD69 and CD38) and cell death (annexin V, Live/dead fixable dead cell stain (Invitrogen)) was monitored in various cell subpopulations (CD3, CD4, CD8) using flow cytometry. Changes in the production of 19 cytokines/chemokines were determined in multiplex bead-based assay. Student’s t test was used to determine statistical significance of the differences in cumulative p24 values between untreated and TLR ligand-treated tissues.

Results:  We demonstrate differential effect of various TLR ligands on both HIV-1 replication and cell activation or death. Effect on HIV-1 replication depends on:  the TLR receptor engaged, the HIV-1 viral strain, and the duration of the presence of a TLR ligand during the infection. Our results indicate that the altered cytokine profiles (namely MIP1α, MIP1b, and SDF-1) have the major direct effect on HIV-1 replication in ex vivo lymphoid tissue, while the effect of cell activation or death is mainly indirect.

Conclusions:  HIV-1 disease progression may be affected by the engagement of TLR by microbial components derived from HIV-1 co-pathogens.