Neisseria gonorrhoeae Enhances HIV-1 Infection of Primary Resting CD4+ T Cells through TLR2 Activation

Abstract

Sexually transmitted infections increase the likelihood of HIV-1 transmission. We investigated the effect of Neisseria gonorrheae (gonococcus [GC]) exposure on HIV replication in primary resting CD4+ T cells, a major HIV target cell during the early stage of sexual transmission of HIV. GC and TLR2 agonists, such as peptidylglycan (PGN), Pam3CSK4, and Pam3C-Lip, a GC-derived synthetic lipopeptide, but not TLR4 agonists including LPS or GC lipooligosaccharide enhanced HIV-1 infection of primary resting CD4+ T cells after viral entry. Pretreatment of CD4+ cells with PGN also promoted HIV infection. Anti-TLR2 Abs abolished the HIV enhancing effect of GC and Pam3C-Lip, indicating that GC-mediated enhancement of HIV infection of resting CD4+ T cells was through TLR2. IL-2 was required for TLR2–mediated HIV enhancement. PGN and GC induced cell surface expression of T cell activation markers and HIV coreceptors, CCR5 and CXCR4. The maximal postentry HIV enhancing effect was achieved when PGN was added immediately after viral exposure. Kinetic studies and analysis of HIV DNA products indicated that GC exposure and TLR2 activation enhanced HIV infection at the step of nuclear import. We conclude that GC enhanced HIV infection of primary resting CD4+ T cells through TLR2 activation, which both increased the susceptibility of primary CD4+ T cells to HIV infection as well as enhanced HIV-infected CD4+ T cells at the early stage of HIV life cycle after entry. This study provides a molecular mechanism by which nonulcerative sexually transmitted infections mediate enhancement of HIV infection and has implication for HIV prevention and therapeutics.

Nuclear Receptor Signaling Inhibits HIV-1 Replication in Macrophages through Multipletrans-Repression Mechanisms

“…This indicates that NR signaling, in addition to directly repressing virus expression in infected cells, is capable of dampening the proinflammatory cytokine response that activates HIV-1 expression in an autocrine or paracrine fashion. , it is not surprising that a number of TLR ligands activate HIV-1 expression in immune cells (3,11,34,36,114,145,161). In agreement with other reports (3,11,36,98,114,145,161), we show that signaling through TLR2 activates HIV-1 expression in macrophages and DCs ( Fig.…”

HIV Type 1 Infection Up-Regulates TLR2 and TLR4 Expression and Function in Vivo and in Vitro

“…19 Thus, TLR activation may promote HIV-1 infection due to the effect of downstream signaling effectors on viral replication. 47 To evaluate the modulation of the TLRs in other cell subpopulation during HIV-1 infection, TLRs expression was assessed in MDMs. An increase in TLR2 and TLR4 expression either in MDMs infected by HIV-1 in vitro and stimulated with their specific agonist, or in monocytes, pDCs, and mDCs of HIV-1-infected patients, was detected.…”

Neisseria gonorrhoeae-derived heptose elicits an innate immune response and drives HIV-1 expression

“…With regards to Ng-specific ligands, Pam(3)C-Lip, a synthetic Ng-like lipopeptide, enhances HIV-1 infection of resting CD4 + T cells via TLR2 (21). However, Ng still drives HIV-1 LTR expression in T-cell lines that do not express TLR2 (18,28), indicating that other Ng factors are key to the induction of HIV-1 expression in CD4 + T cells.…”

“…There is ligand specificity in TLR-driven HIV-1 induction, because another TLR4 agonist, LPS, does not induce HIV-1 expression in the same cell line (17,18). TLR2 agonists including dipalmitoyl-S-glyceryl-L-Cys-Ser-(Lys) 4 (Pam 2 CSK 4 ) and peptidoglycan promote the replication of HIV-1 from resting CD4 + T cells (21), and flagellin has been shown to reactivate latent HIV-1 in CD4 + T cells and to induce viral gene expression in quiescent central memory CD4 + T cells (25).…”

“…The best-characterized class of these receptors is the family of Toll-like receptors (TLRs) that, upon recognition of conserved microbial-associated molecular patterns (MAMPs), trigger a cascade of signaling events that modulate both the adaptive and innate immune responses (19). TLR activation modulates HIV-1 infection and/or transmission, and, depending on the specific TLR agonist and the target cell, TLR activation can either promote or inhibit HIV-1 expression in vitro (17,18,(20)(21)(22)(23)(24)(25)(26).…”