Semen exosomes inhibit HIV infection and HIV‐induced proinflammatory cytokine production independent of the activation state of primary lymphocytes

Abstract

Semen exosomes (SE) inhibit HIV infection. However, the effect of SE on cell activation and inflammation remains unknown. We characterized the response of peripheral blood mononuclear cells (PBMCs) from HIV‐uninfected and antiretroviral therapy‐suppressed HIV‐infected (HIV+) subjects to SE. Quiescent PBMCs or T‐cell receptor (TCR)‐activated PBMCs from HIV− and HIV+ donors were stimulated with SE in the presence/absence of ex vivo HIV infection. In HIV‐infected PBMCs, SE did not reactivate HIV, did not induce lymphoblast development, nor increase CD69+/CD25+ numbers. Furthermore, SE inhibited de novo HIV infection without altering cell activation. SE also asynchronously downregulated HIV‐inducible IL1β, IL8, and TNFα and upregulated CXCL10. These data suggest that SE inhibits HIV infection and production of HIV‐induced proinflammatory cytokines while preserving lymphocyte activation.

Electrostatic Surface Properties of Blood and Semen Extracellular Vesicles: Implications of Sialylation and HIV-Induced Changes on EV Internalization

“…These stark differences in the functions of EVs are even more remarkable when autologous EVs were used [ 38 , 51 ]. Indeed, considering our previous findings that SEVs, but not BEVs—unless they carry antiretroviral drugs [ 38 ]—inhibit HIV [ 36 , 37 , 40 , 41 ], independent of immune cell activation [ 39 ], it is possible that sialic acid content of SEVs may play critical role in HIV pathogenesis. One class of sialic acid receptors are sialic acid-binding immunoglobulin-like lectins (Siglecs), which upon sialic acid ligation act to dampen host immune responses and set appropriate thresholds of immune activation [ 24 ].…”

“…TZM-bl cells were obtained through the NIH AIDS Reagent Program and maintained in Dulbecco’s modified Eagle’s medium (DMEM) (Gibco-BRL/Life Technologies) supplemented with 10% fetal bovine serum (FBS) (Atlanta Biologicals, Flowery Branch, GA, USA) that was EV-depleted by 16 h ultracentrifugation at 100,000× g , 1% Penicillin-streptomycin (Thermofisher, Grand Island, NY, USA), 1 µg/mL Amphotericin B (Thermofisher), 2 mM sodium pyruvate (Corning, Corning, NY, USA), 1% of glutamate (Thermofisher), and 10 mM HEPES buffer (Fisher Biotech, Fair Lawn, NJ, USA) at pH 8. Isolation of primary cells was performed as previously described [ 37 , 39 , 40 ]. Frozen primary peripheral blood mononuclear cells (PBMCs), isolated from blood collected from 3 healthy donors, were thawed at 37 °C and individually washed with complete Roswell Park Memorial Institute (RPMI) media (Corning).…”

“…In this case, the functions of EVs depend on their cargo, which they derive from the producer cells. A good example of this producer cell mediated regulation of EV composition and function is the differences between autologous blood and semen derived EVs in HIV inhibition [ 37 , 38 , 39 ] and proteome composition [ 38 ]. In the context of HIV, blood and semen EVs (BEVs and SEVs) are of particular importance since both body fluids play important roles in HIV transmission.…”

Long-Term Low-Dose Delta-9-Tetrahydrocannbinol (THC) Administration to Simian Immunodeficiency Virus (SIV) Infected Rhesus Macaques Stimulates the Release of Bioactive Blood Extracellular Vesicles (EVs) that Induce Divergent Structural Adaptations and Signaling Cues

“…We have previously used different isolation protocols to purify EVs from both human semen and blood [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 44 ] and, recently, we optimized the isolation protocol that utilized a size-guided chromatographic technique to purify EVs from all body fluids [ 42 ]. We used this protocol to purify EVs from blood to gain novel insights into the effect of SIV infection and THC treatment on BEV size and concentration.…”

“…Further, there is a significant knowledge gap in the contribution of extracellular vesicles (EVs) to the effects of THC in the setting of HIV/SIV infection. EVs are a key player in the pathogenesis of viral infections [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. EVs are cargo-carrying, quasi-nanovesicles that mediate distal and proximal intercellular communications [ 45 , 46 , 47 ].…”