DIFFERENT TGF-BETA PROFILES IN SIVMAC AND SIVAGM INFECTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The generalized T-cell activation characterizing HIV-1 and SIVmac infections in humans and macaques (MACs) is not found in the non-pathogenic SIVagm infection in African green monkeys (AGMs). We have previously shown that TGF-¿1, Foxp3 and IL-10 are induced very early after SIVagm infection. In SIVmac-infected MACs, plasma TGF-¿1 induction persists during primary infection. We hypothesized that MACs are unable to respond to TGF-¿1 and thus cannot control virus-driven inflammation. We therefore compared the very early expression dynamics of pro- and anti-inflammatory molecules as well as of factors involved in the TGF-¿1 signaling in SIV-infected AGMs and MACs. Levels of transcripts encoding pro- and anti-inflammatory molecules (TNF- ¿, IFN- ¿, IL-10, T-BET, GATA-3) as well as for TGF-¿1 signaling mediators (smad3, smad4, smad7) were followed by real time PCR in a prospective study enrolling 6 AGMs and 6 MACs. During primary SIVmac infection, up-regulations of TNF- ¿, IFN- ¿ and T-BET responses (days 116 p.i.) were stronger whereas IL-10 response was delayed (4th week p.i.) compared to SIVagm infection. Up-regulation of smad7 (days 38 p.i.), a cellular mediator inhibiting the TGF-¿1 signaling cascade, characterized SIV-infected MACs. In AGMs, we found increases of GATA-3 but not T-BET, a longer lasting up-regulation of smad4 (days 121 p.i), a mediator enhancing TGF-¿1 signaling, and no smad7 up-regulations. Our data suggest that the inability to control virus-driven inflammation and activation during the pathogenic HIV-1/SIVmac infections is due to up-regulation of smad7 that inhibits early TGF-beta expression.