Acquired Immunodeficiency Syndrome: Desoutter JF

Ploquin MJ, Desoutter JF, Santos PR, Pandrea I, Diop OM, Hosmalin A, Butor C, Barre-Sinoussi F, Müller-Trutwin MC. · Unité de Régulation des Infections Rétrovirales, Institut Pasteur, Paris, France. · Retrovirology. · Pubmed #16800882 links to  free full text

Abstract: BACKGROUND: 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-beta1, Foxp3 and IL-10 are induced very early after SIVagm infection. In SIVmac-infected MACs, plasma TGF-beta1 induction persists during primary infection 1. We raised the hypothesis that MACs are unable to respond to TGF-beta1 and thus cannot resorb virus-driven inflammation. We therefore compared the very early expression dynamics of pro- and anti-inflammatory markers as well as of factors involved in the TGF-beta1 signaling pathway in SIV-infected AGMs and MACs. METHODS: Levels of transcripts encoding for pro- and anti-inflammatory markers (tnf-alpha, ifn-gamma, il-10, t-bet, gata-3) as well as for TGF-beta1 signaling mediators (smad3, smad4, smad7) were followed by real time PCR in a prospective study enrolling 6 AGMs and 6 MACs. RESULTS: During primary SIVmac infection, up-regulations of tnf-alpha, ifn-gamma and t-bet responses (days 1-16 p.i.) were stronger whereas il-10 response was delayed (4th week p.i.) compared to SIVagm infection. Up-regulation of smad7 (days 3-8 p.i.), a cellular mediator inhibiting the TGF-beta1 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 1-21 p.i), a mediator enhancing TGF-beta1 signaling, and no smad7 up-regulations. CONCLUSION: Our data suggest that the inability to resorb virus-driven inflammation and activation during the pathogenic HIV-1/SIVmac infections is associated with an unresponsiveness to TGF-beta1.

Kornfeld C, Ploquin MJ, Pandrea I, Faye A, Onanga R, Apetrei C, Poaty-Mavoungou V, Rouquet P, Estaquier J, Mortara L, Desoutter JF, Butor C, Le Grand R, Roques P, Simon F, Barré-Sinoussi F, Diop OM, Müller-Trutwin MC. · Unité de Biologie des Rétrovirus, Institut Pasteur, Paris, France. · J Clin Invest. · Pubmed #15761496 links to  free full text

Abstract: T cell activation levels in HIV infection are predictive of AIDS progression. We searched for the immunological correlates of protection against disease progression by studying the early stages of nonpathogenic SIV infection in African green monkeys (SIVagm). The African green monkeys (AGMs) displayed high peak viremias and a transient decline in levels of blood CD4(+) and CD8(+) T cells between days 5 and 17 after infection. A concomitant increase in levels of CD4(+)DR(+), CD8(+)DR(+), and CD8(+)CD28(-) cells was detected. After the third week, T cell activation returned to baseline levels, which suggested a protective downregulation of T cell activation. A very early (24 hours after infection) and strong induction of TGF-beta1 and FoxP3 expression was detected and correlated with increases in levels of CD4(+)CD25(+) and CD8(+)CD25(+) T cells. This was followed by a significant increase in levels of IL-10, whereas IFN-gamma gene upregulation was more transient, and levels of TNF-alpha and MIP-1alpha/beta transcripts did not increase in either blood or tissues. The profiles were significantly different during primary SIV infection in macaques (SIVmac); that is, there was a delayed increase in IL-10 levels accompanied by moderate and persistent increases in TGF-beta levels. Together, our data show that SIVagm infection is associated with an immediate antiinflammatory environment and suggest that TGF-beta may participate in the generation of Tregs, which may prevent an aberrant chronic T cell hyperactivation.