BackgroundThe barrier to a cure for HIV infection is the persistence of HIV latently-infected cells in blood and tissues despite long-term antiretroviral therapy (ART). These infected cells do not express enough viral antigens to be eliminated by the immune system, and different strategies to reactivate these cells have been proposed, including the usage of the human lectin, Galectin-9 (Gal-9) 1,2). However, Gal-9 modulates HIV transcription through activating the T-cell receptor (TCR) -downstream ERK and CREB signaling pathways in an Lck-dependent manner 3). This Gal-9-mediated activation of TCR-downstream signaling pathways can lead to several undesirable effects due to T cell expansion, activation, and/or exhaustion. Indeed, recent studies showed that Gal-9, which is rapidly and sustainably elevated during HIV infection 4), may contribute to the state of chronic immune activation and inflammation during HIV infection 5-7). This potential “double-edged sword” effect of Gal-9 during HIV infection raises the question of the overall beneficial (by reactivating latent infection) versus detrimental (by undesirable effects on T cells) impact of Gal-9 on HIV persistence in vivo. The evaluation of the overall impact of Gal-9 on HIV persistence requires a relevant in vivo animal model of HIV infection during ART suppression. In this report, we evaluated the impact of Gal-9 in a humanized mouse model of HIV infection (the bone marrow-liver-thymus humanized (BLT) mouse model of HIV latency). Using two independent cohorts of BLT mice, we found that Gal-9 treatment was tolerable and did not significantly induce plasma markers of inflammation or T cell markers of immune activation/exhaustion. However, Gal-9 treatment during ART significantly increased levels of tissue-associated HIV DNA and RNA than control. These data highlight the overall adverse effects of Gal-9 on HIV persistence and the potential need to block Gal-9 interactions during ART-suppressed HIV infection.DesignWe used the BLT (bone marrow, liver, thymus) humanized mouse model to evaluate the overall impact of Gal-9 on HIV persistence in vivo during antiretroviral therapy (ART).MethodsTwo independent cohorts of BLT mice with high human immune reconstitution were infected with HIV, placed on ART, and then treated with either recombinant Gal-9 or control during ART suppression. Plasma viral loads and levels of tissue-associated HV DNA and RNA were measured by ddPCR and qPCR. Markers of T cell activation/exhaustion were measured by flow cytometry, and plasma markers of inflammation were measured by multiplex cytokine arrays.ResultsGal-9 treatment was tolerable in ART-suppressed humanized mice and did not significantly induce plasma markers of inflammation or T cell markers of activation/exhaustion. However, Gal-9 treatment during ART significantly increased levels of tissue-associated HIV DNA and RNA than controls (P=0.0007 and P=0.011, respectively, for cohort I and P=0.002 and P=0.005, respectively, for cohort II). ConclusionsOur study highlights the overall adverse effects of Gal-9 on HIV persistence and the potential need to block Gal-9 interactions during ART-suppressed HIV infection.Progress after the granted periodGal-9 treatment is tolerable in vivo but induces levels of tissue-associated HIV DNA and RNA during ARTWe generated two independent cohorts of humanized mice (n=9 for cohort I and n=6 for cohort II) for this study (Figure 1A). We achieved high levels of immune reconstitution as measured by the percentage of human CD45+ cells in the blood (Figure 1B). The BLT humanized mice were then infected with HIV (HIVSUMA transmitted/founder virus) for three weeks. Mice were then placed on ART for five weeks and then treated with either phosphate-buffered saline (PBS) control or 2 mg/kg recombinant Gal-9 for two weeks (intraperitoneal (IP) injections every other day; seven doses). Mice were then euthanized, and blood and tissues (liver, spleen, and lung) were collected (Figure 98Reversal of HIV latency byGalectin-9 in vivoMohamed Abdel-MohsenZhe Yuan, Leila B. Giron, Toshiro Niki, Lishomwa C. Ndhlovu,Luis, J MontanerThe Wistar Institute, Philadelphia, PA, USA
元のページ ../index.html#98