Publications (106) View all
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Article: Interleukin-7 promotes HIV persistence during antiretroviral therapy.
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ABSTRACT: HIV persists in latently infected memory CD4(+) T cells during antiretroviral therapy (ART). When administered to HIV-infected subjects receiving suppressive ART, interleukin-7 (IL-7) increases the number of CD4(+) T cells by promoting their survival and proliferation. However, little is known about the impact of IL-7 on HIV persistence during ART. By isolating large numbers of CD4(+) T cells from HIV-infected subjects, we demonstrate that IL-7 enhances viral production in productively infected cells but does not disrupt viral latency in latently infected cells isolated from subjects who received ART for years. When administered to virally suppressed subjects, IL-7 led to the rapid proliferation of memory CD4(+) T cells, which resulted in a 70% increase in the absolute number of circulating CD4(+) T cells harboring integrated HIV DNA 4 weeks after therapy. The genetic diversity of the viral reservoir increased transiently in the majority of the subjects studied before returning to baseline values. Altogether, our results indicate that IL-7 promotes the mechanisms of HIV persistence during ART by enhancing residual levels of viral production and inducing proliferation of latently infected cells and suggest that IL-7 does not represent a suitable candidate therapeutic strategy for HIV eradication. (AIDS Clinical Trials Group protocol 5214, NCT00099671, http://clinicaltrials.gov/ct2/show/NCT00099671).Blood 04/2013; · 9.90 Impact Factor -
Article: Multiple Cycles of Rituximab Therapy in Chronic Refractory Immune Thrombocytopenia: A Case Report With a 10-Year Follow-up.
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ABSTRACT: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated low platelet counts often leading to mucocutaneous bleeding. Administration of rituximab was shown to increase platelet counts in patients relapsing chronic ITP. However, duration of response with rituximab and the long-term benefit remains unknown. Herein, the authors presented a case of a 36-year-old splenectomised man with a relapsing ITP who received a total of 10 cycles of rituximab over the last decade with the concomitant assessments of circulating B cells. The data show that rituximab can be an effective therapy over 10 years, and monitoring B cells may help to herald ITP recurrence.American journal of therapeutics 03/2013; 20(2):219-22. -
Article: Profound metabolic, functional, and cytolytic differences characterize HIV-specific CD8 T cells in primary and chronic HIV infection.
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ABSTRACT: Immediate-early host-virus interactions that occur during the first weeks after HIV infection have a major impact on disease progression. The mechanisms underlying the failure of HIV-specific CD8 T-cell response to persist and control viral replication early in infection are yet to be characterized. In this study, we performed a thorough phenotypic, gene expression and functional analysis to compare HIV-specific CD8 T cells in acutely and chronically infected subjects. We showed that HIV-specific CD8 T cells in primary infection can be distinguished by their metabolic state, rate of proliferation, and susceptibility to apoptosis. HIV-specific CD8 T cells in acute/early HIV infection secreted less IFN-γ but were more cytotoxic than their counterparts in chronic infection. Importantly, we showed that the levels of IL-7R expression and the capacity of HIV-specific CD8 T cells to secrete IL-2 on antigenic restimulation during primary infection were inversely correlated with the viral set-point. Altogether, these data suggest an altered metabolic state of HIV-specific CD8 T cells in primary infection resulting from hyperproliferation and stress induced signals, demonstrate the discordant function of HIV-specific CD8 T cells during early/acute infection, and highlight the importance of T-cell maintenance for viral control.Blood 09/2012; 120(17):3466-77. · 9.90 Impact Factor -
Article: Human Immunodeficiency Virus Rebound in Blood and Seminal Plasma Following Discontinuation of Antiretroviral Therapy.
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ABSTRACT: Abstract Although there is discordance between human immunodeficiency virus (HIV) blood plasma and seminal plasma viral loads (VL), little is known about the dynamics of VL rebound in these compartments upon discontinuation of highly active antiretroviral therapy (HAART). Therefore, we sought to examine the relationship between blood and semen VL rebound after discontinuation of HAART. Participants in this substudy were men enrolled from two centers of a multicenter, placebo-controlled randomized trial of HIV therapeutic vaccination using ALVAC with or without Remune. With at least 2 years of sustained virologic suppression and following a 20-week vaccination course, subjects underwent structured HAART interruption. Fourteen men provided semen samples. Seven to 12 weeks after HAART interruption, all 14 men had detectable blood VLs whereas 8 of 14 had detectable seminal VLs. There was a significant correlation between blood and seminal VLs (Spearman r=0.58, p=0.03) at the time of semen collection. An earlier time to detectable blood VL after HAART interruption was associated with higher seminal VL (Spearman r=-0.64, p=0.02). These findings support the compartmentalization of HIV and underscore the importance of understanding the genital tract as an HIV reservoir in the quest to minimize HIV transmission.AIDS research and human retroviruses 08/2012; · 2.18 Impact Factor -
Article: CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction.
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ABSTRACT: Chronic viral infections lead to persistent CD8 T cell activation and functional exhaustion. Expression of programmed cell death-1 (PD-1) has been associated to CD8 T cell dysfunction in HIV infection. Herein we report that another negative regulator of T cell activation, CD160, was also upregulated on HIV-specific CD8 T lymphocytes mostly during the chronic phase of infection. CD8 T cells that expressed CD160 or PD-1 were still functional whereas co-expression of CD160 and PD-1 on CD8 T cells defined a novel subset with all the characteristics of functionally exhausted T cells. Blocking the interaction of CD160 with HVEM, its natural ligand, increased HIV-specific CD8 T cell proliferation and cytokine production. Transcriptional profiling showed that CD160(-)PD-1(+)CD8 T cells encompassed a subset of CD8(+) T cells with activated transcriptional programs, while CD160(+)PD-1(+) T cells encompassed primarily CD8(+) T cells with an exhausted phenotype. The transcriptional profile of CD160(+)PD-1(+) T cells showed the downregulation of the NFκB transcriptional node and the upregulation of several inhibitors of T cell survival and function. Overall, we show that CD160 and PD-1 expressing subsets allow differentiating between activated and exhausted CD8 T cells further reinforcing the notion that restoration of function will require multipronged approaches that target several negative regulators.PLoS Pathogens 08/2012; 8(8):e1002840. · 9.13 Impact Factor
