Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients

<p>Abstract</p> <p>Background</p> <p>The presence of HIV-1 preintegration reservoir was assessed in an <it>in vitro </it>experimental model of latent HIV-1 infection, and in patients treated or not with highly active antiretroviral therapy (HAART).</p> <p>Results</p> <p>In resting CD4⁺T lymphocytes latently infected <it>in vitro </it>with HIV-1, we demonstrated that the polyclonal activation induced a HIV-1 replication, which could be prevented by the use of an HIV-1 integrase inhibitor. We also showed that this reservoir was labile since the rescuable HIV-1-antigens production from unintegrated HIV-1 genomes declined over time. These data confirm that our experimental approach allows the characterization of a functional unintegrated HIV-1 reservoir. We then explored the preintegration reservoir in HIV-1-infected patients. This reservoir was detected in 11 of 12 untreated patients, in 4 of 10 sustained responders to HAART, and in one incomplete responder. This reservoir was also inducible, labile, and anti-HIV-1 integrase drug inhibited its induction. Finally, this reservoir was associated with the presence of spontaneous HIV-1 antigens producing CD4⁺T cells in blood from 3 of 3 untreated patients and 2 of 2 sustained responders to HAART harboring a preintegration reservoir.</p> <p>Conclusion</p> <p>This preintegration phase of HIV-1 latency could be a consequence of the ongoing viral replication in untreated patients and of a residual viral replication in treated patients.</p

Inflammatory control in AIDS-resistant non human primates

International audienceAfrican non human primates are natural hosts of SIV. The infection is non-pathogenic despite plasma viral load levels similar to those in HIV-1 infected humans and SIVmac-infected macaques (MAC) progressing towards AIDS. The most striking difference between non-pathogenic SIV and pathogenic HIV-1/SIVmac infections is the lack of chronic T cell activation in natural hosts. In HIV and SIVmac infections, chronic T cell activation is known to drive CD4+T cell depletion. Intense research efforts are worldwide put on the search of the mechanisms that can control chronic T cell activation in HIV/SIV infections. Innate immune responses play a determinant role in the regulation of T cell activation profiles. Type I interferons (IFN-I) are part of the first-wave response of the innate immune system in viral infections. We compared the IFN-I responses between pathogenic (MAC) and non-pathogenic SIV infections (African Green monkey, AGM) at the level of blood and lymph nodes (LN) during the early and chronic stage of infection. During the acute SIVagm infection, we detected high amounts of IFN-α in the plasma of AGMs, although the mean levels at the peak were three times lower than in MAC. The microarray data revealed a rapid and strong up-regulation of type I Interferon-Stimulated Genes (ISG) in AGMs during acute SIVagm infection. ISGs denote the in vivo activity of IFN-I. Using a functional assay, we demonstrated that low IFN-α concentrations (50 times lower than the IFN-α levels in plasma at the peak) were sufficient to induce strong ISG responses in AGM and MAC cells. Surprisingly, our direct comparison of blood and LNs showed that ISG induction was broader in blood of AGMs than in MAC, while in LN, it was the contrary. Thus, in AGMs, less ISG were induced in LNs as compared to MAC already during the acute phase of infection. Moreover, our tight kinetic analysis showed that this ISG expression was efficiently controlled after day 28 post-infection in AGMs, while in MAC the ISGs expression remained uncontrolled. Finally, we identified genes that were differentially expressed between the two species and which might be involved in the discriminating responses. Altogether, this shows that AGMs are capable to mount a well coordinated and efficient regulative response to innate immune activation

Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection.

International audienceHuman immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques (MAC) lead to chronic inflammation and AIDS. Natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM), are protected against SIV-induced chronic inflammation and AIDS. Here, we report that AGM plasmacytoid dendritic cells (pDC) express extremely low levels of CD4, unlike MAC and human pDC. Despite this, AGM pDC efficiently sensed SIVagm, but not heterologous HIV/SIV isolates, indicating a virus-host adaptation. Moreover, both AGM and SM pDC were found to be, in contrast to MAC pDC, predominantly negative for CCR5. Despite such limited CD4 and CCR5 expression, lymphoid tissue pDC were infected to a degree similar to that seen with CD4(+) T cells in both MAC and AGM. Altogether, our finding of efficient pDC infection by SIV in vivo identifies pDC as a potential viral reservoir in lymphoid tissues. We discovered low expression of CD4 on AGM pDC, which did not preclude efficient sensing of host-adapted viruses. Therefore, pDC infection and efficient sensing are not prerequisites for chronic inflammation. The high level of pDC infection by SIVagm suggests that if CCR5 paucity on immune cells is important for nonpathogenesis of natural hosts, it is possibly not due to its role as a coreceptor. The ability of certain key immune cell subsets to resist infection might contribute to the asymptomatic nature of simian immunodeficiency virus (SIV) infection in its natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM). This relative resistance to infection has been correlated with reduced expression of CD4 and/or CCR5. We show that plasmacytoid dendritic cells (pDC) of natural hosts display reduced CD4 and/or CCR5 expression, unlike macaque pDC. Surprisingly, this did not protect AGM pDC, as infection levels were similar to those found in MAC pDC. Furthermore, we show that AGM pDC did not consistently produce type I interferon (IFN-I) upon heterologous SIVmac/HIV type 1 (HIV-1) encounter, while they sensed autologous SIVagm isolates. Pseudotyping SIVmac/HIV-1 overcame this deficiency, suggesting that reduced uptake of heterologous viral strains underlays this lack of sensing. The distinct IFN-I responses depending on host species and HIV/SIV isolates reveal the host/virus species specificity of pDC sensing

Se protéger du SIDA ? L’exemple des singes d’Afrique.

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The early Th17/Treg ratio predicts the immune activation set point in patients with primary HIV infection

International audienceBACKGROUND:Persistent systemic immune activation plays a central role in the pathogenesis of HIV disease. Impairment of the intestinal barrier and subsequent microbial translocation might be involved in chronic immune activation. Th17 cells are important in the maintenance of intact epithelium and host defense against extracellular pathogens. The ratio between the two closely related CD4 subsets Th17 and Tregs has been recently found to shrink with HIV/SIV disease progression. The aim of the study was to analyze, in patients with early primary HIV infection (PHI), the relationship between Th17/Treg ratio and the immune activation set point, known to predict disease progression.METHODS:27 patients with early PHI were included in a prospective longitudinal study and followed-up for 6 months. T-cell activation and CD4+CD25+CD127lowFoxp3+ Treg frequency were assessed on fresh PBMC. Th17 cells were quantified by intracellular cytokine staining on sorted peripheral CD4 T cells stimulated with PMA/ionomycin for 5h. Correlations were assessed using spearman non-parametric tests. Plasma I-FABP, a marker of mucosal damages and soluble CD14 (sCD14) were measured by ELISA.RESULTS:A strong negative relationship was found at baseline between the Th17/Treg ratio and the proportion of activated CD8 T cells expressing CD38/HLA-DR (p=0.008) or Ki-67 (P=0.001). At baseline, Th17/Treg ratios also negatively correlated with sCD14 plasma levels (p=0.003). I-FABP levels, which were similar to controls at baseline, increased at month 6. The Th17/Treg ratio at baseline (but not the proportion of Th17 cells) negatively correlated with the frequency of HLA-DR+CD38+ or Ki-67+ CD8 T cells at month 6, defining the immune activation set point (p=0.02 and p=0.0005 respectively). sCD14 plasma levels were also found to predict the immune set point (p=0.02).CONCLUSION:Our data do not support early mucosal damages in PHI. However, the early Th17/Treg balance correlates with sCD14 levels and predicts the immune activation set point

Phenotype Alterations in Regulatory T-Cell Subsets in Primary HIV Infection and Identification of Tr1-like Cells as the Main Interleukin 10-Producing CD4+ T Cells

International audienceBackground: Conventional regulatory T cells (Tregs) can suppress human immunodeficiency virus type 1 (HIV-1)-specific immune responses but cannot control immune activation in primary HIV infection. Here, we characterized Treg subsets, using recently defined phenotypic delineation, and analyzed the relative contribution of cell subsets to the production of immunosuppressive cytokines in primary HIV infection.Methods: In a longitudinal prospective study, ex vivo phenotyping of fresh peripheral blood mononuclear cells from patients with primary HIV infection was performed at baseline and month 6 of follow-up to characterize Treg subsets, immune activation, and cytokine production in isolated CD4(+) T cells.Results: The frequency of CD4(+)CD25(+)CD127(low) Tregs and the distribution between the naive, memory, and activated/memory Treg subsets was similar in patients and healthy donors. However, Tregs from patients with primary HIV infection showed peculiar phenotypic profiles, such as elevated FoxP3, ICOS, and CTLA-4 expression, with CTLA-4 expression strikingly increased in all Treg subsets both at baseline and month 6 of follow-up. The great majority of interleukin 10 (IL-10)-producing CD4(+) T cells were FoxP3(neg) (ie, Tr1-like cells). In contrast to conventional Tregs, Tr1-like cells were inversely correlated with immune activation and not associated with lower effector T-cell responses.Conclusion: FoxP3(neg) Tr1-like cells-major contributors to IL-10 production-may have a beneficial role by controlling immune activation in early HIV infection

Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients-1

<p><b>Copyright information:</b></p><p>Taken from "Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients"</p><p>http://www.retrovirology.com/content/4/1/60</p><p>Retrovirology 2007;4():60-60.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2048509.</p><p></p>vated in four experiments (nos. 1, 2, 3, and 4) or directly polyclonaly activated and cultured with L-731,988 in two other assays (nos. 3 and 4). . latently infected resting CD4T cells were directly polyclonaly activated or preincubated 2 days before polyclonal activation in two experiments (nos. 3 and 4)

Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients-7

<p><b>Copyright information:</b></p><p>Taken from "Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients"</p><p>http://www.retrovirology.com/content/4/1/60</p><p>Retrovirology 2007;4():60-60.</p><p>Published online 29 Aug 2007</p><p>PMCID:PMC2048509.</p><p></p>vated in four experiments (nos. 1, 2, 3, and 4) or directly polyclonaly activated and cultured with L-731,988 in two other assays (nos. 3 and 4). . latently infected resting CD4T cells were directly polyclonaly activated or preincubated 2 days before polyclonal activation in two experiments (nos. 3 and 4)