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Demographics of HIV-Infected Patients with PCNSL and Matched HIV-Infected Controls HIV þ patients with PCNSL HIV þ patients without PCNSL
Source publication
Each cell in HIV-associated primary central nervous system lymphoma (PCNSL) harbors latent EBV. Notably, the triggering of TLR9, a key event in HIV pathogenesis, also promotes EBV latency and transformation. We hypothesized that because only a minority of HIV-infected patients develops PCNSL, their B cells exhibit aberrant signaling responses to TL...
Citations
... Lower surface levels of CD21 is a marker of B cell exhaustion [53]. Another B-cell activation marker, CD80, interacts with the CTLA-4 receptor on T-cells which contributes to lowering T-cell reactivity [54]. Conversely, CD80 also stimulates T-cells via CD28 [55]. ...
Background:
HIV-2 may slow progression of a subsequently acquired HIV-1 infection through cross-neutralizing antibodies and polyfunctional CD8+ T cells. We hypothesized that HIV-1/2 dually infected patients compared to HIV-1 infected patients had more preserved immune maturation subsets and less immune activation of T and B-cells.
Methods:
ART-naïve patients with HIV-1 (n = 83) or HIV-1/2 dual (n = 27) infection were included in this cross-sectional study at an HIV clinic in Guinea-Bissau. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry according to T-cell maturation and activation, regulatory T cell fraction, and B-cell maturation and activation.
Results:
HIV-1/2 dually infected patients had lower levels of HIV-1 RNA compared with patients with HIV-1 infection, but the levels of total HIV RNA (HIV-1 + HIV-2) were similar in the two patient groups. T-cell maturation, and proportions of regulatory T cells (FoxP3+) were also similar in the two groups. HIV-1/2 dually infected patients had higher proportions of CD4+ and CD8+ T cells positive for the activation marker CD38, but there was no difference in other T-cell activation markers (CD28, CTLA-4, PD-1). HIV-1/2 dually infected patients also had higher proportions of IgM-only B cells and plasmablasts.
Conclusion:
HIV-1/2 was not associated with less immune perturbations than for HIV-1 infection.
... TLR9 substantially suppresses BZLF-1-mRNA expression by histone modifications in acute EBV infection ex vivo and in latently BL cells in vitro, suggesting that immune activation can also promote EBV-driven lymphomagenesis by suppressing the viral lytic cycle (Ladell et al., 2007). Patients who developed PCNSL expressed more CD80 and CD86 in their B cells and responded to TLR9 agonist better than patients without tumors (Audigé et al., 2010). ...
Epstein–Barr virus (EBV) is a ubiquitous human γ-herpes virus which establishes a life-long asymptomatic infection in immunocompetent hosts. In human immunodeficiency virus type 1 (HIV-1) infected patients, the impaired immunosurveillance against EBV may favor the development of EBV-related diseases, ranging from lymphoproliferative disorders to B cell non-Hodgkin’s lymphomas (NHL). Antiretroviral therapy (ART) has significantly modified the natural course of HIV-1 infection, resulting in decreased HIV-1 plasmaviremia, increased CD4 lymphocytes, and decreased opportunistic infections, indicating a restoration of immune functions. However, the impact of ART appears to be less favorable on EBV-related malignancies than on other AIDS-defining tumors, such as Kaposi’s sarcoma, and NHL remains the most common cancer during the ART era. EBV-driven tumors are associated with selective expression of latent oncogenic proteins, but uncontrolled lytic cycle with virus replication and/or reactivation may favor cell transformation, at least in the early phases. Several host’s factors may promote EBV reactivation and replication; besides immunodepression, inflammation/chronic immune stimulation may play an important role. Microbial pathogen-associated molecular patterns and endogenous damage-associated molecular patterns, through Toll-like receptors, activate the immune system and may promote EBV reactivation and/or polyclonal expansion of EBV-infected cells. A body of evidence suggests that chronic immune stimulation is a hallmark of HIV-1 pathogenesis and may persist even in ART-treated patients. This review focuses on lymphomagenesis driven by EBV both in the context of the natural history of HIV-1 infection and in ART-treated patients. Understanding the mechanisms involved in the expansion of EBV-infected cells is a premise for the identification of prognostic markers of EBV-associated malignancies.
... Human B cells like innate cells express TLRs and multiple studies demonstrate that ligation of these TLRs leads to activation and cytokine secretion, including during inflammationassociated diseases. [26][27][28] Nonetheless, few studies have investigated B cell TLR expression and signaling during HIV infection, and previous studies were focused on TLR9 pathways. 29 In this comprehensive study we investigate the B cell expression/responsiveness to TLR2, TLR4, and TLR9. ...
... Conflicting results have been reported regarding the ex vivo responsiveness of innate cells from HIV ART + individuals to in vitro TLR stimulation. [26][27][28] Similarly, contradictory reports have been published regarding the responsiveness of B cells from HIV-infected individuals to TLR9 stimulation. 11,16,17 We investigated the response of B cells from HIV-infected subjects to further TLR stimulation by exposing PBMCs from HIV ART + and HIVsubjects to TLR2, 4, or 9 ligands and evaluated the upregulation of CD40, CD54, and IL-6 expression. ...
The mechanisms underlying B-cell activation that persists during antiretroviral therapy (ART) are unknown. Toll-like receptor (TLR) signaling is a critical mediator of innate cell activation and though B cells express TLRs, few studies have investigated a role for TLR-signaling in B-cell activation during HIV-infection. We addressed this question by assessing the activated phenotype and TLR expression/responsiveness of B cells from ART-treated HIV-infected subjects (HIVART+).We evaluated activation markers implicated in B-cell mediated T-cell trans infection during HIV pathogenesis. We found no significant difference in TLR expression between B cells of HIVART+ and HIV- subjects. However, B cells of HIVART+ subjects exhibited heightened expression of endogenous levels of IL-6 (p=0.0051), T-cell cognate ligands CD40 (p=0.0475), CD54 (p=0.0229), and phosphorylated p38 (p<0.0001), a marker of TLR signaling. In vitro, B cells of HIVART+ individuals were less responsive to TLR stimulation compared to B cells of HIV- subjects. The activated phenotype of in vitro TLR-stimulated B cells of HIV- subjects was similar to ex vivo B cells from HIVART+ individuals. TLR2 stimulation was a potent mediator of B-cell activation, whereas B cells were least responsive to TLR4 stimulation. Compared to HIV- subjects, the serum level of lipoteichoic acid (TLR2-ligand) in HIVART+ subjects was significantly higher (p=0.0207), correlating positively with viral load (p=0.0127, r=0.6453). Our data suggest that, during HIV-infection TLR-activated B cells may exert a pathogenic role and B cells from HIVART+ subjects respond to in vitro TLR stimulation, yet exhibit a TLR tolerant phenotype suggesting prior in vivo TLR stimulation.
Background:
Immunological and virological status of HIV-infected individuals entering the Brazilian public system over time was analyzed. We evaluated the impact of ART on virological, immunological and antiretroviral resistance over time.
Methods:
CD4+ T cell counts, viral loads and genotypes from patients over 13 years old from 2001-2011 were analyzed according to demographic data. We compared groups using parametric t-tests and linear regression analysis in the R statistical software language.
Results:
Mean baseline CD4+ T cell counts varied from 348 (2003) to 389 (2009) and was higher among women (p = 1.1 x 10-8), lower in older patients (p< 1 x 10-8) and lower in less developed regions (p = 1.864 x 10-5). Percentage of treated patients with undetectable viral loads increased linearly from 46% (2001) to 77% (2011), was lower among women (p = 2.851 x 10-6), younger ages (p = 1 x 10-3), and in less developed regions (p = 1.782 x 10-4). NRTI acquired resistance was 86% in 2001-3 and decreased over time. NNRTI resistance increased from 2001-3(50%) to 2006-9 (60%), PI resistance decreased from 2001-3 (60%) to 2009 (40%), and 3-class resistance was stable over time around 25%. Subtype prevalence comprised B (75.3%), B/F recombinants (12.2%), C (5.7%), F (5.3%) and B/C recombinants (1.5%), with regional variations. Three-class resistance was 26.5% among Bs, 22.4% among Fs and 17.2% among Cs.
Conclusions:
HIV diagnosis occurs late, especially among elderly Brazilians. Younger individuals need special attention due to poor virological response to treatment. Antiretroviral Resistance profile is subtype related.
HIV related mutations can be associated with decreased susceptibility to antiretrovirals and treatment failures. There is scarce information about HIV mutations in persons failing HIV treatment in North of Brazil. Our aim was to evaluate evolution of HIV subtypes and mutations patterns related to antiretroviral therapy in this region. We investigated HIV resistance profile in adults failing antiretroviral regimen in Northern Brazil from January, 2004, through December, 2013. Genotype data was evaluated through Stanford University algorithm. There were 377 genotypes from different individuals to evaluate. Resistance mutations were similar to worldwide reports and related to antiretroviral exposure. Most prevalent mutations in the reverse transcriptase gene were M184V (80.1%) and K130N (40.6%). Thymidine associated mutations were more frequent in multiexperienced patients. Most common protease mutations were M46I, V82A, I54V, L90M, I84V, M46L, and L76V. Subtype B was the most prevalent (90.7%). There were differences between subtypes B and non-B mutations. We documented for the first time subtypes and patterns of HIV associated mutations in Northern Brazil. A1 subtype was identified for the first time in this area. Depending on drug regimen and how experienced the patient is, an empirical switch of a failing antiretroviral treatment could be a reasonable option.
Introduction
In Brazil, the use of antiretrovirals is widespread: more than 260,000 individuals are currently undergoing treatment. We conducted a survey targeting antiretroviral-naïve individuals who were initiating antiretroviral therapy (ART) according to local guidelines. This survey covered five Brazilian regions.
Methods
The HIV Threshold Survey methodology (HIV-THS) of the World Health Organization was utilized, and subjects were selected from seven highly populated cities representative of all Brazilian macro-regions. Dried blood spots (DBS) were collected on SS903 collection cards and were transported by regular mail at room temperature to a single central laboratory for genotyping.
Results
We analysed samples from 329 individuals initiating highly active antiretroviral therapy (HAART), 39 (11.8%) of whom were harbouring transmitted drug resistance (TDR). The mean CD4+ T cell count was 253 cells/µL, and the mean viral load was 142,044 copies/mL. The regional prevalence of resistance was 17.0% in the Northeast, 12.8% in the Southeast, 10.6% in the Central region, 8.5% in the North and 8.5% in the South. The inhibitor-specific TDR prevalence was 6.9% for nucleoside reverse transcriptase inhibitors, 4.9% for non-nucleoside reverse transcriptase inhibitors and 3.9% for protease inhibitors; 3.6% of individuals presented resistance to more than one class of inhibitors. Overall, there were trends towards higher prevalences of subtype C towards the South and subtype F towards the North. Of the DBS samples collected, 9.3% failed to provide reliable results.
Discussion
We identified variable TDR prevalence, ranging from intermediate to high levels, among individuals in whom HIV disease progressed, thus implying that resistance testing before initiating ART could be effective in Brazil. Our results also indicate that the use of DBS might be especially valuable for providing access to testing in resource-limited and remote settings.
There are 31 million adults living with HIV-1 non-B subtypes globally, and about 10 million are on antiretroviral therapy (ART). Global evidence to guide clinical practice on ART response in HIV-1 non-B subtypes remains limited. We systematically searched 11 databases for the period 1996 to 2013 for evidence. Outcomes documented included time to development of AIDS and/or death, resistance mutations, opportunistic infections, and changes in CD4 cell counts and viral load. A lack of consistent reporting of all clinical end points precluded a meta-analysis. In sum, genetic diversity that precipitated differences in disease progression in ART-naïve populations was minimized in ART-experienced populations, although variability in resistance mutations persisted across non-B subtypes. To improve the quality of patient care in global settings, recording HIV genotypes at baseline and at virologic failure with targeted non-B subtype-based point-of-care resistance assays and timely phasing out of resistance-inducing ART regimens is recommended.
To evaluate antiretroviral phenotypic susceptibility of wild-type HIV-1 strains circulating in Brazil, samples from antiretroviral-naïve individuals infected with subtypes C (n=16), F (n=9), or B/F (n=7), where reverse transcriptase is B and protease is F, were phenotyped using the AntivirogramTM Assay (Virco, Mechelen, Belgium). Reduced susceptibility to protease inhibitors (PIs) was observed in one C and three F isolates. None of these samples had any known PI resistance mutations. The Phenotypic Fold Change to one PI was above the biologic cut-off in 3 of 96 (3.1%) of clade F phenotypic determinations and 1 of 96 (1.0%) of C. Phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor (NRTI) was found for two B/F, four C, and three F isolates. The Phenotypic Fold Change in susceptibility to NRTIs was above the cut-off value in 9 of 111 (8.1%) of clade C determinations, as compared to 3 of 63 (4.8%) for clade F and 2 of 49 (4.1%) for clade B. The Phenotypic Fold Change to non-NRTI (NNRTI) was above the cut-off in 7 of 32 (21.9%) of C isolates determinations, whereas none of the F isolates had decrease of susceptibility. Only two of the sixteen C samples had a known NNRTI resistance mutation. The NNRTI Fold Change was above the cut-off value in 3 of 14 (21.4%) of phenotypic determination of Brazilian B/F recombinants, representing clade B reverse transcriptase. NNRTI susceptibility should be better investigated in clade C and B/F recombinants.
Objectives:
To assess the virologic and immunological response of darunavir/ritonavir plus optimized background therapy in highly antiretroviral-experienced HIV-infected patients in Brazil.
Methods:
Prospective cohort study carried out in a tertiary center in Sao Paulo, Brazil. Three-class antiretroviral-experienced patients with confirmed virologic failure began darunavir/ritonavir plus optimized background therapy (nucleoside/tide reverse transcriptase inhibitors ± raltegravir ± enfuvirtide ± maraviroc) after performing a genotypic resistance assay. Clinical evaluation and laboratory tests were collected at baseline and at weeks 12, 24, and 48. Multivariate analysis was performed to identify predictors of virologic response at 48 weeks.
Results:
Ninety-two patients were included. The median of darunavir resistant mutation was 1 (range 0-6). The median genotypic sensitivity score in the optimized background therapy was 2 (interquartile range 1-2). At week 48, 83% (95% CI: 75-90%) had an HIV RNA level <50 copies/mL and the median CD4 cell count was 301 (interquartile range 224-445) cells/mm(3). Baseline HIV RNA >100000 copies/mL was inversely associated with virologic success at week 48 (HR: 0.22, 95% CI: 0.06-0.85, p=0.028).
Conclusions:
Darunavir/ritonavir plus optimized background therapy was a highly effective salvage regimen under clinical routine conditions in a referral center in Brazil, which is similar to the reported in high-income countries.
