Showing papers by "Esper G. Kallas published in 2011"

Differential Persistence of Transmitted HIV-1 Drug Resistance Mutation Classes

Abstract: Although the epidemiology of transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations has been studied in a variety of settings [1–5], less is known about whether transmitted mutations persist without selection pressure from antiretroviral therapy (ART). Because many drug resistance mutations impair HIV fitness [6–10], replacement of TDR mutations with wild-type variants may confer a potential survival advantage. This is particularly true when resistant and wild-type viral populations co-exist, as typically occurs when resistance develops during treatment. However, when HIV is transmitted by a single drug-resistant virion, the emergence of wild-type variants requires evolution and back-mutation rather than emergence of an existing wild-type variant. Several studies have reported long-term persistence of most TDR mutations but have also documented replacement of certain mutations with wild-type variants [11–16]. Although valuable, these investigations did not have sufficient person-years of follow-up to quantify and compare replacement rates for each therapeutic drug class. Improved understanding of how quickly different mutation classes are replaced by wild-type variants is important for several reasons. First, most HIV diagnoses occur during chronic infection, rather than during acute and/or early infection. By the time genotyping is performed, TDR mutations may have waned below the detection threshold for population genotyping, but persist as minority variants. Therefore, knowledge about mutation replacement rates for each drug class could help clinicians interpret resistance tests performed during chronic infection. Second, the degree to which drug resistance will propagate among recently infected individuals depends on several factors including (1) the prevalence of drug resistance among chronically infected persons who are receiving partially suppressive therapy and (2) how long TDR persists in untreated persons and, thus, can propagate even without drug selection. The importance of propagation of transmitted mutations becomes amplified in resource-limited settings. Without genotyping and viral load monitoring, patients may initiate incompletely suppressive treatment regimens and sustain prolonged exposure to them. This leads to additional selection of drug resistance mutations [17, 18], further increasing the risk of resistance propagation and limiting patients’ second-line treatment options. Third, the interpretation of population-based surveys of TDR prevalence depends on understanding how long mutations persist after they are transmitted, because surveys will underestimate mutations that are quickly replaced by wild-type variants. To provide more detailed information about persistence of specific mutations, we analyzed participants in 2 large early infection cohorts with sustained periods of follow-up without treatment.

Characterization of Partial and Near Full-Length Genomes of HIV-1 Strains Sampled from Recently Infected Individuals in São Paulo, Brazil

Abstract: Background Genetic variability is a major feature of human immunodeficiency virus type 1 (HIV-1) and is considered the key factor frustrating efforts to halt the HIV epidemic. A proper understanding of HIV-1 genomic diversity is a fundamental prerequisite for proper epidemiology, genetic diagnosis, and successful drugs and vaccines design. Here, we report on the partial and near full-length genomic (NFLG) variability of HIV-1 isolates from a well-characterized cohort of recently infected patients in Sao Paul, Brazil. Methodology HIV-1 proviral DNA was extracted from the peripheral blood mononuclear cells of 113 participants. The NFLG and partial fragments were determined by overlapping nested PCR and direct sequencing. The data were phylogenetically analyzed. Results Of the 113 samples (90.3% male; median age 31 years; 79.6% homosexual men) studied, 77 (68.1%) NFLGs and 32 (29.3%) partial fragments were successfully subtyped. Of the successfully subtyped sequences, 88 (80.7%) were subtype B sequences, 12 (11%) BF1 recombinants, 3 (2.8%) subtype C sequences, 2 (1.8%) BC recombinants and subclade F1 each, 1 (0.9%) CRF02 AG, and 1 (0.9%) CRF31 BC. Primary drug resistance mutations were observed in 14/101 (13.9%) of samples, with 5.9% being resistant to protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTI) and 4.9% resistant to non-NRTIs. Predictions of viral tropism were determined for 86 individuals. X4 or X4 dual or mixed-tropic viruses (X4/DM) were seen in 26 (30.2%) of subjects. The proportion of X4 viruses in homosexuals was detected in 19/69 (27.5%). Conclusions Our results confirm the existence of various HIV-1 subtypes circulating in Sao Paulo, and indicate that subtype B account for the majority of infections. Antiretroviral (ARV) drug resistance is relatively common among recently infected patients. The proportion of X4 viruses in homosexuals was significantly higher than the proportion seen in other study populations.

Systemic lupus erythematosus exhibits a dynamic and continuum spectrum of effector/regulatory T cells.

Abstract: Objective: The identification of regulatory T cells (Treg cells) as CD4+CD25high cells may be upset by the increased frequency of activated effector T cells (Teff cells) in inflammatory diseases such as systemic lupus erythematosus (SLE). This study aimed to evaluate the frequency of T-cell subsets according to the expression of CD25 and CD127 in active (A-SLE) and inactive SLE (I-SLE).Methods: Peripheral blood mononuclear cells (PBMCs) from 26 A-SLE patients (SLE Disease Activity Index (SLEDAI) = 10.17 ± 3.7), 31 I-SLE patients (SLEDAI = 0), and 26 healthy controls (HC) were analysed by multicolour flow cytometry.Results: CD25high cell frequency was increased in A-SLE (5.2 ± 5.7%) compared to I-SLE (3.4 ± 3.4%) and HC (1.73 ± 0.8%) (p < 0.01). However, the percentage of FoxP3+ cells in the CD25high subset was decreased in A-SLE (24.6 ± 16.4%) compared to I-SLE (33.7 ± 16) and HC (45 ± 25.1%) (p < 0.01). This was partly due to the increased frequency of Teff cells (CD25highCD127+FoxP3O) in A-SLE (10.7 ± 7...

Prevalence, Incidence Density, and Genotype Distribution of GB Virus C Infection in a Cohort of Recently HIV-1-Infected Subjects in Sao Paulo, Brazil

Abstract: Background The results of previous studies elsewhere have indicated that GB virus C (GBV-C) infection is frequent in patients infected with the human immunodeficiency virus type 1 (HIV-1) due to similar transmission routes of both viruses. The aim of this study was to determine the prevalence, incidence density and genotypic characteristics of GBV-C in this population. Methodology/Principal Findings The study population included 233 patients from a cohort primarily comprised of homosexual men recently infected with HIV-1 in Sao Paulo, Brazil. The presence of GBV-C RNA was determined in plasma samples by reverse transcriptase-nested polymerase chain reaction and quantified by real-time PCR. GBV-C genotypes were determined by direct sequencing. HIV viral load, CD4+ T lymphocyte and CD8+ T lymphocyte count were also tested in all patients. The overall prevalence of GBV-C infection was 0.23 (95% CI: 0.18 to 0.29) in the study group. There was no significant difference between patients with and without GBV-C infection and Glycoprotein E2 antibody presence regarding age, sex, HIV-1 viral load, CD4+ and CD8+T cell counts and treatment with antiretroviral drugs. An inverse correlation was observed between GBV-C and HIV-1 loads at enrollment and after one year. Also, a positive but not significant correlation was observed between GBV-C load and CD4+ T lymphocyte. Phylogenetic analysis of the GBV-C isolates revealed the presence of genotype 1 and genotype 2, these sub classified into subtype 2a and 2b. Conclusion/Significance GBV-C infection is common in recently HIV -1 infected patients in Sao Paulo, Brazil and the predominant genotype is 2b. This study provides the first report of the GBV-C prevalence at the time of diagnosis of HIV-1 and the incidence density of GBV-C infection in one year.

HTLV-1 tax specific CD8+ T cells express low levels of Tim-3 in HTLV-1 infection: implications for progression to neurological complications.

Abstract: The T cell immunoglobulin mucin 3 (Tim-3) receptor is highly expressed on HIV-1-specific T cells, rendering them partially “exhausted” and unable to contribute to the effective immune mediated control of viral replication. To elucidate novel mechanisms contributing to the HTLV-1 neurological complex and its classic neurological presentation called HAM/TSP (HTLV-1 associated myelopathy/tropical spastic paraparesis), we investigated the expression of the Tim-3 receptor on CD8+ T cells from a cohort of HTLV-1 seropositive asymptomatic and symptomatic patients. Patients diagnosed with HAM/TSP down-regulated Tim-3 expression on both CD8+ and CD4+ T cells compared to asymptomatic patients and HTLV-1 seronegative controls. HTLV-1 Tax-specific, HLA-A*02 restricted CD8+ T cells among HAM/TSP individuals expressed markedly lower levels of Tim-3. We observed Tax expressing cells in both Tim-3+ and Tim-3− fractions. Taken together, these data indicate that there is a systematic downregulation of Tim-3 levels on T cells in HTLV-1 infection, sustaining a profoundly highly active population of potentially pathogenic T cells that may allow for the development of HTLV-1 complications.

HTLV-1 Tax Specific CD8+ T cells express low levels of Tim-3 in HTLV-1 infection: implications for progression to neurological complications

Abstract: The T cell immunoglobulin mucin 3 (Tim-3) receptor is highly expressed on HIV-1-specific T cells, rendering them partially ‘‘exhausted’’ and unable to contribute to the effective immune mediated control of viral replication. To elucidate novel mechanisms contributing to the HTLV-1 neurological complex and its classic neurological presentation called HAM/TSP (HTLV-1 associated myelopathy/tropical spastic paraparesis), we investigated the expression of the Tim-3 receptor on CD8 T cells from a cohort of HTLV-1 seropositive asymptomatic and symptomatic patients. Patients diagnosed with HAM/TSP down-regulated Tim-3 expression on both CD8 and CD4 T cells compared to asymptomatic patients and HTLV-1 seronegative controls. HTLV-1 Tax-specific, HLA-A*02 restricted CD8 T cells among HAM/TSP individuals expressed markedly lower levels of Tim-3. We observed Tax expressing cells in both Tim-3 and Tim-3 fractions. Taken together, these data indicate that there is a systematic downregulation of Tim-3 levels on T cells in HTLV-1 infection, sustaining a profoundly highly active population of potentially pathogenic T cells that may allow for the development of HTLV-1 complications. Citation: Ndhlovu LC, Leal FE, Hasenkrug AM, Jha AR, Carvalho KI, et al. (2011) HTLV-1 Tax Specific CD8+ T Cells Express Low Levels of Tim-3 in HTLV-1 Infection: Implications for Progression to Neurological Complications. PLoS Negl Trop Dis 5(4): e1030. doi:10.1371/journal.pntd.0001030 Editor: Sunit Kumar Singh, Centre for Cellular and Molecular Biology (CCMB), India Received October 19, 2010; Accepted February 27, 2011; Published April 26, 2011 Copyright: 2011 Ndhlovu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Support for this work was provided by funds from the National Institutes of Health (NIH), University of California, San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research (P30 AI027763). Additional support was provided by the Brazilian Program for STD and AIDS, Ministry of Health (914/BRA/3014 UNESCO/Kallas), the São Paulo City Health Department (2004-0.168.922-7/Kallas), Fundação de Amparo a Pesquisa do Estado de São Paulo (04/ 15856-9/Kallas and 2010/05845-0/Kallas and Nixon), the John E. Fogarty International Center (D43 TW00003). The project described was also supported by Award Number R56AI083112 from the National Institute of Allergy and Infectious Diseases (LCN). Additional support was provided by the Montana State Complex Biological Systems Research Scholars Program, funded by the Howard Hughes Medical Institute to AH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: L.C. Ndhlovu, R. Brad Jones, M.A. Ostrowski and D.F. Nixon are named as inventors on a patent application related to modulation of Tim-3 in viral infections. * E-mail: lndhlovu@medsfgh.ucsf.edu; lndhlovu@hawaii.edu . These authors contributed equally to this work. \" These authors also contributed equally to this work.

Pandemic influenza A H1N1/09 virus infection in hematopoietic SCT recipient.

Abstract: In April 2009, the first cases of the novel influenza A H1N1 virus infection were reported in Mexico.1 As of 27 October 2009, the novel influenza H1N1 virus had caused at least 5642 deaths reported worldwide.1 The pandemic influenza H1N1/09 virus infection was considered widespread in Brazil on 16 July 2009 and after 2 months, there were 9249 confirmed cases, including 699 deaths.2