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C Balotta

Publications and source records attributed to C Balotta.

At least 19 recordsLinked to original sources
PubMed2002

Comparison between HIV- and CMV-specific T cell responses in long-term HIV infected donors.

The mechanisms underlying non-progression in HIV-1 infection are not well understood; however, this state has been associated previously with strong HIV-1-specific CD8+ T cell responses and the preservation of proliferative CD4+ T cell responses to HIV-1 antigens. Using a combination of interferon-gamma (IFN-gamma) ELISpot assays and tetramer staining, the HIV-1-specific CD8+ T cell populations were quantified and characterized in untreated long-term HIV-1-infected non-progressors and individuals with slowly progressive disease, both in relation to CD4+ T cell responses, and in comparison with responses to cytomegalovirus (CMV) antigens. High levels of CD8+ T cell responses specific for HIV-1 or CMV were observed, but neither their frequency nor their phenotype seemed to differ between the two patient groups. Moreover, while CMV-specific CD4+ T cell responses were preserved in these donors, IFN-gamma release by HIV-1-specific CD4+ T cells was generally low. These data raise questions with regard to the role played by CD8+ T cells in the establishment and maintenance of long-term non-progression.

Adult↗
PubMed2001

Secondary mutations in the protease region of human immunodeficiency virus and virologic failure in drug-naive patients treated with protease inhibitor-based therapy.

The role of mutations in protease (PR) and reverse-transcriptase (RT) of human immunodeficiency virus (HIV) in predicting virologic failure was assessed in 248 antiretroviral-naive HIV-positive patients who began a PR inhibitor-containing antiretroviral regimen. Genotypic testing was performed on plasma samples stored before the start of therapy. Twenty-seven patients (10.9%) had mutations in the RT, 5 (2%) carried primary mutations in the PR, and 131 (52.8%) showed only secondary PR mutations. Virologic failure at week 24 occurred in 62 (25.0%) of 248 patients. There was a statistically significant correlation between virologic failure and the number of PR mutations (P= .04, chi(2) test). Mutations at codons 10 and 36 of PR (present in 39.3% and 40.0% of patients in whom treatment failed, respectively) were identified by stepwise logistic regression as the strongest predictors of virologic failure (odds ratio, 2.20; 95% confidence interval, 1.30-3.75; P= .004). If confirmed in independent studies, this result may justify the increased use of HIV genotyping in drug-naive patients requiring antiretroviral therapy.

Acute Disease↗
PubMed2001

Increasing prevalence of non-clade B HIV-1 strains in heterosexual men and women, as monitored by analysis of reverse transcriptase and protease sequences.

OBJECTIVE: We evaluated the prevalence of HIV-1 non-clade B over time in a formerly clade B-restricted area. Protease and reverse transcriptase regions of the pol gene were used for phylogenetic and recombination analysis and for clade assignment to HIV-1 A-D, F-H, J, and K strains of the M group. METHODS: The pol gene of 349 HIV-1 patients belonging to the Italian Cohort Naive for Antiretrovirals (ICONA) were genotypically analyzed to study the prevalence of antiretroviral-associated resistance mutations. All HIV-1 pol sequences and 32 HIV reference strains were analyzed, including the reference strains for the major HIV-1 subtypes. The non-clade B sequences according to the HIV-1 Subtyping Tool program were further studied by a bootscan analysis (SimPlot) to investigate the likelihood of recombination between subtypes. RESULTS: Phylogenetic analysis detected 19 of 349 (5.4%) non-clade B subtypes. The proportions of patients carrying non-clade B virus before and after 1997 were 1.9% and 8.4%, respectively (p =.008). Among whites, heterosexual infection and female gender were significantly associated with the presence of non-clade B subtypes (p =.001 and.005, respectively). Non-clade B HIV-1 was harbored by 14.5% of the heterosexuals who were found to be HIV-1 positive after 1997, 60% of whom were women. Bootscan analysis identified four strains as F, two as A, one as C, one as G, and 11 (57.9 %) as non-clade B recombinant subtypes. CONCLUSION: Detection of HIV-1 subtypes and intersubtype recombinants in a previously clade B-homogeneous area indicates that the HIV-1 epidemic is evolving in Italy and that heterosexuals and women are at increased risk of infection with non-clade B HIV-1 subtypes. Sequences inferred from the pol gene yield to establish the subtype of circulating HIV-1 strains. As a consequence, genotyping of pol gene for testing resistance to antiretrovirals warrants concomitant surveillance of non-clade B subtypes.

Adult↗
PubMed2001

Decreased function of Fas in patients displaying delayed progression of HIV-induced immune deficiency.

INTRODUCTION: In acquired immune deficiency syndrome patients, apoptosis of uninfected lymphocytes may contribute to development of immune deficiency. This process may involve recruitment of Fas by human immunodeficiency virus products. In line with this possibility, the viral envelope glycoprotein gp120 does not induce death of T cells from subjects with the autoimmune/lymphoproliferative syndrome displaying defective Fas function. This study evaluates the possibility that Fas function defects delay progression of HIV-induced immune deficiency. MATERIALS AND METHODS: The susceptibility to Fas-induced cell death was assessed on T cells from 18 'long-term non-progressor', four 'non-progressor', four 'progressor' asymptomatic HIV-1-infected, and nine AIDS patients using anti-Fas monoclonal antibodies. RESULTS: Fas-induced cell death was significantly lower in long-term non-progressors and non-progressors than in normal controls, progressors, and AIDS. The single-patient data showed that 9/18 long-term non-progressors and 3/4 non-progressors, but no progressors or AIDS were resistant to Fas. Analysis of the uninfected parents of two long-term non-progressors displaying decreased Fas-function showed that the mother of one of them and the father of the other displayed the same Fas function defect as their children. Fusion of T cells from Fas-resistant individuals with a Fas-sensitive cell line gave rise to Fas-resistant hybrid lines not carrying HIV, which suggests that the resistant phenotype is due to molecules exerting a dominant negative effect on a normal Fas system. CONCLUSION: These data suggest that Fas-resistance in long-term non-progressors may be due to inherited alterations of the Fas signaling pathway and may be a novel factor in delayed progression.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Prevalence of multiple dideoxynucleoside analogue resistance (MddNR) in a multicenter cohort of HIV-1-infected Italian patients with virologic failure.

We evaluated the prevalence of both Q151M and 6-bp insert at position 69 of RT region responsible for multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 variants in 177 patients who failed to respond to combination therapy. Patients had received protease inhibitors (PI) and/or nonnucleoside reverse transcriptase inhibitors (NNRTIs) after a long-term experience with nucleoside reverse transcriptase inhibitors (NRTIs) (including zidovudine monotherapy). Two of 177 patients (1.1%) showed the specific complex of Q151M mutation, while 4 (2.3%) had the 69 6-bp insert. Mutations that belong to the 151 set in the absence of the pivotal Q151M substitution were detected in as many as 3.9% of the patients. One patient exhibited a 69S [VG] insert that has not been previously phenotypically characterized. This HIV-1 isolate had high levels of resistance to all NRTIs except stavudine. MddNR is an emerging problem after sequential therapy with this class of compounds among HIV-1-infected patients. Either didanosine (ddI) or zidovudine (ZDV) monotherapy allowed the emergence of MddNR variants containing Q151M complex. Monotherapy with ZDV and ddI or subsequent treatments with various NRTI combinations were the common background in the patients with the 69 insert. The overall prevalence of MddNR (3.4%) in Italy is comparable with that observed in several other European countries (3.4%-6.5%). These data suggest that patients failed by NRTI regimens should be analyzed for the presence of both patterns of MddNR.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Quantitative evaluation of the recombinant HIV-1 phenotype to protease inhibitors by a single-step strategy.

OBJECTIVE: To develop and optimize a fast and quantitative recombinant strategy for evaluating the HIV-1 phenotype to protease inhibitors (PI). DESIGN AND METHODS: A non-replicative HIV-1 molecular vector (designated pdelta prodelta env) capable of expressing exogenous HIV-1 protease-encoding sequences was developed in this study. The HIV-1 protease sequences were amplified from either viral isolates or plasma samples (both from 21 HIV-1-infected individuals, 19 of whom were failing different anti-HIV-1 combination treatments) and cloned in the pdelta prodelta env backbone. The HIV-1 recombinant phenotype to PI was determined directly after transfection of viral chimeric clones by measuring protease activity and calculating a percentage sensitivity index (SI%; the ratio between the results from each clone and those from a PI-sensitive reference strain). RESULTS: The SI% values obtained from the recombinant clones paralleled the IC50 results of the viral isolates and documented different degrees of resistance and cross-resistance to PI, compatible, with few exceptions, with the respective genotype. Interestingly, an inverse correlation between SI% values and the presence of primary mutations for resistance to PI (P = 0.0038 and P = 0.0414, for indinavir and ritonavir, respectively) and a difference in SI% between samples harbouring an increasing number of mutations (indinavir, P = 0.022; ritonavir, P = 0.0466) were observed. CONCLUSION: The data substantiate the reliability of the novel strategy for a fast (5 day) quantitative evaluation of HIV-1 phenotype to PI, and indicate that this method may contribute to the understanding of mechanisms of virus resistance to PI.

Chimera↗
PubMed2000

Neurological symptoms during primary human immunodeficiency virus (HIV) infection correlate with high levels of HIV RNA in cerebrospinal fluid.

This analysis involves 22 patients with diagnosed symptomatic human immunodeficiency virus (HIV) infection. Neurologic symptoms were present in 11 patients, ranging from severe and persistent headache to clinical signs suggestive of meningitis. A strong correlation between neurological symptoms and cerebrospinal fluid (CSF) viral load was found. The mean CSF HIV ribonucleic acid (RNA) level was 4. 12 log for patients with neurological symptoms and 2.58 log for patients without neurological symptoms (P<.00001). Plasma viral load alone does not correlate or predict central nervous system (CNS) involvement. In our sample of patients, HIV RNA levels could be detected in most patients regardless of the presence of neurological symptoms. Moreover, early treatment including drugs with high levels of penetration in the CNS must be considered for patients with primary HIV infection.

Central Nervous System Viral Diseases↗
PubMed2000

Susceptibility to PNU-140690 (Tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors.

In our study we examined the anti-human immunodeficiency virus type 1 (anti-HIV-1) activity of a novel HIV-1 protease inhibitor, PNU-140690 (tipranavir), against patient-derived isolates resistant to multiple other protease inhibitors (PIs). The aim of our experiments was to investigate the genotypes and the in vitro phenotypes of drug resistance of PNU-140690. We carried out drug susceptibility tests with peripheral blood mononuclear cells and a fixed amount of infectious virus (1,000 50% tissue culture infective doses) to determine the 50% inhibitory concentration (IC(50)) and IC(90), PCR assays for the detection of drug resistance mutations in RNA in plasma, and direct sequencing of PCR products. Phenotypic resistance to PIs was invariably related to genotypic mutations. The substitutions among the amino acid residues of the protease included L10I, K20R, L24I, M36I, N37D, G48V, I54V, L63P, I64V, A71V, V77I, V82A, I84V, and L90M. Isolates from all of the patients had developed a maximal degree of resistance to indinavir, ritonavir, and nelfinavir (IC(50)s, >0.1 microM). We also compared these mutations with the amino acid changes previously described in association with in vivo tipranavir administration. The mutations included the following: I15V, E35D, N37D, R41K, D60E, and A71T. Infections with IIIB, 14aPre, and N70 were inhibited by an average drug IC(90) of 0.18 +/- 0.02 microM in multiple experiments. The average mean +/- standard error of mean IC(90) for the entire group of multidrug-resistant isolates derived from the mean values for two culture wells with p24 antigen supernatant appeared to be 0.619 +/- 0.055 microM (range, 0.31 to 0.86 microM). Tipranavir retained a sustained antiviral activity against PI-MDR clinical isolates and might be useful in combination regimens with other antiretroviral agents for patients who have already failed other PI-containing therapies.

Anti-HIV Agents↗
PubMed2000

Prevalence of transmitted nucleoside analogue-resistant HIV-1 strains and pre-existing mutations in pol reverse transcriptase and protease region: outcome after treatment in recently infected individuals.

We retrospectively studied 38 Italian recently HIV-1-infected subjects who seroconverted from 1994 to 1997 to investigate: (i) the prevalence of nucleoside reverse transcriptase inhibitors (NRTI)-related mutations at primary infection; (ii) the proportion of naturally occurring mutations in reverse transcriptase (RT) and protease regions of patients naive for non-nucleoside RT inhibitors (NNRTIs) and protease inhibitors (PIs); (iii) the drug-susceptibility to NRTIs and PIs in subjects with NRTI- and/or PI-related mutations; and (iv) the outcome of seroconverters treated with various NRTIs or NRTI/PI regimens. Baseline HIV-1 plasma viraemia and absolute CD4 count at baseline could not be used to distinguish patients with NRTI- and/or PI-related pre-existing mutations from those with wild-type virus (P = 0.693 and P = 0.542, respectively). The frequency of zidovudine-related mutations was 21% in the study period. The response to treatment was not significantly different in subjects with or without genotypic zidovudine-related mutations at primary infection (P = 0.744 for HIV-1 RNA and P = 0.102 for CD4 cells). Some natural variation (2.6%) was present within regions 98-108 and 179-190 of RT involved in NNRTI resistance. The high natural polymorphism in the protease region present in our patients was similar to that reported by others. In our study some PI-associated substitutions, thought to be compensatory in protease enzymatic function, could confer intermediate to high PI-resistance. As discrepancies between genotypic and phenotypic results may exist in recent seroconverters, our data suggest that the role of transmitted NRTI- and PI-resistant variants remain to be fully elucidated in vivo.

Anti-HIV Agents↗
PubMed2000

Persisting HIV-1 replication triggered by acute hepatitis A virus infection.

We report the case of two patients in whom acute hepatitis A was associated with a marked and prolonged increase in human immunodeficiency virus type 1 (HIV-1) viral load. Although in one patient the rise in HIV-1 RNA might also have been related to the interruption of antiretroviral therapy, we also observed a similar pattern in the other patient who had a stable undetectable plasma viraemia prior to acute hepatitis and never received treatment with anti-retrovirals. Our observation supports the hypothesis that immune activation that is induced by acute hepatitis A virus (HAV) infection may trigger HIV-1 replication. This highlights the importance of maintaining antiretroviral therapy throughout the acute phase of hepatitis A and of preventing HAV infection through active immunization.

Adult↗
PubMed1999

Identification of two distinct subsets of long-term nonprogressors with divergent viral activity by stromal-derived factor 1 chemokine gene polymorphism analysis.

Stromal-derived factor (SDF)-1, the natural ligand for CXCR4, is present in a common polymorphic variant defined by a G-->A transition in the 3' untranslated region of the gene. In persons infected with human immunodeficiency virus type 1 (HIV-1), the homozygous genotype (SDF1-3'A/3'A) has been postulated to interfere with the appearance of T-tropic syncytium-inducing strains. The polymorphism of SDF1 was correlated with HIV-1 phenotype, plasma viremia, and unspliced and multiply spliced specific transcripts in 158 virologically characterized HIV-1-infected patients (39 recent seroconverters, 75 typical progressors, and 44 AIDS patients) and in 42 HIV-1-infected long-term nonprogressors (LTNPs). Analysis of SDF1 allele distribution revealed that SDF1-3'A/3'A status is associated with low CD4 cell count (P=.0449) but not with a specific HIV-1 phenotype. In LTNPs, SDF1-+/+ condition defined a subset of persons with lower HIV-1 replication than in heterozygous subjects. The low viral activity in SDF1-+/+ LTNPs suggests that other factors play a major role in vivo in determining the course of HIV-1 infection.

Adult↗
PubMed1998

Clinical outcome and predictive factors of failure of highly active antiretroviral therapy in antiretroviral-experienced patients in advanced stages of HIV-1 infection.

OBJECTIVE: To verify the effectiveness of highly active antiretroviral therapy (HAART) and to identify any factors predictive of clinical outcome in a clinical setting. DESIGN: Observational study. METHODS: Treatment failure (i.e., the occurrence of new or recurrent AIDS-defining events, death or any definitive discontinuation) and the course of CD4+ cell counts and HIV RNA copies were evaluated in 250 heavily pretreated HIV-infected patients starting HAART [153 with indinavir (IDV), 55 with ritonavir (RTV), 43 with saquinavir (SQV)]. Univariate and multivariate analyses were performed to identify predictors of worse outcome. RESULTS: During a median follow-up of 8 months, 75 patients (30%) had treatment failure because of the occurrence of an AIDS-defining event or death (n = 24), inefficacy (n = 24), or severe intolerance (n = 27). Twenty new and six recurrent AIDS-defining events, and nine deaths occurred (six out of 20 AIDS-defining events and two out of nine deaths within 1 month of treatment). CD4+ counts were above 200 x 10(6)/l at AIDS diagnosis in only two patients. None of the SQV patients, 12 (7.8%) of the IDV patients, and 15 (27.3%) of the RTV-treated patients were considered non-compliant. The SQV-containing regimens independently correlated with treatment failure (relative risk, 2.46; 95% confidence interval, 1.20-5.03; versus IDV). Low compliance partially determined outcome in RTV-treated patients; both severe immunodepression and AIDS at baseline were predictive of treatment failure. There was a 10-fold increase in CD4+ cell counts in the patients treated with IDV and RTV; the best virological outcome occurred in IDV-treated patients, with 68.4% of patients showing undetectable HIV RNA copies after 6 months. CONCLUSIONS: HAART was effective in 70% of patients; low compliance and previous AIDS diagnosis represented predictive factors of therapy failure.

Adult↗
PubMed1998

Low CD4 counts rather than superantigenic-like effects account for differences in expressed T-cell receptor (TCR) repertoires between HIV-1 seropositive long-term non-progressors and individuals with progressive disease.

Analysis of HIV-infected individuals who have stable CD4 counts many years after seroconversion may provide an insight as to how the host's immune system can successfully control HIV infection. In this study we analysed the T-cell receptor (TCR) Vbeta repertoire in 13 HIV+ individuals, seven of whom were classed as long-term non-progressors (LTNP), using a technique which couples anchor PCR (AnPCR) amplification of beta-chain cDNA to differential probe hybridization with non-radioactively labelled Vbeta family specific oligonucleotide probes. There were no significant differences in the expressed TCR repertoires between the LTNP group and the other HIV-infected individuals. However, there was a statistically significant inverse correlation between CD4 count and the number of Vbeta family-specific perturbations in the recent seroconverters (SC) and those with progressive infection (PI), consistent with other shared features of clinical disease progression (Th1/Th2 switch and high frequency of viral isolation). We conclude that long-term clinical non-progression in HIV-1 infection is not associated with the loss or expansion of a particular Vbeta family; instead, low CD4 count in the PI and SC individuals was correlated with increased number of Vbeta family-specific perturbations relative to the LTNP group and that it is hence unlikely that HIV encodes a superantigen.

Adult↗