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Francesco Mazzotta

Publications and source records attributed to Francesco Mazzotta.

At least 19 recordsLinked to original sources
PubMed2007

IL-22 participates in an innate anti-HIV-1 host-resistance network through acute-phase protein induction.

Certain individuals are resistant to HIV-1 infection, despite repeated exposure to the virus. Although protection against HIV-1 infection in a small proportion of Caucasian individuals is associated with mutant alleles of the CCR5 HIV-1 coreceptor, the molecular mechanism underlying resistance in repeatedly HIV-1-exposed, uninfected individuals (EU) is unclear. In this study, we performed complementary transcriptome and proteome analyses on peripheral blood T cells, and plasma or serum from EU, their HIV-1-infected sexual partners, and healthy controls, all expressing wild-type CCR5. We report that activated T cells from EU overproduce several proteins involved in the innate immunity response, principally those including high levels of peroxiredoxin II, a NK-enhancing factor possessing strong anti-HIV activity, and IL-22, a cytokine involved in the production of acute-phase proteins such as the acute-phase serum amyloid A (A-SAA). Cell supernatants and serum levels of these proteins were up-regulated in EU. Moreover, a specific biomarker for EU detected in plasma was identified as an 8.6-kDa A-SAA cleavage product. Incubation of in vitro-generated myeloid immature dendritic cells with A-SAA resulted in CCR5 phosphorylation, down-regulation of CCR5 expression, and strongly decreased susceptibility of these cells to in vitro infection with a primary HIV-1 isolate. Taken together, these results suggest new correlates of EU protection and identify a cascade involving IL-22 and the acute phase protein pathway that is associated with innate host resistance to HIV infection.

Acute-Phase Proteins↗
PubMed2006

Specific mutations in HIV-1 gp41 are associated with immunological success in HIV-1-infected patients receiving enfuvirtide treatment.

OBJECTIVES: To investigate gp41 variability and correlation with viro-immunological parameters in 54 HIV-1-infected patients receiving enfuvirtide added as single active drug to a failing regimen. METHODS: One hundred and two HIV-1 gp41 sequences and clinical follow-up from 54 enfuvirtide-treated patients were analysed from baseline to week 36 of treatment. The association of mutations with viraemia/CD4 count was assessed by Mann-Whitney test. RESULTS: The addition of enfuvirtide to the failing regimen induced at week 4 a viraemia decrease from 5.1 to 4.3 log(10)/mL (P = 0.0002) and a CD4 increase from 48 to 106 cells/mm(3) (P = 0.008). While viraemia rebounded to 4.8 and 4.6 log(10)/mL at week 12 and 36, respectively, CD4 continued to increase to 136 cells/mm(3) at week 36. Enfuvirtide resistance mutations, rarely found at baseline, occurred in 45/54 (83.3%) enfuvirtide-treated patients. V38A/E were the most represented mutations at all time-points. The presence of V38A/E was significantly associated with a 4.5-fold CD4 increase from baseline to week 24 and with a 6-fold increase at week 36 (P = 0.004 and 0.02 compared without V38A/E, respectively), without significant correlation with viraemia. In contrast, Q40H + L45M (present in six enfuvirtide-treated patients at week 36) correlated with CD4 loss from baseline to week 36 (P = 0.02), without significant correlation with viraemia. Mutation N126K (observed in six enfuvirtide-treated patients, never found at baseline) abrogates the fourth gp41 glycosylation site and correlates with a 2.1-fold CD4 increase at week 24. CONCLUSIONS: Specific enfuvirtide resistance mutations (V38A/E) are associated with a sustained CD4 increase, without remarkable effects upon viraemia. This CD4 recovery, due to virus- and immune-mediated mechanisms most probably not applicable to protease/reverse transcriptase inhibitors, is important for innovative therapeutic strategies.

Adult↗
PubMed2005

Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER Cohort.

BACKGROUND: The risk of hepatotoxicity associated with different highly active antiretroviral therapy (HAART) regimens (containing multiple-protease inhibitors, single-protease inhibitors or non nucleoside reverse transcriptase inhibitors) in HIV-HCV co-infected patients has not been fully assessed. METHODS: Retrospective analysis of a prospective cohort of 1,038 HIV-HCV co-infected patients who commenced a new HAART in the Italian MASTER database. Patients were stratified into naïve and experienced to antiretroviral therapy before starting the study regimens. Time to grade > or =III hepatotoxicity (as by ACTG classification) was the primary outcome. Secondary outcome was time to grade IV hepatotoxicity. RESULTS: Incidence of grade > or =III hepatotoxicity was 17.71 per 100 patient-years (p-yr) of follow up in naïve patient group and 8.22 per 100 p-yrs in experienced group (grade IV: 4.13 per 100 p-yrs and 1.08 per 100 p-yrs, respectively). In the latter group, the only independent factors associated with shorter time to the event at proportional hazards regression model were: previous liver transaminase elevations to grade > or =III, higher baseline alanine amino-transferase values, and use of a non nucleoside reverse transcriptase inhibitor based regimen. In the naive group, baseline aspartate transaminase level was associated with the primary outcome. CONCLUSION: Use of a single or multiple protease inhibitor based regimen was not associated with risk of hepatotoxicity in either naïve or experienced patient groups to a statistically significant extent. A cautious approach with strict monitoring should be applied in HIV-HCV co-infected experienced patients with previous liver transaminase elevations, higher baseline alanine amino-transferase values and who receive regimens containing non nucleoside reverse transcriptase inhibitors.

Adult↗
PubMed2005

Genotypes at chromosome 22q12-13 are associated with HIV-1-exposed but uninfected status in Italians.

OBJECTIVE: Despite multiple and repeated exposures to HIV-1, some individuals possess no detectable HIV genome and show T-cell memory responses to the viral antigens. HIV-1-reactive mucosal IgA detected in such uninfected individuals suggests their possible immune resistance against HIV. We tested if the above HIV-1-exposed but uninfected status was associated with genetic markers other than a homozygous deletion of the CCR5 gene. METHODS: Based on our mapping in chromosome 15 of a gene controlling the production of neutralizing antibodies in a mouse retrovirus infection, we genotyped 42 HIV-1-exposed but uninfected Italians at polymorphic loci in the syntenic segment of human chromosome 22, and compared them with 49 HIV-1-infected and 47 uninfected healthy control individuals by a closed testing procedure. RESULTS: A significant association was found between chromosome 22q12-13 genotypes and a putative dominant locus conferring anti-HIV-1 immune responses in the exposed but uninfected individuals. Distributions of linkage disequilibrium across chromosome 22 also differed between the exposed but uninfected and two other phenotypic groups. CONCLUSIONS: The data indicated the presence of a new genetic factor associated with the HIV-1-exposed but uninfected status.

Animals↗
PubMed2005

A randomized controlled trial to evaluate antiretroviral salvage therapy guided by rules-based or phenotype-driven HIV-1 genotypic drug-resistance interpretation with or without concentration-controlled intervention: the Resistance and Dosage Adapted Regimens (RADAR) study.

BACKGROUND: It is not well defined whether concentration-controlled intervention (CCI) and rules-based human immunodeficiency virus (HIV) type 1 genotype drug-resistance interpretation (GI) or virtual phenotype drug-resistance interpretation (VPI) may improve the outcome of HIV salvage therapy. METHODS: In a prospective, randomized, controlled trial, patients were randomized (on a factorial basis) to change treatment after either GI or VPI, and they then were further randomized to the control arm (no CCI) or the CCI arm. Protease inhibitor (PI) and nonnucleoside reverse-transcriptase inhibitor (NNRTI) trough concentration (Ctrough) values were determined at weeks 1, 4, 12, and 24 of the study. RESULTS: Among 230 patients, virological benefit (defined by an HIV RNA load of <400 copies/mL at week 24) was not statistically different, either between patients in the GI and VPI arms or between patients in the CCI and control arms. A virological benefit was found for patients in the CCI arm, compared with patients in the control arm, but this benefit was not statistically significant (56.8% vs. 64.3% at week 4 and 63.6% vs. 74% at week 12). Dosage adaptation was possible for only a fraction of patients, because of low rates of treatment adherence or patient refusal to increase dosages. In the logistic regression analysis, independent predictors of virological response at week 24 were a PI Ctrough value and/or an NNRTI Ctrough value in the higher quartiles (or above cutoff levels) and a low number of PIs previously received. Moreover, receipt of a regimen that contained PIs boosted with ritonavir was an independent predictor of virological response. CONCLUSIONS: The present study did not support the routine use of CCI for patients undergoing salvage treatment, probably as a result of existing difficulties associated with its clinical application. However, a higher Ctrough value appeared to be correlated with treatment response. No major differences were found between VPI or GI when they are used together with expert advice for the selection of salvage treatment combinations.

Adult↗
PubMed2005

Distinct patterns of HIV-specific memory T lymphocytes in HIV-exposed uninfected individuals and in HIV-infected patients.

BACKGROUND: Repeated exposure to HIV is not always associated with infection and multiple cohorts of HIV-exposed but seronegative individuals (ESN) have been described. HIV-specific CD4 and CD8 T lymphocytes are detected both in HIV patients and in ESN; we verified whether different patterns of HIV-specific memory T lymphocytes would be detected in individuals in whom exposure to HIV results or does not result in infection. METHODS: Gag-specific T cells were analysed in 15 ESN, 14 HIV patients, and 15 healthy controls using extensive flow cytometry analysis. RESULTS: Data confirmed that gag-specific T lymphocytes are present in ESN. Gag-specific T cells mainly secrete interleukin-2 in ESN and interferon-gamma in HIV patients. In addition the CD4/CD8 and the memory/naive ratios are altered, central memory (45RA-/CCR7+) CD4 and CD8 T lymphocytes are more abundant, and terminally differentiated (45RA+/CCR7- and 27-/28-) CD8 T lymphocytes are augmented in ESN individuals. CONCLUSIONS: Exposure to HIV occurs in high risk seronegative individuals; the observation that naive cells and CM are skewed in ESN indicate that this exposure is robust enough to modulate the CM/EM ratio. The increase in late effectors and in natural killer cells seen in ESN suggests a role for these cells in preventing actual infection.

Adult↗
PubMed2005

HIV-1 subtypes and circulating recombinant forms (CRFs) from HIV-infected patients residing in two regions of central and southern Italy.

A total of 347 pol gene sequences from 88 Tuscan and 259 Apulian subjects (including 52 non-Italians and 9 children) were analyzed phylogenetically. Forty-four (12.6%) non-B subtypes were found, including 3.4% C, 1.4% F1, 0.8% G, and 0.3% each for J and A pure subtypes, and 3.7% CRF02_AG, 1.4% CRF01_AE, 0.6% BF, and 0.3% CRF06-cpx recombinant forms. An additional sample close-matched the pol gene of an unique recombinant form (URF AGK 99GR303). The non-B subtypes were from 40 adults and 4 children; 12 of these 44 patients were epidemiologically linked. Thirty-three of the 44 non-B viruses pertained to non-Italian immigrants and 11 to Italians, signifying that 63.4% immigrants and 3.7% Italians harbored non-B subtypes. The overall frequency of non-B subtypes was higher in Tuscany than in Apulia (18.1% vs. 10.8%). Moreover, 6.1% and 3.0% non-B subtypes were found among Italians from Florence and Apulia, respectively, while 52.1% and 72.4% of immigrants living in Tuscany and Apulia harbored non-B subtypes. Women infected by means of sexual contact prevailed among non-Italian adults; the majority of Italians were males and admitted high-risk sexual behavior. Four Italians had a history of extensive travel in countries of high endemicity. Social and epidemiological changes are responsible for an increasing circulation of non-B subtypes in Italy. Although non-B subtypes principally infect non-Italian patients, in Italy they can no longer be considered exclusively restricted to subjects from endemic areas.

Adolescent↗
PubMed2004

Selection of antiretroviral therapy guided by genotypic or phenotypic resistance testing: an open-label, randomized, multicenter study (PhenGen).

The phenotype/genotype (PhenGen) open-label, randomized, multicenter study evaluated the genotype/virtual phenotype (vPt) and real phenotype (rPt) for choosing a new highly active antiretroviral therapy regimen at failure. Patients with a plasma viral load (pVL) between 2000 and 200,000 copies/mL and a CD4 cell count >200/microL, failing > or =2 regimens (<6 drugs), were randomized for vPt or rPt. Three hundred three patients were enrolled: 111 and 108 patients received a new treatment in the vPt and rPt arms, respectively. The 2 groups were comparable for baseline patient characteristics and treatment history. The new therapy was in agreement with expert advice in 58.5% of cases. After 6 months, no statistical differences were found in the mean absolute change from baseline CD4 cells (+55 and +46 cells/muL; P = 0.7), mean pVL log decrease (-1.35 and -1.37; P = 0.8), or proportion of patients with a pVL <400 copies/mL (54.8% in vPt arm and 52.6% in rPt arm; P = 0.9). At multivariate analysis, variables independently associated with failure of the new regimen were: pVL at baseline (odds ratio [OR] = 1.81; P < 0.021), number of nucleoside reverse transcriptase inhibitor-associated mutations (OR = 1.21; P = 0.001), number of protease mutations (OR = 1.15; P < 0.001), and recycling of indinavir (OR = 4.63; P = 0.019). Patients' adherence to the prescribed regimen (OR = 0.23; P < 0.001), number of active drugs in the new regimen (OR = 0.55; P = 0.001), and adherence to expert advice (OR = 0.37; P < 0.001) predicted virologic response. The vPt is as predictive of treatment outcome as the rPT. Use of expert advice significantly improved the response to therapy.

Adult↗
PubMed2004

Human alpha defensin in HIV-exposed but uninfected individuals.

Human alpha defensins 1, 2, and 3 are produced by CD8 T cells of HIV-infected long-term nonprogressors and have an antiviral activity. alpha Defensins were examined in peripheral blood mononuclear cells (PBMCs), cervical-vaginal mononuclear cells (CVMCs), and cervical biopsies of 9 HIV-1-exposed but uninfected women (ESNs), 10 HIV-infected patients (HIV), and 13 low-risk healthy controls (HCs). Results showed that, whereas alpha defensin production and alpha defensin-expressing CD8 lymphocytes were comparable in ESNs and HIV patients, constitutive alpha defensin production by peripheral CD8 and CVMCs was augmented in ESNs compared with HCs (P = 0.001 and P = 0.058, respectively); alpha defensin mRNA was increased in PBMCs of ESNs; unstimulated, alpha defensin-expressing peripheral and mucosal CD8 lymphocytes were 10-fold higher in ESNs compared with HCs (P = 0.003 and P = 0.01, respectively); and alpha defensin mRNA and alpha defensin-expressing cells were augmented in cervical biopsies of ESN compared with HCs (mRNA:P = 0.03). The differences were reduced upon in vitro mitogen stimulation. A robust constitutive production of alpha defensin is seen in HIV-exposed uninfected individuals; these peptides could have a role in the potentially protective immune response that characterizes ESNs.

Biopsy↗
PubMed2004

Drug resistance mutations and newly recognized treatment-related substitutions in the HIV-1 protease gene: prevalence and associations with drug exposure and real or virtual phenotypic resistance to protease inhibitors in two clinical cohorts of antiretroviral experienced patients.

This study aimed at identifying HIV-1 protease amino acid changes associated with protease inhibitor (PI) exposure and susceptibility. New amino acid substitutions were correlated with the number of experienced PIs, reaching statistical significance only for those at positions 3, 44, and 74. The correspondence multivariate model demonstrated that > or =3 experienced PIs and substitutions or mutations at positions 3, 46, 54, 73, 74, and 84 were correlated with PI cross-resistance, including resistance for lopinavir and amprenavir in this cohort of patients who were naive for these drugs.

Amino Acid Substitution↗
PubMed2003

HIV susceptibility to amprenavir: phenotype-based versus rules-based interpretations.

OBJECTIVES: The objective was to study genotypic correlates of discordant interpretations of amprenavir (APV) resistance between a rules-based algorithm and either recombinant phenotype or virtual phenotype. METHODS: HIV resistance mutations found in patients from the GenPheRex study were interpreted with VGI-TRUGENE (version 5.0; VGI) and compared with either recombinant-phenotype (Antivirogram, r-PHT) or virtual-phenotype (Virtual-Phenotype, v-PHT) interpreted through Virco biological cut-offs. RESULTS: Among 180 samples available, 56 (31.1%) were discordant with the observed genotype interpretation results, as a result of being judged as sensitive by r-PHT or v-PHT but resistant by VGI (S/R). Only the I84V mutation was almost invariably found in concordant resistant isolates compared with S/R isolates (60% versus 0%, respectively; P < 0.0001). Notwithstanding this, the number of multi-protease inhibitor-associated mutations (PAMs) was significantly higher in the concordant resistant isolates; the prevalence of >3 PAMs was 56.52% versus 33.93% in R/R and S/R isolates, respectively (P = 0.01). Correspondence analysis confirmed the relevance of PAMs, although additional mutations appeared to be correlated with APV resistance. CONCLUSIONS: The rate of discordance between rules-based and either r-PHT or v-PHT interpretations for APV was high. Mutation I84V and accumulation of >3 PAMs were found to be associated with resistance as interpreted with all systems tested. However, our results indicate that a number of mutations may have an impact on APV resistance, but that they are missed by current interpretation algorithms and this merits further investigations.

Algorithms↗
PubMed2003

Gender differences in antiretroviral drug-related adipose tissue alterations. Women are at higher risk than men and develop particular lipodystrophy patterns.

Adipose tissue alterations (ATAs) were clinically assessed in 2258 HIV-1-infected outpatients consecutively observed in 6 Italian clinical centers and were found to be present in 29.5% of the men and 41.9% of the women. A logistic regression model including age, HIV disease Centers for Disease Control stage, CD4 cell counts, HIV RNA load, the duration of antiretroviral therapy, the number of drugs taken, and the use of d4T showed that men had a 0.47 adjusted risk of presenting with ATAs (95% CI: 0.38-0.58, P < 0.0001). The risks of having ATAs (except circumscribed lipomas) in any body region, presenting with fat accumulation, or being affected by combined forms of ATA were also lower in men, whereas the risk of developing pure lipoatrophy was similar in the 2 genders. Our results indicate that women are at higher risk of developing antiretroviral treatment-related ATAs and show a particular and complex ATA pattern.

Adipose Tissue↗
PubMed2003

Comparison between rules-based human immunodeficiency virus type 1 genotype interpretations and real or virtual phenotype: concordance analysis and correlation with clinical outcome in heavily treated patients.

We compared 2 rules-based genotype interpretation systems and real or virtual phenotype through a retrospective analysis of a prospective trial. Genotypes were determined with VircoGEN II (VIRCO) and were interpreted with either RetroGram 1.4 or TRUGENE HIV-1 (guidelines 3.0) or original virtual phenotype (Virtual Phenotype; VIRCO), as available in the year 2000. Among 188 human immunodeficiency virus (HIV) type 1 isolates, overall concordance (kappa agreement) was observed for the 2 rules-based systems, whereas striking discordances were noted between them and real and virtual phenotype interpretations for stavudine, didanosine, zalcitabine, abacavir, and amprenavir (kappa<0.4). Clinical evaluation of a subset of 173 patients showed that both rules-based sensitivity scores were independently associated with HIV RNA loads <400 copies/mL at week 16 of during-treatment analysis (TRUGENE: odds ratio [OR], 2.90; 95% confidence interval [CI], 1.52-5.52; P=.001; RetroGram: OR, 2.34; 95% CI, 1.21-4.55; P=.012), whereas, in contrast to real or virtual phenotype, interpretations according to biological cut-offs were not (OR, 1.91; 95% CI, 0.77-4.76; P=.162).

Adult↗
PubMed2003

Mucosal and systemic HIV-1-specific immunity in HIV-1-exposed but uninfected heterosexual men.

BACKGROUND: Despite multiple, repeated exposures to HIV-1, some individuals never seroconvert. Mucosal and systemic immune correlates of this condition have been analysed in HIV-1-exposed women but no data are available concerning mucosal immunity and HIV-1-specific immune responses in exposed but uninfected men. DESIGN: We analysed cellular and humoral immune parameters in peripheral lymphocytes, seminal fluid and urethral swabs of 14 recently HIV-1-exposed seonegative (ESN) heterosexual men, seven HIV-seropositive patients and seven healthy controls. RESULTS: HIV-1-specific IgA were detected in urethral swabs of 11 out of 14 ESN and of six out of seven HIV-seropositive patients; Env- and Gag-specific IFNgamma-producing CD4 and CD8 peripheral lymphocytes were present in ESN and HIV-seropositive patients; seminal lymphocytes, but not peripheral blood lymphocytes, of ESN were enriched in activated populations (CD8CD38RO and CD4CD25). p24-specific cytotoxic T lymphocytes were correlated with the percentage of CD4 in the HIV-seropositive partners. High urethral concentrations of HIV-1-specific IgA were seen in those ESN with the most recent unprotected sexual episode. CONCLUSIONS: This is the first report of HIV-specific mucosal immunity in ESN men. These data add to the body of knowledge of the immune correlates present in exposed, uninfected individuals and might be important in vaccine design.

Adult↗
PubMed2003

Real versus virtual phenotype to guide treatment in heavily pretreated patients: 48-week follow-up of the Genotipo-Fenotipo di Resistenza (GenPheRex) trial.

We compared viroimmunologic response after real phenotype (r-PHT) versus virtual phenotype (v-PHT) in patients failing highly active antiretroviral therapy (HAART). A total of 201 patients with >2 years of exposure, more than six experienced drugs, >1000 HIV RNA copies/mL, and on stable HAART for >6 months were randomized to the r-PHT or v-PHT arm. The primary end point was the proportion of HIV plasma viral load (pVL) <400 copies/mL. Secondary end points were absolute pVL change, proportion of pVL reduction >0.5 log(10) copies/mL, and absolute CD4 cell change. In the intention-to-treat-last observation carried forward analysis, study outcomes were not significantly different between arms over 48 weeks of follow-up: 20% and 24% pVL <400 copies/mL; 58% and 61% pVL reduction >0.5 log(10) copies/mL; -0.92 and -0.94(10) log copies/mL mean pVL decrease; and +41.6 and +94.4 cells/mm(3) mean absolute CD4 increase in the r-PHT and v-PHT arms, respectively. On-treatment analyses gave similar results. In the multivariate analysis of pVL <400 copies/mL, the following covariates were independent predictors at week 48: adherence (OR p= 0.25; p=.002), baseline CD4 (OR = 4.39; p=.007), intravenous drug use as risk factor for HIV acquisition (OR = 0.33; p=.024), and sensitivity score of the new regimens by biologic cut-offs (OR = 1.84; p=.029). Prescribed drugs for which patients were naive resulted in marginal prediction (OR = 1.93; p=.054). In conclusion, virologic and immunologic outcomes did not differ when r-PHT or v-PHT was used in this cohort of heavily pretreated patients. Several factors should be considered to take better advantage of resistance testing, including treatment history, clinical status, and patients' ability to adhere to treatment.

Adult↗
PubMed2003

[Type I autoimmune hepatitis. An atypical case].

Typically, autoimmune hepatitis (AIH) arises in young women, but recent papers have shown that it can affect older people too. The authors describe a case of AIH in a 70 ys old man affected by acute cholostatic hepatitis. The diagnosis of type I AIH was based on immunological features (high levels of ANA) together with histological picture in the absence of other known causes of hepatitis. Corticosteroid therapy is an effective treatment of type I AIH in older patients. AIH should be considered for the diagnosis of hepatitis in older male patients too.

Age Factors↗