The development of artificial neural networks to predict virological response to combination HIV therapy.

Introduction: When used in combination, antiretroviral drugs are highly effective for suppressing HIV replication. Nevertheless, treatment failure commonly occurs and is generally associated with viral drug resistance. The choice of an alternative regimen may be guided by a drug-resistance test.

Natural variability in the HR-1 and HR-2 domains of HIV type 1 gp41 from different clades circulating in Italy.

The human immunodeficiency virus type 1 (HIV-1) HR-1 and HR-2 gp41 regions were sequenced in a total of 228 plasma or peripheral blood mononuclear cell samples obtained from an equal number of enfuvirtide-naive subjects for pol genotypic resistance testing in clinical practice. Phylogenetic analysis of the env sequences indicated that 102 belonged to subtype B and 95 to non-B subtypes (31 CRF02_AG, 21 F1, 14 C, 11 A1/A2/A3, 9 CRF01_AE, 9 others) while the remaining 31 were unique recombinant forms. There was considerable variability in the consensus sequence of different clades, particularly in HR-2.

Both human immunodeficiency virus cellular DNA sequencing and plasma RNA sequencing are useful for detection of drug resistance mutations in blood samples from antiretroviral-drug-naive patients.

Genotypic antiretroviral testing is recommended for newly infected drug-naive subjects, and the material of choice is plasma RNA. Since drug resistance mutations (DRMs) may persist longer in cellular DNA than in plasma RNA, we investigated whether the use of peripheral blood mononuclear cell (PBMC) human immunodeficiency virus (HIV) DNA increases the sensitivity of genotypic testing in antiretroviral-drug-naive subjects. We compared the rate of primary drug resistance in plasma RNA and PBMC DNA in 288 HIV type 1-infected drug-naive persons tested at a single clinical virology center from June 2004 to October 2006.

Evidence of differential selection of HIV-1 variants carrying drug-resistant mutations in seroconverters.

Objectives: To estimate the relative efficiency of transmission of different HIV-1 drug-resistance mutations from patients failing treatment, considered as potential transmitters (PTs), to seroconverters (SCs).

Design: Ecological cross-sectional study.

Methods: HIV-1 protease and reverse transcriptase (RT) sequence data, obtained from 155 SCs and 2,690 PTs at the Department of Molecular Biology of the University of Siena, Italy, in the period 1997-2004 were used.

Frequency and treatment-related predictors of thymidine-analogue mutation patterns in HIV-1 isolates after unsuccessful antiretroviral therapy.

We investigated, in patients tested between 1991 and 2004, the patterns of mutually exclusive human immunodeficiency virus-1 thymidine-analogue mutations (TAMs) in 4039 reverse-transcriptase sequences with > or = 1 TAM. TAM pattern 1, which included M41L and L210W and excluded K70R and is coupled with more-extensive cross-resistance to drugs, became the most frequent pattern after 1996. In 1465 genotypes from 684 patients in whom highly active antiretroviral therapy (HAART) was unsuccessful, predictors of this pattern were the number of previous HAART regimens undergone (adjusted odds ratio [OR], 1.

The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes.

Background: The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance substitutions. This study compared the genetic barrier between subtypes using some 2000 HIV-1 sequences (>600 of non-B subtype) isolated from anti-retroviral-naive patients in Europe.

Prevalence of skin allograft discards as a result of serological and molecular microbiological screening in a regional skin bank in Italy.

Background: Postmortem skin is widely used in the treatment of patients with severe burns. Skin specimens must be screened for transmissible agents including human immunodeficiency virus (HIV), hepatitis B (HBV) and C (HCV) virus, human T-cell lymphotropic virus (HTLV), cytomegalovirus (CMV) and Treponema pallidum.

Methods: Four hundred and sixty-one cadaveric donors underwent serological and molecular microbiological (polymerase chain reaction, PCR) screening at Siena Skin Bank between 2000 and 2004.

A child with vestibular neuritis. is adenovirus implicated?

Vertigo in children is relatively under examined in the literature. Among its causes, vestibular neuritis (VN) represents only 2% of cases, with its etiology remaining unknown. We report for the first time a 4-year-old boy with vestibular neuritis and serological results compatible with adenoviral infection.

Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management.

Background: Infection with drug-resistant human immunodeficiency virus type 1 (HIV-1) can impair the response to combination therapy. Widespread transmission of drug-resistant variants has the disturbing potential of limiting future therapy options and affecting the efficacy of postexposure prophylaxis.

Methods: We determined the baseline rate of drug resistance in 2208 therapy-naive patients recently and chronically infected with HIV-1 from 19 European countries during 1996-2002.

[Heteroaggressiveness' assessment].

In this article we describe topics associated with violence and aggressiveness. We review the psychological, social and neurobiological bases of aggressiveness according to different theoretical views. Different ideas about dangerousness are listed, and at the same time we try to delimit this term within the forensic psychiatric field.

Longitudinal study in HIV/HCV-coinfected HAART-naive patients and role of HCV genotype.

To evaluate the impact of highly active antiretroviral therapy (HAART) on the course of hepatitis C (HCV) infection, we studied the biological and virological characteristics of 23 HCV/HIV-coinfected HAART-naive patients. The HCV genotype, HCV and HIV viral loads, serum alanine aminotransferase, CD4+ and CD8+ cell/mm3 were determined at baseline, 1 month, 6 months and 12 months after initiation of HAART. Results were analyzed both in terms of total population and of HCV genotype.

Gln145Met/Leu changes in human immunodeficiency virus type 1 reverse transcriptase confer resistance to nucleoside and nonnucleoside analogs and impair virus replication.

The frequencies of multidrug resistance-associated mutations at codons 145, 151, and 69 of the human immunodeficiency virus (HIV) reverse transcriptase (RT) gene in strains from a group of 3,595 highly active antiretroviral therapy (HAART)-experienced patients were 0.22, 2.36, and 0.

Clinically validated genotype analysis: guiding principles and statistical concerns.

Whereas previously the output of HIV resistance tests has been based on therapeutically arbitrary criteria, there is now an ongoing move towards correlating test interpretation with virological outcomes on treatment. This approach is undeniably superior, in principle, for tests intended to guide drug choices. However the predictive accuracy of a given stratagem that links genotype or phenotype to drug response is strongly influenced by the study design, data capture and analytical methodology used to derive it.

Comparative evaluation of three computerized algorithms for prediction of antiretroviral susceptibility from HIV type 1 genotype.

Objectives: To compare three methods for using HIV-1 genotype to predict antiretroviral drug susceptibility.

Methods: We applied three genotypic interpretation algorithms to 478 reverse transcriptase (RT) and 410 protease sequences for which phenotypic data were available. Sequences were obtained from clinical practice and from published sequences in the Stanford HIV-1 RT and Protease Sequence Database.

Immunological recovery despite virological failure is independent of human immunodeficiency virus-type 1 resistant mutants in children receiving highly active antiretroviral therapy.

Relationships between human immunodeficiency virus-type-1 (HIV-1) drug-resistant mutants and immunological recovery were investigated after 12-week antiretroviral therapy in 43 children infected perinatally with virological failure. Twenty-two children received highly active antiretroviral therapy (HAART) and 21 received double therapy with reverse transcriptase inhibitors. At baseline, no difference in reverse transcriptase or protease inhibitors resistant mutants was present among the groups.

Low frequency of plasma nerve-growth factor detection is associated with death of memory B lymphocytes in HIV-1 infection.

Nerve growth factor (NGF) regulates B cell activation and differentiation and is an autocrine survival factor for memory B lymphocytes. We have reported recently that the number of memory B cells is reduced during HIV-1 infection. In this study we evaluated whether alteration in the NGF supply was involved in memory B cell loss in HIV-1-infected subjects.

Surrogate markers as a guide to evaluate response to antiretroviral therapy.

The development of an increasing number of antiretroviral agents has dramatically reduced HIV-associated morbidity and mortality. However, most of these drugs have been approved through clinical trials where only surrogate markers for clinical endpoints have been used. Ideally, a surrogate marker should be biologically plausible, predictive of disease progression and measurable by standardized assays.

Divergent distribution of HIV-1 drug-resistant variants on and off antiretroviral therapy.

Objective: To investigate the distribution of drug-resistant HIV-1 variants in plasma RNA and peripheral blood monuclear cell (PBMC) DNA at treatment failure while on therapy and after stopping therapy.

Design: Fifty-eight patients failing their first highly active antiretroviral treatment while on therapy and 50 patients after a median of 18.6 weeks after treatment interruption following multiple treatment failures were analysed.

Performance of an in-house genotypic antiretroviral resistance assay in patients pretreated with multiple human immunodeficiency virus type 1 protease and reverse transcriptase inhibitors.

An in-house genotypic antiretroviral resistance assay was evaluated by testing 32 plasma samples obtained from heavily pretreated human immunodeficiency virus type 1 (HIV-1)-infected patients failing multiple antiretroviral regimens. The same samples were also sent to Virco Laboratories for genotypic (VircoGEN) and phenotypic (Antivirogram) resistance analysis. Sequencing results obtained by in-house (HG) and VircoGEN (VG) genotyping were concordant for 387 of 400 (96.

Plasma levels of soluble CD27: a simple marker to monitor immune activation during potent antiretroviral therapy in HIV-1-infected subjects.

Plasma levels of soluble CD27 (sCD27) are elevated in diseases characterized by T cell activation and are used as a marker of immune activation. We assessed the usefulness of determining plasma sCD27 as a marker for monitoring immune activation in HIV-1-infected patients treated with highly active antiretroviral therapy (HAART). A first cross-sectional examination of 68 HIV-1-infected and 18 normal subjects showed high levels of sCD27 in HIV-1 infection; plasma sCD27 was correlated to HIV-1 viraemia and inversely correlated to CD4+ T cell count.

Broad nucleoside-analogue resistance implications for human immunodeficiency virus type 1 reverse-transcriptase mutations at codons 44 and 118.

Two large, independent human immunodeficiency virus type 1 resistance databases containing >7700 reverse-transcriptase (RT) sequences were used to analyze the epidemiology of amino acid substitutions at codons 44 and 118, which confer moderate lamivudine resistance in the presence of zidovudine resistance. As expected, E44A/D and V118I mutations were strongly associated with M41L, D67N, L210W, and T215Y but also with other mutations, including K43E/N/Q, T69D, V75M, H208Y, R211K, and K219R. Both E44D and V118I were more frequently associated with stavudine and didanosine than with zidovudine and lamivudine treatment.

Immunoglobulin gene rearrangement analysis in composite hodgkin disease and large B-cell lymphoma: evidence for receptor revision of immunoglobulin heavy chain variable region genes in Hodgkin-Reed-Sternberg cells?

Immunoglobulin heavy chain gene (IgH) rearrangement was studied in a patient showing the occurrence of classical Hodgkin disease and large B-cell lymphoma (LBCL) in the same lymph node. The VHDHJH region was amplified by polymerase chain reaction, the template being the DNA extracted from single Hodgkin and Reed-Sternberg and LBCL cells, microdissected on hematoxylin-eosin-stained sections by laser capture. A repeated VH4DH3JH4 segment was found in Reed-Sternberg cells, whereas a repeated VH3DH3JH4 segment was observed in LBCL cells.