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PubMed2004

Evaluation of a sampling methodology for rapid assessment of Aedes aegypti infestation levels in Iquitos, Peru.

An epidemic of dengue during 2001 in Northwestern Peru reemphasized the need for efficient, accurate, and economical vector surveillance. Between November 1998 and January 1999, we carried out extensive entomological surveys in two neighborhoods of approximately 600 contiguous houses located in the Amazonian city of Iquitos, providing a unique opportunity to evaluate the Aedes aegypti (L.) rapid assessment survey strategy. Based on Pan American Health Organization recommendations, this strategy is used by the Peruvian Ministry of Health (MOH). In our analysis all household locations, including closed and unoccupied houses, were georeferenced and displayed in a geographic information system, which facilitated simulations of MOH surveys based on hypothetical systematic sampling transects. Larval, pupal, and adult mosquito indices were calculated for each simulation (n = 10) and compared with the indices calculated from the complete data set (n = 4). The range of indices calculated from simulations was moderately high, but included actual indices. For example, simulation ranges for house indices (HI, percentage of infested houses from complete survey) were 38-56% (45%), 36-42% (38%), 21-34% (30%), and 13-33% (27%) in four surveys. HI, Breteau index, pupae per hectare, adult index, and adults per hectare were more robust entomological indicators (coefficient of variation [CV]/mean = 0.1-2.9) than the container index, pupae per person, pupae per house, adults per person, and adults per house (CV/mean >20). Our results demonstrate that the MOH's Ae. aegypti risk assessment program provides reasonable estimates of indices based on samples from every house. However, it is critical that future studies investigate the association of these indices with rates of virus transmission to determine whether sampling variability will negatively impact the application of indices in a public health context.

Aedes↗
PubMed1999

Viral persistence, antibody to E1 and E2, and hypervariable region 1 sequence stability in hepatitis C virus-inoculated chimpanzees.

The relationship of viral persistence, the immune response to hepatitis C virus (HCV) envelope proteins, and envelope sequence variability was examined in chimpanzees. Antibody reactivity to the HCV envelope proteins E1 or E2 was detected by enzyme-linked immunosorbent assay (ELISA) in more than 90% of a human serum panel. Although the ELISAs appeared to be sensitive indicators of HCV infection in human serum panels, the results of a cross-sectional study revealed that a low percentage of HCV-inoculated chimpanzees had detectable antibody to E1 (22%) and E2 (15%). Viral clearance, which was recognized in 28 (61%) of the chimpanzees, was not associated with an antibody response to E1 or E2. On the contrary, antibody to E2 was observed only in viremic chimpanzees. A longitudinal study of animals that cleared the viral infection or became chronically infected confirmed the low level of antibody to E1, E2, and the HVR-1. In 10 chronically infected animals, the sequence variation in the E2 hypervariable region (HVR-1) was minimal and did not coincide with antibody to E2 or to the HVR-1. In addition, low nucleotide and amino acid sequence variation was observed in the E1 and E2 regions from two chronically infected chimpanzees. These results suggest that mechanisms in addition to the emergence of HVR-1 antibody escape variants are involved in maintaining viral persistence. The significance of antibodies to E1 and E2 in the chimpanzee animal model is discussed.

Amino Acid Sequence↗
PubMed1994

Correlates and predictive models for blood pressure values in residents of two communities in Taiwan.

Factors predicting systolic blood pressure (SBP) and diastolic blood pressure (DBP) were extensively studied in residents aged 18 years and above from 10 villages in two Taiwanese communities. In women, the associated factors identified included age, body mass index, waist/hip ratio (not selected as a factor for DBP), plasma uric acid, plasma chloride, urinary sodium/creatinine ratio, urinary calcium/creatinine ratio, education level, ancestral origin, parental hypertension status, and marital status. In men, the factors were age, body mass index, plasma triglyceride concentration, urinary sodium/creatinine ratio, smoking status, alcohol drinking status, parental hypertension status (not selected for DBP), and marital status (not selected for DBP). The degree of BP variation which could be significantly explained by the measured factors differed between SBP and DBP, and differed between men and women: 18% in men and 39% in women for SBP variation; 15% in men and 27% in women for DBP variation. Factors other than those included in the models should be explored, particularly for men. This study identifies, for Chinese populations, predictive factors of BP well-known in Western societies (BMI, urinary sodium, plasma uric acid, alcohol consumption) and factors less emphasized in other studies (plasma triglyceride and marital status). A positive association between BP and urinary Na, a lack of association between BP and urinary K, and opposite findings in the relationship between BP and the education level for men (positive relation) and women (negative relation) are worth noting.

Adolescent↗
PubMed2000

Restricted VH3 gene usage in phage-displayed Fab that are selected by intravenous immunoglobulin.

OBJECTIVE: To perform a comparative analysis of 1) intravenous Ig (IVIG)-bound Fab fragments from a patient with autoimmune thrombocytopenia that had progressed to systemic lupus erythematosus (SLE) and 2) IVIG-selected Fabs from an SLE patient without thrombocytopenia. METHODS: IVIG preparations have been successfully used to treat certain cases of autoimmune thrombocytopenia and SLE. Specific interactions of IVIG with the components of the immune system are not well characterized. To investigate these, we had previously cloned a large number of phage-displayed IgG Fab fragments, derived from 3 patients with autoimmune thrombocytopenia, that were specifically bound by IVIG molecules during panning. Many of these Fabs reacted with platelets. Sequencing revealed that the most frequently used VH germline gene segments of all IVIG-bound Fabs were 3-23 and 3-30/3-30.5. One patient's autoimmune thrombocytopenia had progressed to SLE. Using the same cloning and panning procedures, we performed a comparative analysis of this patient's IVIG-bound Fab fragments and the IVIG-selected Fabs from an SLE patient without thrombocytopenia. RESULTS: We observed an exclusive selection of antibodies derived from 3-23 and 3-30/3-30.5 germline segments. In contrast to the Fab fragments from the autoimmune thrombocytopenia patient who developed SLE, none of the IVIG-selected Fabs from the SLE patient without thrombocytopenia bound to thrombocytes. CONCLUSION: Our results suggest a preferential interaction of a subfraction of IVIG-representative of normal Ig repertoires-with antibodies and B cell receptors derived from these 2 gene segments. Importantly, these are the most frequently rearranged VH germline genes among human B cells. This kind of interaction is characteristic of a B cell superantigen, since light chains, antigen specificity, and the high variation in the third complementarity-determining region 3 showed little influence on the selection of 3-23- or 3-30/3-30.5-derived Fabs by IVIG. However, at least some of the contact residues on Fabs for IVIG appear to be different from those for staphylococcal protein A and human immunodeficiency virus gp 120. The IVIG-selected Fabs may now be used to clone antibodies representative of this IVIG subfraction to study their possible regulatory influence on the B cell repertoire during normal development and disease.

Antigens, Bacterial↗
PubMed1998

Research on pelvic angle variation when using a pelvic support.

A pelvic support consisting of a forward sloping wedge of foam has been tested as an addition to conventional office seating for VDT work. In experiment 1 a questionnaire investigation was carried out on the impressions of 10 male and 10 female subjects who sat using pelvic supports. A general result from the questionnaire was that the waist and pelvis were felt to be stable and the evaluation was more positive with the support than without. In experiment 2, pelvis and chest inclinations were measured during sitting with and without the pelvic support. Over a long work period, significant differences were not observed. In both cases, subjects were able to move freely and there were no significant changes in posture. In experiment 3, pelvis and chest inclinations were measured in conditions of no pelvic support and with supports of 10, 20 and 30 degrees. The experiment demonstrated that a support angle of 10 degrees was stable and comfortable. In this research, it was found that the change of inclination of the pelvis can be measured continuously using an angle of inclination sensor. Imposing a forward slope of 4 to 10 degrees on the seat pan surface using the pelvic support had a positive effect, while angles of 20 and 30 degrees had a negative effect.

Adult↗
PubMed2000

13C NMR lineshapes of acetone adsorbed on silica.

13C NMR data, obtained as a function of temperature with magic-angle spinning (MAS) and either cross polarization or direct polarization, are reported on acetone and a sample of acetone (an approximately equal mixture with 13C labels at C-1 or C-2) adsorbed on dry silica gel. Various contributions to the observed linewidths and T2C values are considered in terms of a previously established model of the acetone/SiO2 system; in that model, acetone species are in equilibrium between a physisorbed-acetone (non-hydrogen-bonded) state and a state consisting of acetone units that are hydrogen bonded to silanol moieties on the silica surface. Spin dynamics simulations are useful in interpreting the effects of variations of experimental parameters. It is concluded that the main linewidth contributions, which increase at lower temperatures, are: (a) a dispersion of chemical shifts in the hydrogen-bonded state, associated with the inhomogeneous character of the silica surface; (b) the interference between MAS averaging of the chemical shift anisotropy (especially for the carbonyl carbon) and molecular motion and/or chemical exchange; and (c) chemical exchange broadening. Prominence of the last of these contributions is most consistent with data obtained as a function of magnetic field strength, MAS speed, and temperature.

Acetone↗
PubMed1992

Characterization of the specificity of the human antibody response to the V3 neutralization domain of HIV-1.

The major neutralization domain of HIV-1, contained in the third variable region (V3) of the external envelope, is highly variable at positions flanking a conserved glycine-proline-glycine sequence. We investigated the relation between V3 sequences of HIV-1 variants circulating in a host and that host's antibody specificity. Multiple V3 sequences were obtained directly, via PCR and subsequent cloning, from serum RNA or cellular DNA from 26 individuals (from 12 around seroconversion). Then, specificity of sera from these individuals to a panel of V3 peptides was determined. The specificity (best recognized peptide) of the early antibody response accurately reflected the virus population circulating around seroconversion in 12/12 individuals and 4/4 HIV-1-infected chimpanzees. A change in serum specificity at later stages of infection was rare: five years after seroconversion, only 3 of 46 individuals had a specificity that differed completely from that in the first year. However, the V3 domain of the virus does change over time, as evidenced by the poor correlation between V3 sequences obtained late in infection and V3 antibody reactivity at the same time point. Thus, in contrast to the accurate antibody response to HIV-1 variants early after infection, generally a specific response to variants emerging at later stages seemed to be absent or of low level. Instead, the early response appeared to be preserved. Finally, we made use of the observed accurate reflection to analyze the variation for the V3 domain of HIV-1 in the Netherlands by probing specificities of early sera from 129 Dutch seroconverting individuals. Specific reactivity to RKSIHIGPGRAFYTTG was found in 36%, to RKSINIGPGRAFYTTG in 12% and to RKSIPIGPGRAFYTTG in 18% of these Dutch sera.

Amino Acid Sequence↗
PubMed2006

Proactive telephone counseling as an adjunct to minimal intervention for smoking cessation: a meta-analysis.

Proactive telephone counseling is an effective adjunct to minimal intervention for smoking cessation, but its effect has not been quantitatively synthesized thoroughly. The present meta-analysis reviewed 22 studies published between January 1990 and December 2003 and found that there was a heterogeneous, significant adjunct effect of proactive telephone counseling for smoking cessation. This meta-analytic review also found that the following study characteristics explained most of the variation in the adjunct effect: year of publication, follow-up time, mean age of participants, proportion of female participants, participants' readiness to quit smoking and number of cigarettes smoked per day before intervention. In other words, based on the 22 studies, proactive telephone counseling is effective as an adjunct to other minimal interventions for younger, male, light-smoking participants. The results of this meta-analytic review imply that researchers and health care providers may need to focus on participants as much as on intervention process to obtain more effective interventions.

Counseling↗
PubMed2005

Sub-array normalization subject to differentiation.

From microarray measurement, we seek differentiation of mRNA expressions among different biological samples. However, each array has a 'block effect' due to uncontrolled variation. The statistical treatment of reducing the block effect is usually referred to as normalization. Our perspective is to find a transformation that matches the distributions of hybridization levels of those probes corresponding to undifferentiated genes between arrays. We address two important issues. First, array-specific spatial patterns exist due to uneven hybridization and measurement process. Second, in some cases a substantially large portion of genes are differentially expressed between a target and a reference array. For the purpose of normalization we need to identify a subset that exclude those probes corresponding to differentially expressed genes and abnormal probes due to experimental variation. Least trimmed squares (LTS) is a natural choice to achieve this goal. Substantial differentiation is protected in LTS by setting an appropriate trimming fraction. To take into account any spatial pattern of hybridization, we divide each array into sub-arrays and normalize probe intensities within each sub-array. We illustrate the problem and solution through an Affymetrix spike-in dataset with defined perturbation and a dataset of primate brain expression.

Animals↗
PubMed1989

Stereophotogrammetric analysis of occlusal morphology of extant hominoid molars: phenetics and function.

Because teeth are commonly preserved in the fossil record, dental remains have often been employed in estimating evolutionary relationships among fossil hominoids. This is appropriate, however, only to the extent that dental morphology is phylogenetically informative. I have used phenetic analytic techniques to assess whether hominoid molars are likely to be useful for phylogenetic inference. Thirty-four occlusal landmarks for first and second molars were chosen; seven on each maxillary and ten on each mandibular tooth. Three-dimensional locations of these points were determined from stereophotographs of dental arcades of more than 260 specimens from six taxa (gorilla, chimpanzee, human, orangutan, siamang, and gibbon). Analytic emphasis was on canonical variates analyses of landmark coordinates for mandibular and maxillary second molars, adjusted for intergroup size differences. There is little correspondence between the systematic implications of hominoid molar morphometrics and reliable estimates of evolutionary propinquity based on interhominoid biomolecular similarities. The former seem to have been determined largely by dietary constraints. Although this suggests the possibility of using the protocol employed here to infer diets of fossil hominoids, molar crown measurements seem unlikely to serve well as phylogenetic indicators in the Hominoidea.

Animals↗
PubMed1999

Structural variability of CD44v molecules and reliability of immunodetection of CD44 isoforms using mAbs specific for CD44 variant exon products.

CD44 can be considered structurally and functionally one of the most variable surface molecules. Alternative splicing of variant exons as well as posttranslational modifications of the molecule (differences in glycosylation) generate a rich repertoire of CD44 isoforms (CD44v), some of which seem to play a key role in tumor growth and progression. Immunodetection of CD44 isoforms in vivo, using mAbs specific for CD44 variant exon products, is largely used to identify those CD44 molecules involved in tumor growth and progression and to interfere with CD44-mediated processes. In the present work we demonstrate that the immunoreactivity of some mAbs directed to CD44 exon-specific epitopes can be impaired by the structural variability of the molecule. Our findings demonstrate that (1) specific exon assortment and/or posttranslational modifications of CD44v molecules can mask CD44 exon-specific epitopes; (2) glycosaminoglycan side chains, carried by some CD44v isoforms of high molecular weight, may play a critical role in determining the exact conformation of the molecule, which is necessary for the detection of CD44 variant epitopes by specific mAbs; and (3) in a panel of stable transfectants expressing CD44 N-glycosylation site-specific mutants, generated in the constant region of CD44 extracellular domain, asparagine-isoleucine substitution is sufficient per se to impair the immunoreactivity of several mAbs to pan-CD44. Thus, conformational changes due to the alternative splicing of CD44 variant exons and/or posttranslational modifications of the molecule (different degree of glycosylation), which are cell type-specific, are likely to generate CD44 variants that elude immunodetection. These findings strongly suggest that immunohistochemical analysis of CD44 expression in vitro and in vivo, using mAbs specific for CD44 variant exon epitopes, can potentially be impaired by a large number of false negative results.

Antibodies, Monoclonal↗
PubMed2025

CCT8 drives colorectal cancer progression via the RPL4-MDM2-p53 axis and immune modulation.

PURPOSE: Colorectal cancer (CRC) ranks high in global mortality, emphasizing the need for effective interventions. The aim of the research is to elucidate the oncogenic role of CCT8 in CRC and its interaction with RPL4 in the RPL4-MDM2-p53 axis. METHODS: TIMER 2.0, TCGA, and GTEx databases were used to analyze CCT8 expression patterns in CRC. Immunohistochemistry was performed to examine CCT8 distribution in CRC tissues and adjacent non-tumor tissues. Functional assays, including CCK-8, transwell, wound-healing, and flow cytometry, were conducted using DLD-1 and HCT116 cell lines to assess the effects of CCT8 on cell proliferation, migration, invasion, and apoptosis. Gene set enrichment analysis, protein-protein interaction network analysis, and co-immunoprecipitation were performed to explore the interaction between CCT8 and RPL4 and their role in the RPL4-MDM2-p53 pathway. Additionally, gene set variation analysis was applied to investigate the relationship between CCT8/RPL4 expression and immune infiltration patterns in CRC. RESULTS: CCT8 was significantly upregulated in CRC and associated with tumor progression. Mechanistically, CCT8 potentially synergizes with RPL4 concluded from their positive correlation and similar immune infiltration patterns, influencing the RPL4-MDM2-p53 axis and contributing to p53 ubiquitination and degradation. CONCLUSION: These findings underscore the oncogenic significance of CCT8 in CRC and shed light on its molecular mechanisms, paving the way for potential therapeutic applications.

Humans↗
PubMed2001

Morphometric variation in the hominoid orbital aperture: a case study with implications for the use of variable characters in Miocene catarrhine systematics.

Variable characters are ubiquitous in hominoid systematics and present a number of unique problems for phylogenetic analyses that include extinct taxa. As yet, however, few studies have quantified ranges of variation in complex morphometric characters within extant taxa and then used those data to assess the consistency with which discrete character states can be applied to poorly represented fossil species. In this study, ranges of intrageneric morphometric variation in the shape of the hominoid orbital aperture are estimated using exact randomization of average pairwise taxonomic distances (ATDs) derived from size-adjusted centroid, height-width, and elliptic Fourier (EF) variables. Using both centroid and height-width variables, 19 of the 21 possible ATDs between individuals representing seven extinct catarrhine taxa (Aegyptopithecus, Afropithecus, Ankarapithecus, Ouranopithecus, Paranthropus, Sivapithecus and Turkanapithecus) can be observed within a single extant hominoid subspecies, although generally with low probabilities. A resampling study is employed as a means for gauging the effect that this intrataxonomic variation may have on the consistency with which discrete orbital shape character states can be delimited given the small sample sizes available for most Miocene catarrhine taxa preserving this feature (i.e., n=1). For each type of morphometric variable, 100 cluster (UPGMA) analyses of pairwise ATDs are performed in which a single individual is randomly selected from each hominoid genus and analyzed alongside known extinct taxa; consensus trees are computed in order to obtain the frequencies with which different shape clusters appeared in each of the three analyses. The two major clusters appearing most frequently in all three consensus trees are found in only 57% (centroid variables), 49% (height-width variables), and 36% (EF variables) of these trees. If ranges of variation within represented extinct taxa could also be estimated, these frequencies would certainly be far lower. Hominoids clearly exhibit considerable intrageneric, intraspecific, and even intrasubspecific variation in orbit shape, and substantial morphometric overlap exists between taxa; consequently, discrete character states delimiting these patterns of continuous variation are likely to be highly unreliable in phylogenetic analyses of living and extinct species, particularly as the number of terminal taxa increases. Morphological phylogenetic studies of extant catarrhines that assess the effect of different methods (e.g., use of objective a priori weighting or frequency coding of variable characters, inclusion vs. exclusion of variable characters, use of specific vs. supraspecific terminal taxa) on phylogenetic accuracy may help to improve the techniques that systematists employ to make phylogenetic inferences about extinct taxa.

Animals↗
PubMed2006

A conserved quadruplex motif located in a transcription activation site of the human c-kit oncogene.

The c-kit gene encodes a receptor tyrosine kinase, whose engagement by its ligand triggers signals leading to cell proliferation. c-kit activity is elevated in gastrointestinal stromal tumors (GISTs), and its therapeutic inhibition by small molecules such as imatinib is clinically validated. We identified a putative quadruplex forming 21-nucleotide sequence upstream of the c-kit transcription initiation site (c-kit21), on the G-rich strand, which occupies a site required for core promoter activity. Here, we show by nuclear magnetic resonance (NMR), circular dichroism (CD), and ultraviolet (UV) spectroscopic methods that c-kit21 forms quadruplexes under physiological conditions. Mutational analysis of c-kit21 has provided insights into its structural polymorphism. In particular, one mutated form appears to form a single quadruplex species that adopts a parallel conformation. The quadruplex-forming sequence shows a high level of sequence conservation across human, mouse, rat, and chimpanzee. The small variation in sequence between the quadruplex in human/chimpanzee as compared to the rat/mouse was examined more closely by biophysical methods. Despite a variation in the sequence and length of loop 2, the quadruplexes showed both comparable CD spectra, indicative of parallel quadruplexes, and also similar thermal-stability profiles, suggesting conservation of biophysical characteristics. Collectively, the evidence suggests that this quadruplex is a serious target for a detailed functional investigation at the cell-biology level.

Amino Acid Motifs↗
PubMed2004

A prospective comparison between findings from a clinical examination and results of bitewing and panoramic radiographs for dental caries diagnosis in children.

AIM: To compare the findings of a clinical examination with those from bitewing (BW), panoramic (Pan) and panoramic plus bitewing (PanBW) radiographs for dental caries in children. METHOD: A population of 39 children, aged 3.8 to 11.9 years, who required radiographs as part of their initial assessment for care in the Department of Paediatric Dentistry (Leeds), was selected. Each subject was examined clinically for dental caries. Subsequently, a paediatric dentist and a specialist in dental radiography read the radiographs. ANALYSIS: A database in Microsoft Access was used to compare the examiners readings for each radiographic view; agreements were taken to be a consensus. Disagreements were re-viewed by both examiners to arrive at a consensus. Radiographic results were compared with those of the clinical examination. RESULTS: The clinical examination identified 6.0% (95% CI 4.1 to 7.8, p<0.001) more carious surfaces than Pan. Clinical examinations also identified more carious surfaces than BW 1.2% (95% CI -0.7 to 3.2, p<0.247) and PanBW 0.6% (95% CI -1.1 to 2.3, p<0.533) but these differences were not statistically significant. When occlusal surfaces only were compared, the clinical examination identified significantly more carious occlusal surfaces then BW (15.2%, p<0.001), Pan (17.1%, p<0.001) and PanBW (13.5%, p<0.001). Comparing the approximal surfaces only, the BW and PanBW identified significantly more carious surfaces than the clinical examination, 5.1% (p<0.001) and 4.3% (p<0.001) respectively. CONCLUSION: The use of a clinical examination with PanBW provided the maximum information on dental caries in the primary and mixed dentitions, particularly for approximal surfaces. This is important in planning comprehensive dental care for children.

Chi-Square Distribution↗
PubMed2004

Distinguishing humans from great apes with AluYb8 repeats.

Humans and chimpanzees share some 99% of DNA and amino acid identity, yet they exhibit important biomedical, morphological, and cognitive differences, difficult to accommodate within the remaining 1% of sequence diversity. Other types of genetic variation must be responsible for the taxonomic differences. Here we trace the evolution of AluYb8 repeats from a single origin at the roots of higher primates to a large increase in their number in humans. We identify nine AluYb8 DNA repeats in the chimpanzee genome compared to over 2200 repeats in the human, which represents a 250-fold increase in the rate of change in the human lineage and far outweighs the 99% sequence similarity between the two species. It is estimated that the average age of the human Yb8Alus is about 3.3 million years (My); almost 10% of them are identical in sequence, and hence are of recent origin. Genomic variations of this magnitude, distinguishing humans from great apes have not been realized. This explosive Alu expansion must have had a profound effect on the organization of our genome and the architecture of our chromosomes, inferentially altering profiles of gene expression and chromosome choreography in cell division. Additionally, we conclude that this major evolutionary process of Alu proliferation is driven by internal forces, written in the chemistry of DNA, rather than by external selection.

Alu Elements↗
PubMed1999

A comparative study of the chemical stability of various mitomycin C solutions used in glaucoma filtering surgery.

OBJECTIVE: To determine the chemical stability of various mitomycin C (MMC) solutions used in glaucoma filtering surgery. METHODS: A survey of the MMC solutions currently in use in 21 hospitals (11 in Canada, 10 in the United States) was conducted. A comparative study of the chemical stability of five different representative solutions was performed. The effects of buffer and storage variables on the chemical breakdown of MMC in the solutions were studied by means of high-performance liquid chromatography (HPLC). RESULTS: The survey revealed 33 different variations (including recipes and storage conditions) in the preparation of MMC solutions. Although the majority of the hospitals (15 of 21; 72%) were preparing stable solutions, six of the hospitals (28%) were preparing potentially unstable solutions. The stability of the solutions varied in a nonuniform manner when stored at different temperatures in different buffers. CONCLUSION: The lack of standardization and quality control of MMC solutions used in filtering surgery allows for the possibility of hospitals preparing unstable solutions.

Buffers↗
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↗