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PubMed2004

A new subtype of 3' region of cagA gene in Helicobacter pylori strains isolated from Zhejiang Province in China.

AIM: To isolate the subtypes of 3' region of cagA gene in Helicobacter pylori (H pylori) strains from Zhejiang Province in China and to investigate their relations to H pylori-associated gastroduodenal diseases. METHODS: One hundred and thirty-seven H pylori clinical strains were isolated from the gastric mucosa specimens of 74 patients with chronic gastritis, 61 with peptic ulceration, and 2 with gastric cancer. Bacterial genomic DNA was extracted and 3' region of cagA gene was amplified by polymerase chain reaction (PCR). Subtypes of 3' region of cagA gene were determined by the size of PCR amplified segments. The sequences of the subtypes were analyzed by PCR-based sequencing. RESULTS: Of the 137 H pylori isolates from Zhejiang Province, 132 (96.4%) yielded PCR products that could be classified into three groups of subtypes, named as subtypes I, II, and III according to their sizes. The sizes of subtypes I, II, and III were 648-650 bp, 705-707 bp, and 815 bp, respectively. Among the 132 cagA-positive H pylori strains, 123 (93.2%) belonged to the group of subtype I, 6 (4.5%) presented subtype II, 1 (0.8%) was subtype III, and 2 (1.5%) presented subtypes I and III both. The primary structure of subtype I was composed of 3 repeats of R1, 1 repeat of R2 and 1 repeat of R3. Subtype II possessing 4 repeats of R1, 2 repeats of R2 and 1 repeat of R3 was a newly found type of 3' region of cagA gene which had not been reported before. The primary structure of subtype III consisted of 4 repeats of R1, 1 repeat of R2 and 2 repeats of R3. Comparison of the sequences of subtype I strains with the corresponding sequences deposited in GenBank, showed a similarity of 95.0% (94.0-96.1%) for nucleotide sequences and 95.9% (94.9-97.4%) for deduced amino acid sequences. Comparison of the sequences of subtype III strains with the corresponding sequences deposited in GenBank, showed a similarity of 93.9% (90.8-96.9%) for nucleotide sequences and 93.2% (90.2-96.2%) for deduced amino acid sequences. Among subtype II strains, the nucleotide and deduced amino acid sequences showed a similarity of 95.2% (94.1-96.5%) and 96.4% (93.8-97.9%), respectively. There were no statistical differences in the distribution of subtypes of 3' region of cagA gene among different H pylori-associated gastroduodenal diseases (chi(2) = 11.544, P>0.05). CONCLUSION: There are three subtypes (I, II, and III) of 3' region of cagA gene in H pylori strains isolated from Zhejiang Province, and subtypeIis predominant. Subtype II is a newly found subtype of 3' region of cagA gene. The result of this study does not support the view that the subtypes of 3' region of cagA gene in H pylori isolated from Zhejiang Province are correlated with the clinical outcomes of H pylori infection.

Adolescent↗
PubMed2002

HBV subtype as a marker of the clinical course of chronic HBV infection in Japanese patients.

Hepatitis B virus (HBV) genotype C is predominant in Japan. However, many HBV subtypes are involved in each genotype, and the clinical manifestations in the patients associated with each subtype remain unknown. Therefore, we investigated the relationship between HBV subtype and clinical aspects of chronic HBV infection. The subtype of 237 patients with chronic HBV infection, including 74 asymptomatic carriers, was determined. The subtypes of 110 HBV carriers undergoing long-term follow-up management were determined twice to detect subtypic changes. The clinical features of the patients were also studied with regard to presence or absence of subtypic change. The subtypic distribution in the 237 HBV carriers was as follows: subtype adr, 161 (68%); subtype adw, 25 (11%); subtype adwr, 12 (5%); subtype ar, 24 (10%); subtype adyr, 4 (2%); and unclassified, 8 (3%). The proportion of asymptomatic carriers in patients with subtype adw was significantly higher than those in patients with subtype adr (56% vs. 28%, P < 0.05). In addition, the proportion of HCC in patients with subtype adwr was significantly higher than those in patients with subtype adr (25% vs. 6%, P < 0.05). The prevalence of subtype adr in 74 asymptomatic carriers tended to decrease with age (82% in carriers aged < or =35 years vs 43% in those aged > or =61 years, P < 0.05). The subtypic change and the course of chronic HBV infection had no significant correlation. These results suggest that HBV subtypes are associated with the clinical course of chronic HBV infection.

Adult↗
PubMed2001

Alpha-adrenoceptor subtypes.

Different studies have led to our present knowledge of the membrane receptors responsible for mediating the responses to the endogenous catecholamines. These receptors were initially differentiated into alpha - and beta-adrenoceptors. Alpha-adrenoceptors mediate most excitatory functions, and were in turn differentiated in the 1970s into alpha(1)- and alpha(2)-adrenoceptors. The alpha(1)-adrenoceptor type usually mediates responses in the effector organ. The alpha(2)-adrenoceptor type is located presynaptically and regulates the release of the neurotransmitter but it is also present in postsynaptical locations. Both alpha-adrenoceptors are important for the control of vascular tone, but we now know that neither alpha(1)- nor alpha(2)-adrenoceptors constitute homogeneous groups. Each alpha-adrenoceptor type can be subdivided into different subtypes and in this review we have turned our attention to these. The alpha(1)- and the alpha(2)-adrenoceptor subtypes were previously defined pharmacologically by functional and binding studies, and later they were also isolated and identified using cloning methods. In fact, the study of alpha-adrenoceptors was revolutionized by the techniques of molecular biology which permitted us to establish the present classification. The present classification of alpha(1)-adrenoceptors stands as follows: alpha(1A)-adrenoceptor subtype (cloned alpha(1c) and redesignated alpha(1a/c)), alpha(1B)-adrenoceptor subtype (cloned alpha(1b)) and alpha(1D)-adrenoceptor subtype (cloned alpha(1d) and redesignated alpha(1a/d)). It has not been easy to establish the distribution of these alpha(1)-adrenoceptor subtypes in the various organs and tissues, or to define the functional response mediated by each one in the different species studied. Nevertheless it seems that the alpha(1A)-adrenoceptor subtype is more implicated in the maintenance of vascular basal tone and of arterial blood pressure in conscious animals, and the alpha(1B)-adrenoceptor subtype participates more in responses to exogenous agonists. It has also been observed that the expression of the alpha(1B)-adrenoceptor subtype can be modified in pathological situations and particular attention has been paid to the regulation of expression of this receptor. The present classification of alpha(2)-adrenoceptors stands as follows: alpha(2A/D)-adrenoceptor subtype (today it is accepted that the alpha(2A)-adrenoceptor subtype and the alpha(2D)-adrenoceptor subtype are the same receptor but they were identified in different species: the alpha(2A) in human and the alpha(2D) in rat); alpha(2B)-adrenoceptor subtype (cloned alpha(2b)) and alpha(2C)-adrenoceptor subtype (cloned alpha(2c)). Today we know that the alpha(2A/D)- and alpha(2B)-adrenoceptor subtypes in particular control arterial contraction, and that the alpha(2C)-adrenoceptor subtype is responsible above all for venous vasoconstriction. We also know that the alpha(2 A/D)-adrenoceptor subtype fundamentally mediates the central effects of the alpha(2)-adrenoceptor agonists. Despite the validity of the above-mentioned classification of the alpha(1)- and alpha(2)-adrenoceptors, it seems clear that the contractions of a large number of tissues including smooth muscle are mediated by more than one alpha-adrenoceptor subtype. Moreover, few ligands recognise only one alpha-adrenoceptor subtype and the lack of specifity in the different drugs for each one limits their administration in vivo and their therapeutic use.

Adrenergic alpha-Agonists↗
PubMed1999

The distribution of HIV-1 subtypes in Fukuoka, Japan.

To determine the incidence of human immunodeficiency virus type-1 (HIV-1) subtypes in Fukuoka, Japan, viruses from 41 HIV-1 infected individuals were subtyped. Subtyping by V3-loop enzyme-linked immunosorbent assay (ELISA) showed 31 of the 41 subjects as subtype B (MN type), one as subtype A, one as subtype C, and eight untypable. The subject infected with subtype C was identified as a foreigner; the subtype A subject was Japanese. A phylogenetic analysis of nucleic acid sequences from the env C2-V3 region was also conducted. Genetic subtyping was successful for 25 samples: 23 samples were determined as subtype B, one subtype A and one subtype E. One of the individuals infected with subtype B, as well as the subtype A and subtype E subjects, were not Japanese. This study indicated that subtype B (USA and European type) is still dominant among HIV-1 infections in Fukuoka. Further, no Japanese were subtype E positive, which is increasing in the Kanto region. It is notable, however, that subtype A and subtype C infections, which are rare in Japan, were found in Fukuoka, located far from the metropolitan area of Tokyo.

Adolescent↗
PubMed2004

Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C.

OBJECTIVE: Genetic differences between subtypes of HIV-1, even when not associated with key resistance mutations, are known to affect baseline susceptibility to specific antiretroviral drugs and resistance-development pathways. We studied the prevalence and patterns of non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutations in HIV-1 subtype C-infected patients. METHOD: We analysed the genetic variation at sites associated with NNRTI and nucleoside reverse transcriptase inhibitor resistance in subtype C- versus B-infected patients, both drug-naive and -experienced. We extended the comparison to subtype B records from the Stanford database. RESULTS: A total of 150 subtype B and 341 subtype C-infected patients were studied. No significant differences were found in treatment and clinical parameters between the groups. In NNRTI-naive patients, changes in NNRTI positions were present in 9.3% of subtype B- versus 33.1% of subtype C-infected patients (P < 0.001). Differences were seen in both drug-naive (subtype B, 10.0% versus subtype C, 50.1%; P < 0.021) and drug-experienced NNRTI-naive patients (subtype B, 9.0% versus subtype C, 23.8%; P < 0.001). In NNRTI experienced patients, the number of A98G/S changes was significantly higher in subtype C patients treated with either efavirenz or nevirapine (P < 0.0001), and V106M was higher in efavirenz-treated subtype C-infected patients (P < 0.0001). The average mutation rates were 1.26 and 1.67 per patient for subtypes B and C, respectively (P = 0.036). The frequency of nucleoside associated mutations, but not M184V, in treated patients was significantly higher in subgroup B-infected patients (P = 0.028). CONCLUSION: Collectively, these data indicate that genetic variation at NNRTI resistance-associated positions such as V106M and A98S is substantially greater in subtype C-infected patients than in subtype B-infected patients. The natural structure of each subtype probably affects the frequency and pattern of drug resistance mutations selected under treatment.

Adult↗
PubMed2006

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. METHODS: The genetic barrier was calculated as the sum of transitions (scored as 1) and/or transversions (2.5) required for evolution to any major drug resistance substitution. In addition, the number of minor protease substitutions was determined for every subtype. RESULTS: Few dissimilarities were found. An increased genetic barrier was calculated for I82A (subtypes C and G), V108I (subtype G), V118I (subtype G), Q151M (subtypes D and F), L210W (subtypes C, F, G, and CRF02_AG), and P225H (subtype A) (P < 0.001 compared with subtype B). A decreased genetic barrier was found for I82T (subtypes C and G) and V106M (subtype C) (P < 0.001 vs subtype B). Conversely, minor protease substitutions differed extensively between subtypes. CONCLUSIONS: Based on the calculated genetic barrier, the rate of drug resistance development may be similar for different HIV-1 subtypes. Because of differences in minor protease substitutions, protease inhibitor resistance could be enhanced in particular subtypes once the relevant major substitutions are selected.

Adult↗
PubMed2000

Functional differences between the long terminal repeat transcriptional promoters of human immunodeficiency virus type 1 subtypes A through G.

The current human immunodeficiency virus type 1 (HIV-1) shows an increasing number of distinct viral subtypes, as well as viruses that are recombinants of at least two subtypes. Although no biological differences have been described so far for viruses that belong to different subtypes, there is considerable sequence variation between the different HIV-1 subtypes. The HIV-1 long terminal repeat (LTR) encodes the transcriptional promoter, and the LTR of subtypes A through G was cloned and analyzed to test if there are subtype-specific differences in gene expression. Sequence analysis demonstrated a unique LTR enhancer-promoter configuration for each subtype. Transcription assays with luciferase reporter constructs showed that all subtype LTRs are functional promoters with a low basal transcriptional activity and a high activity in the presence of the viral Tat transcriptional activator protein. All subtype LTRs responded equally well to the Tat trans activator protein of subtype B. This result suggests that there are no major differences in the mechanism of Tat-mediated trans activation among the subtypes. Nevertheless, subtype-specific differences in the activity of the basal LTR promoter were measured in different cell types. Furthermore, we measured a differential response to tumor necrosis factor alpha treatment, and the induction level correlated with the number of NF-kappaB sites in the respective LTRs, which varies from one (subtype E) to three (subtype C). In general, subtype E was found to encode the most potent LTR, and we therefore inserted the core promoter elements of subtype E in the infectious molecular clone of the LAI isolate (subtype B). This recombinant LAI-E virus exhibited a profound replication advantage compared with the original LAI virus in the SupT1 T-cell line, indicating that subtle differences in LTR promoter activity can have a significant impact on viral replication kinetics. These results suggest that there may be considerable biological differences among the HIV-1 subtypes.

Base Sequence↗
PubMed2002

Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup.

Large randomised trials are mandatory when one wants to examine the effects of different aspects (such as the treatment modality) of a pathological condition on the overall outcome. This is especially true when studying a disease in which there is a multifactorial influence on progression and outcome such as osteosarcoma. Data on 570 patients with biopsy-proven primary central osteosarcoma of an extremity included in two consecutive studies of the European Osteosarcoma Intergroup (EOI) were analysed in order to evaluate if the histological subtype of the biopsy specimen correlated with the subtype of osteosarcoma represented in the resected specimen, if there was a relationship between the histological subtype and overall survival and if there was a relationship between the histological subtype and histological response to chemotherapy. High-grade osteosarcoma, as defined by established criteria, was subtyped as either conventional, chondroblastic, teleangiectatic, small cell, fibroblastic, osteoclast rich, anaplastic and sclerotic/osteoblastic well differentiated. A panel of experienced pathologists with a special interest in bone pathology was appointed to review the histological diagnosis and to assess the tumour response to chemotherapy on the resected specimen of each patient entered into the trials. Subtyping on the biopsy specimen proved to be highly representative for the subtype of the whole tumour. In 102 patients for which subtyping was performed on the biopsy and the resected specimens, there were only two discrepancies. Of the 568 patients for whom subtype was available, 404 (71%) were of the conventional type, 54 (10%) were chondroblastic, 53 (9%) had fibroblastic tumours and the remainder consisted of rare subtypes. A good response to preoperative chemotherapy was defined as 90% or more necrosis. The proportion of patients responding well to chemotherapy differed significantly between subtypes (Chi-square test statistics=11.44, P=0.01 on 3 degrees of freedom (d.f.)). In comparison with the conventional subtype, there was a higher proportion of good responders in the fibroblastic group and a lower proportion of good responders in the chondroblastic group. Good responders had a significantly better survival than patients who responded poorly to the pre-operative chemotherapy (logrank statistic=25.20, P<0.01 on 1 df). Survival did not differ significantly according to subtype (logrank statistic=2.72, P=0.44 on 3 df), although there was a suggestion that patients with chondroblastic tumours experienced a better long-term survival. This large set of prospectively-collected data provides important information on the relationship between pathological subtype, histological response and survival. Histological response has a known prognostic effect on survival, and we have shown that the rates of response differ by subtype. There is some evidence from this study that the specific histological subtypes, i.e. the chondroblastic subtype, experience better survival. However, despite this large multi-institutional study, we have insufficient numbers of non-conventional tumours to examine this unambiguously for these subsets.

Adolescent↗
PubMed1998

Neutralization susceptibility of B subtype variant B" primary HIV-1 isolates. The HEC/FIOCRUZ AIDS Clinical Research Group.

Susceptibility to autologous and heterologous neutralization of primary human immunodeficiency virus (HIV)-1 isolates belonging to subtype B, to the B"-variant of subtype B or to subtype F from infected individuals residing in Rio de Janeiro was assayed. A lower infectivity of the B"- and F isolates when compared to the classical B-subtype HIV-1 isolates was observed. Comparisons of neutralization susceptibilities were carried out for 19 B-subtype, 11 B"-variant and two F-subtype HIV-1 isolates with plasma from autologous and heterologous samples. Frequency of autologous neutralization was slightly lower for B-subtype isolates in comparison to B"-variant isolates. Heterologous intra-subtype neutralization was significantly lower for B-subtype than for the B"-variant or the F-subtype isolates. While B-subtype isolates were neutralized by most anti-F-subtype plasma, F-subtype isolates, although most susceptible to F-subtype antibodies, were highly susceptible to neutralization by anti-B-subtype antibodies. Cross-neutralization for B"-variant and B-subtype isolates was not as extensive as observed for B- and F-subtype isolates. However, the results presented indicate a quite extensive cross-neutralization between Brazilian HIV-1 isolates.

Antigenic Variation↗
PubMed1997

An association between HIV-1 subtypes and mode of transmission in Cape Town, South Africa.

OBJECTIVES: To determine HIV-1 env and gag subtypes in male homosexual and heterosexual populations in Cape Town, South Africa. DESIGN: DNA was isolated from blood originating from 61 patients attending local clinics. Samples were divided according to presumed mode of transmission: male homosexual (n = 26), heterosexual/vertical (n = 32), blood transfusion (n = 1) and unknown (n = 2). METHODS: Proviral HIV-1 DNA was subtyped by heteroduplex mobility assay (HMA) based on the 799 base-pair V3-V5 region of the env gene (n = 47) or by sequence analysis of the p17 region of the gag gene (n = 33), or both. For HMA, reference plasmids were constructed containing the V1-V5 env region sequences (1.2-kb) representative of local subtypes. Subtype designation of reference subtypes was confirmed by sequence analysis of the V3-loop region. RESULTS: Analysis of the partial gag sequences and HMA of the V3-V5 env region identified three subtypes: B, C and D. A fourth env subtype, subtype E, was also identified by HMA. Subtypes were found to segregate according to mode of transmission, with subtype B viruses found in 96% (25 out of 26) of the male homosexual group and subtype C viruses found in 81% (26 out of 32) of the heterosexual/vertical transmission group. Subtype B viruses were also found in four heterosexual patients, one patient infected by blood transfusion and in two patients with unknown mode of transmission. Subtype D viruses were found in one male homosexual patient and one heterosexual patient. A subtype E virus was identified in a heterosexual patient. No discrepancy was found in subtype designation in samples analysed in both between the gag and env regions (n = 19). CONCLUSIONS: Subtype B viruses were associated with male homosexual transmission and subtype C viruses with heterosexual transmission, suggesting two independent epidemics. This data may have implications in the selection of appropriate vaccines for different risk groups in the country.

Adult↗
PubMed1991

Determination of HBsAg subtypes in different high risk populations using monoclonal antibodies.

Monoclonal antibodies with restricted specificity were used in a modified commercial enzyme immunoassay for detection of HBsAg to subtype HBsAg in sera from 122 Southeast Asian refugees entering the United States, 62 inmates of a correctional facility, and 19 homosexual men. This method was able to classify HBsAg as aywl-2, ayw3, ayw4, ayr, adw2, adw4, or adr. The HBsAg subtype was identified in 183 (90.1%) of the serum samples, but the serum HBsAg concentration was too low to determine the subtype for the 20 (9.9%) remaining samples. Among the Southeast Asian refugees, aywl-2 was demonstrated in 35 (33.0%) of the subtyped serum samples, the adw2 subtype was identified in 33 (31.1%) sera, adr was detected in 37 (34.9%) sera, and the adw 4 subtype as found in 1 (0.9%). The most common subtypes in Vietnam, Laos, and Cambodia were aywl-2, adw2, and adr, respectively. In prison inmates, the ayw3 subtype accounted for 31 (52.5%) of the subtyped serum samples, an ayw2 variant and the adw2 subtype were each found in 13 (22.0%) sera, and the aywl-2 subtype was detected in 2 (3.4%) sera. Many of these inmates admitted intravenous drug use. Among homosexual men, the adw2 subtype was identified in 16 (88.9%) of the subtyped serum samples and the ayw3 subtype was detected in 2 (11.1%) sera. This subtyping method can distinguish between most of the nine major HBsAg subtypes and can be easily performed with these monoclonal antibodies and commercially available reagents.

Antibodies, Monoclonal↗
PubMed1999

Restriction fragment length polymorphism analysis for rapid gag subtype determination of human immunodeficiency virus type 1 in South Africa.

A rapid method for identification of human immunodeficiency virus Type 1 (HIV-1) gag subtypes was developed based on restriction fragment length polymorphism (RFLP) analysis of 400 or 650 bp long polymerase chain reaction (PCR) fragments encompassing the start of the p17 (400 bp) and part of the p24 (650bp) regions. The consensus sequences of subtypes A-D, the only subtypes identified in South Africa, were analyzed to detect restriction endonucleases which generate unique patterns for each subtype. Four restriction endonucleases were identified: AluI, AccI, SwaI and XmnI. Digestion of a 400 bp fragment with AluI allowed identification of subtype C. Samples not identified were then reamplified, and a 650 bp fragment digested with AccI to identify subtype B, followed by SwaI and XmnI to distinguish between subtypes A and D. This strategy was applied to 87 samples previously subtyped by either sequence analysis of the gag p17 region (n = 33); or heteroduplex mobility assay (HMA) based on the env gene (n = 75); or both (n = 21). Out of the 87 samples, RFLP identified two samples as subtype A, 28 as subtype B, 56 as subtype C and one as a subtype D virus. No discrepancies were found between RFLP gag subtypes and gag sequence subtypes demonstrating the reliability of this method. There was also no discordance between gag RFLP subtypes and env HMA subtypes, suggesting that there were no recombinant viruses detected relating to the genomic regions analyzed. RFLP is an effective technique for the rapid screening in an HIV epidemic of limited diversity, such as in South Africa.

DNA, Viral↗
PubMed2001

Catalytic efficiency and vitality of HIV-1 proteases from African viral subtypes.

The vast majority of HIV-1 infections in Africa are caused by the A and C viral subtypes rather than the B subtype prevalent in the United States and Western Europe. Genomic differences between subtypes give rise to sequence variations in the encoded proteins, including the HIV-1 protease. Because some amino acid polymorphisms occur at sites that have been associated with drug resistance in the B subtype, it is important to assess the effectiveness of protease inhibitors that have been developed against different subtypes. Here we report the enzymatic characterization of HIV-1 proteases with sequences found in drug-naive Ugandan adults. The A protease used in these studies differs in seven positions (I13V/E35D/M36I/R41K/R57K/H69K/L89M) in relation to the consensus B subtype protease. Another protease containing a subset of these amino acid polymorphisms (M36I/R41K/H69K/L89M), which are found in subtype C and other HIV subtypes, also was studied. Both proteases were found to have similar catalytic constants, k(cat), as the B subtype. The C subtype protease displayed lower K(m) values against two different substrates resulting in a higher (2.4-fold) catalytic efficiency than the B subtype protease. Indinavir, ritonavir, saquinavir, and nelfinavir inhibit the A and C subtype proteases with 2.5-7-fold and 2-4.5-fold weaker K(i)s than the B subtype. When all factors are taken into consideration it is found that the C subtype protease has the highest vitality (4-11 higher than the B subtype) whereas the A subtype protease exhibits values ranging between 1.5 and 5. These results point to a higher biochemical fitness of the A and C proteases in the presence of existing inhibitors.

Adult↗
PubMed1998

HIV type 1 V3 serotyping of Tanzanian samples: probable reasons for mismatching with genetic subtyping.

HIV-1 V3 serotyping is used to classify immunodeficiency viruses on the basis of antibody binding to V3 peptides derived from env genetic subtypes. Although it shows a reasonable overlap, it has been reported to be distinct from viral genetic subtypes. The aim of this study is to determine the feasibility of HIV-1 serotyping to predict genetic subtypes in an East African setting, where multiple HIV-1 subtypes have coexisted for many years. HIV-1 genetic subtypes of 86 AIDS patients in Mbeya Town, southwest Tanzania, were determined, using env nucleic acid sequencing as the basis for comparison. Those data were compared with V3 serotyping results obtained by four different methodologies. Four HIV-1 genetic subtypes were identified, including A (25, 29%), C (47, 55%), D (13, 15%), and G (1, 1%). The sensitivity and specificity of those serotyping assays varied considerably: sensitivity for genetic subtype A (40-48%), C (52-96%), and D (9-31%); and specificity for genetic subtype A (77-95%), C (46-63%), and D (97-100%). We further tried to identify reasons for the discrepancies between serotyping results and genetic subtypes. By means of logistic regression analysis three amino acid residues within the V3 loop (positions 12, 13, and 19; V, H, and A for serotype A, I, R, and T for serotype C) were found to be most important for antibody binding; a deviation from the subtype-specific amino acids was highly related to mismatched results. In addition, we have shown that phenetic analysis of V3 amino acid sequence data could be used to predict the majority of V3 serotypes (93-94%). Our data demonstrated that for the majority of specimens HIV-1 V3 serotyping results closely match the subtype of the analyzed sample as revealed by the V3 loop amino acid sequence. However, our data demonstrate that HIV-1 serotyping is not sufficiently accurate to predict genetic subtypes in Tanzania, where subtypes A, C, D, and G are circulating. This was due to highly similar amino acid sequences throughout the prevalent genetic subtypes, which caused the inability of HIV-1 V3 serotyping to differentiate subtype A from C as well as D from C. Instead, the serotyping results reflect the frequency distribution of V3 serotypes. To investigate HIV-1 genetic subtypes in population-based studies in this African setting additional or modified algorithms are needed.

Acquired Immunodeficiency Syndrome↗
PubMed1998

HIV type 1 in Thailand, 1994-1995: persistence of two subtypes with low genetic diversity.

Extensive transmission of human immunodeficiency virus type 1 (HIV-1) in Thailand began in 1988, resulting in an estimated 800,000 cumulative infections by 1994. During 1994 and 1995, we collected blood specimens from 215 asymptomatic HIV-1-infected people with various risk behaviors from nine locations in all four regions of Thailand. HIV-1 subtypes and genetic heterogeneity were determined for 214 strains by a combination of direct DNA sequencing (n = 95), subtype-specific oligonucleotide probe testing (n = 201), and V3-loop peptide enzyme immunoassay (PEIA) (n = 214). All strains were either env subtype E (175; 81.8%) or B (39; 18.2%). Of the subtype B isolates, 37 (94.9%) were B' and 2 (5.1%) were more typical North American-like B strains (most subtype B strains in Thailand are part of a distinct subcluster within the subtype B branch on phylogenetic trees, termed B'; formerly Thai B or BB). Of 149 viruses from people with sexual risk behaviors from all regions, 146 (98.0%) were subtype E. Of 65 viruses from injecting drug users (IDUs), 29 (44.6%) were subtype E and 36 (55.4%) were subtype B, including 35 B' strains. There was regional variation in the proportions of subtypes E and B' among IDUs. The intrasubtype nucleotide divergence within the V3 and flanking regions of the env gene (mid-C2 to the start of the V4 region) was low (5.7% for subtype E and 3.1% for subtype B') compared with other HIV-1 group M subtypes from different countries. These findings of two subtypes with low heterogeneity indicate that Thailand may be a desirable setting for evaluating candidate HIV-1 vaccines. The mix of subtype E and B' strains among IDUs also offers the opportunity to study phenotypic differences between the two subtypes.

Adolescent↗
PubMed2001

National surveillance of HIV-1 subtypes for England and Wales: design, methods, and initial findings.

The HIV-1 infections detected in an ongoing national unlinked anonymous HIV surveillance program were subtyped and analyzed according to demographic and risk characteristics. Of the 893 anti--HIV-1--positive specimens allocated to an exposure group, 70% could be subtyped. Almost 25% of infections subtyped were non-B, mostly subtypes A, C, and D. Non-B infections were rare in homosexual and bisexual men and in drug injectors. Forty percent of infections in heterosexual men attending genitourinary medicine clinics were non-B subtypes; of these, 25% were subtype A infections and 59% were subtype C infections. For female clinic attendees, 61% were non-B subtype infections, of which 48% were subtype A infections and 42% were subtype C infections. Of the clinic attendees born in the United Kingdom and Europe, 14% of the men and 35% of the women were infected with non-B subtypes. In contrast, 78% of infections in antenatal patients were non-B subtypes, of which 61% were subtype A and 29% were subtype C. Extrapolation to the estimated 29,700 prevalent adult infections in the United Kingdom indicates that approximately 8,100 (27%) such infections are non-B subtypes and that these are found almost entirely in heterosexuals. The findings suggest spread of infection of non-B subtypes to heterosexuals born in the United Kingdom from individuals infected in regions of high prevalence.

Acute Disease↗
PubMed2004

Familial clustering of latent class and DSM-IV defined attention-deficit/hyperactivity disorder (ADHD) subtypes.

BACKGROUND: Findings from family and twin-based studies of Attention Deficit/Hyperactivity Disorder (ADHD) have indicated that inattentive and combined subtypes cluster together among sibling pairs who both express ADHD symptoms. The current report examines the familial clustering of ADHD subtypes, defined according to latent class and DSM-IV criteria, in a general population sample of 2,848 Australian twins, 1,013 of their non-twin siblings and 4,036 female twins from Missouri, USA. Significant clustering of DSM-IV inattentive and combined subtypes, and significant clustering of the same latent classes among siblings was predicted. METHOD: Logistic regression was used to assess 1) the clustering of same and different subtype combinations among twin and twin-sibling pairs and 2) whether genetic influences contribute significantly to the observed patterns of subtype combinations among siblings. RESULTS: With the exception of the DSM-IV hyperactive-impulsive subtype and the severe hyperactive-impulsive latent class, all other sibling DSM-IV and latent class ADHD subtypes consistently exhibited significant same-subtype clustering with MZ probands, DZ probands and their siblings in both samples. Furthermore, a significant genetic influence contributing to subtype concordance was detected for every DSM-IV subtype excluding hyperactive-impulsive, and for all eight latent classes. While some instances of significant different-subtype clustering among siblings was observed across both classification systems and samples, the particular subtype combinations involved were largely inconsistent across samples and no significant genetic influences contributing towards these discordant subtype combinations were detected. CONCLUSIONS: For both DSM-IV and latent class subtypes, the overall pattern of findings in both samples indicated significant familial clustering of same-subtype combinations and significant genetic influences contributing to these patterns of subtype concordance, despite important sample differences. These findings further extend previous work and are most consistent with the presence of multiple independent forms of ADHD.

Adolescent↗
PubMed2000

Genetic diversity of protease and reverse transcriptase sequences in non-subtype-B human immunodeficiency virus type 1 strains: evidence of many minor drug resistance mutations in treatment-naive patients.

Most human immunodeficiency virus (HIV) drug susceptibility studies have involved subtype B strains. Little information on the impact of viral diversity on natural susceptibility to antiretroviral drugs has been reported. However, the prevalence of non-subtype-B (non-B) HIV type 1 (HIV-1) strains continues to increase in industrialized countries, and antiretroviral treatments have recently become available in certain developing countries where non-B subtypes predominate. We sequenced the protease and reverse transcriptase (RT) genes of 142 HIV-1 isolates from antiretroviral-naive patients: 4 belonged to group O and 138 belonged to group M (9 subtype A, 13 subtype B, 2 subtype C, 5 subtype D, 2 subtype F1, 9 subtype F2, 4 subtype G, 5 subtype J, 2 subtype K, 3 subtype CRF01-AE, 67 subtype CRF02-AG, and 17 unclassified isolates). No major mutations associated with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors were detected. Major mutations linked to resistance to non-NRTI agents were detected in all group O isolates (A98G and Y181C) and in one subtype J virus (V108I). In contrast, many accessory mutations were found, especially in the protease gene. Only 5.6% of the 142 strains, all belonging to subtype B or D, had no mutations in the protease gene. Sixty percent had one mutation, 22.5% had two mutations, 9.8% had three mutations, and 2.1% (all group O strains) had four mutations. In order of decreasing frequency, the following mutations were identified in the protease gene: M36I (86.6%), L10I/V (26%), L63P (12.6%), K20M/R (11.2%), V77I (5.6%), A71V (2.8%), L33F (0.7%), and M46I (0.7%). R211K, an accessory mutation associated with NRTI resistance, was also observed in 43.6% of the samples. Phenotypic and clinical studies are now required to determine whether multidrug-resistant viruses emerge more rapidly during antiretroviral therapy when minor resistance-conferring mutations are present before treatment initiation.

Amino Acid Sequence↗