Early immune adaptation in HIV-1 revealed by population-level approaches
Eric S. MartinJonathan M. CarlsonAnh Q. LeDenis ChoperaRachel A. McGovernManal A RahmanCarmond NgHeiko JessenAnthony D. KelleherMartin MarkowitzTodd M. AllenM‐J MilloyMary CarringtonMark A. WainbergZabrina L. Brumme
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Abstract:
The reproducible nature of HIV-1 escape from HLA-restricted CD8+ T-cell responses allows the identification of HLA-associated viral polymorphisms “at the population level” – that is, via analysis of cross-sectional, linked HLA/HIV-1 genotypes by statistical association. However, elucidating their timing of selection traditionally requires detailed longitudinal studies, which are challenging to undertake on a large scale. We investigate whether the extent and relative timecourse of immune-driven HIV adaptation can be inferred via comparative cross-sectional analysis of independent early and chronic infection cohorts. Similarly-powered datasets of linked HLA/HIV-1 genotypes from individuals with early (median < 3 months) and chronic untreated HIV-1 subtype B infection, matched for size (N > 200/dataset), HLA class I and HIV-1 Gag/Pol/Nef diversity, were established. These datasets were first used to define a list of 162 known HLA-associated polymorphisms detectable at the population level in cohorts of the present size and host/viral genetic composition. Of these 162 known HLA-associated polymorphisms, 15% (occurring at 14 Gag, Pol and Nef codons) were already detectable via statistical association in the early infection dataset at p ≤ 0.01 (q < 0.2) – identifying them as the most consistently rapidly escaping sites in HIV-1. Among these were known rapidly-escaping sites (e.g. B*57-Gag-T242N) and others not previously appreciated to be reproducibly rapidly selected (e.g. A*31:01-associated adaptations at Gag codons 397, 401 and 403). Escape prevalence in early infection correlated strongly with first-year escape rates (Pearson’s R = 0.68, p = 0.0001), supporting cross-sectional parameters as reliable indicators of longitudinally-derived measures. Comparative analysis of early and chronic datasets revealed that, on average, the prevalence of HLA-associated polymorphisms more than doubles between these two infection stages in persons harboring the relevant HLA (p < 0.0001, consistent with frequent and reproducible escape), but remains relatively stable in persons lacking the HLA (p = 0.15, consistent with slow reversion). Published HLA-specific Hazard Ratios for progression to AIDS correlated positively with average escape prevalence in early infection (Pearson’s R = 0.53, p = 0.028), consistent with high early within-host HIV-1 adaptation (via rapid escape and/or frequent polymorphism transmission) as a correlate of progression. Cross-sectional host/viral genotype datasets represent an underutilized resource to identify reproducible early pathways of HIV-1 adaptation and identify correlates of protective immunity.To explore the effects of combined CYP1A1 Msp1 genotypes with Ile/Val genotypes on susceptibility to lung cancer. Msp1 and Ile/Val genotypes of CYP1A1 gene were detected with the methods of PCR RFLP and allele specific amplification(ASA) in a case control study,including 92 cases of lung cancer and 98 hospital controls. Msp1 polymorphism site:The risk of lung cancer with the individuals of genotype B or genotype C was 1 85 times greater than that with the individual of genotype A ( χ 2=4 36,P0 05,OR=1 85,95% CI 1 04～3 30 ).Ile/Val polymorphism site:The risk of lung cancer of the individuals with genotype Val/Val was 3 3 times greater than the individual with genotype Ile/Ile ( χ 2=4 12,P0 05,OR=3 3,95% CI 1 02～10 72 ).The lung cancer risks of individuals with combined Ile/Ile genotype and A genotype were compared with these of individuals combined Ile/Val genotype and B ( χ 2=5 81,P0 05,95% CI 1 7～9 96 ),the individuals combined Ile/Val genotype and C genotype ( χ 2=4 74,P0 05,95% CI 1 11～20 9 ) and the individuals combined Val/Val genotype and C genotype ( χ 2=4 42,P0 05,95% CI 1 27～23 6 ). [Conclusion] The genotype C and genotype Val/Val of CYP1A1 gene may be susceptible to lung cancer,the individuals with two susceptible genotypes were more susceptible to lung cancer.
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Objective
To investigate the current distribution of hepatitis C virus (HCV) genotype in Southern China and to understand the HCV transmission and to infer its transmitting trend.
Methods
The HCV gene subtypes of 3 524 specimens from Southern China were detected and analyzed by polyonerase chain reaction (PCR)-fluorescence probe method or sequencing. The regular nested PCR and sequencing were used for the phylogenetic tree analysis when the fluorescence PCR inefficiently identifying virus isolates.
Results
Among 3 524 specimens, there were 2 922 cases from Guangdong, 78 cases from Fujian, 152 cases from Hainan and 372 cases from Guangxi. Genotype 1b comprised the majority (1 808/3 524, 51.3%), followed by genotype 6a (925/3 524, 26.2%), 2a (298/3 524, 8.46%), 3a (246/3 524, 6.98%), 3b (200/3 524, 5.68%) and 1a (27/3 524, 0.77%). In addition, 1 case was genotype 6e, 1 case was genotype 6q, 1 case was genotype 6r, 3 case were genotype 6w, 2 case were genotype 6xa, 2 case were genotype 6n, and 1 case was genotype 6 with unclassified subtype. The genotype 1b accounted for the majority in most areas of 21 cities and counties in Guangdong Province, followed by genotype 6a. But in some areas, the major genotype was genotype 6a, followed by 1b. Genotype 4, genotype 5 and genotype 7 were not found in this study.
Conclusions
In the past two years, genotype 1b and 6a are still the epidemic genotypes in Guangdong, Guangxi and Hainan provinces. However, genotype 6a has replaced 1b as the dominant one in some areas in Guangdong Province. The distributions of HCV genotypes do not change significantly in Guangxi and Fujian provinces.
Key words:
Southern China; Hepatitis C virus; PCR- fluorescent probe method; Genotype distribution; Phylogenetic tree
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【Objective】To investigate the main genotype of hepatitis B virus carrier in Lasa.【Methods】 The S gene were amplified by PCR from the HBsAg positive patients in Tibet.After sequencing the end-labelled PCR production,the gene sequences were compared with the registered standard genotype sequences in GenBank. 【Results】 Of the 60 specimens,46(76.7%) could be detected directly,among them 14 were genotype B(5 were minority),12 were genotype C(5 were minority) and 20 were genotype D(3 were minority).14 specimens which undetected might be mixed genotype.【Conclusion】 Genotype B,C,D and mixed type are detected in Lasa,the dominant genotype of HBV is D in this area,but genotype A and E are not found.
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NS5B
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[Objective] To investigate genotype and subtype of hepatitis B virus in 2 counties(districts) of Sichuan province.[Methods] Virus DNA were extracted from samples both positive for HBsAg and HBeAg.After polymerase reaction(PCR) and sequencing of partial S gene,genotypes and subtypes were analysized by phylogenetic analysis and deduced amino acid sequences,respectively.[Results] Of 49 samples,those with w subdeterminant and those with r subdeterminant be-longed exclusively to genotype B and genotype C,respectively;31 samples were genotype B/subtype adw2,1 was genotype B/subtype ayw1,1 was genotype B/subtype adw3,14 were genotype C /subtype adrq+,and 2 were genotype C /subtype ayr.[Conclusion] Genotype B /subtype adw2 and genotype C/subtype adrq+ accounted for most proportion,and genotype B/sub-type adw2 predominated in 2 counties(districts);rare genotype B/subtype adw3 also existed.
HBeAg
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Objective To detect the polymorphism of CYP1A1-MspI gene in patients with ovarian cancer.and discuss the relationship between the polymorphism ofCYP1A1-MspI gene and correspond cases' general materials and clinical materials.Methods The free peripheral blood samples of 81 cases confirmed to be ovarian cancer by postoperative pathology were collected preoperatively and the polymorphism of CYP1A1-MspI gene was detected.The clinical materials of the 81 cases with different genotypes were compared.The relationship between the polymorphism and clinical materials was analyzed.Results Among the 81 cases of ovarian cancer,there were 47 cases of wild type-genotype A(T/T)(58%),25 cases of mutation heterozygosis-genotype B(T/C)(31%),and 9 cases of mutation homozygosis-genotype C(C/C)(11%).The genotypic frequency distribution in patients aged from 12 to 29 was one case of genotype A(2.1%),5 cases of genotype B(20.0%),and no case of genotype C.The genotypic frequency distribution in patients aged from 30 to 49 was 12 case of genotype A(25.5%),8 cases of genotype B(32.0%),and 3 cases of genotype C(33.3%).The genotypic frequency distribution in patients aged from 50 to 69 was 31 case of genotype A(66.0%),8 cases of genotype B(32.0%) and 4 cases of genotype C(44.4%).The genotypic frequency distribution in patients aged more than 70 years was 3 case were of genotype A(6.4%),4 cases of genotype B(16.0%),2 case of genotype C(22.2%).There were significant differences of the ages of onset between patients with different CYP1A1-MspI genotypes (P0.05).There were 40 cases of genotype A(85.1%),15 cases of genotype B(60.0%),and 9 cases of genotype C(100%) in epithelial cancer patients.There significant differences of the constituent ratio of the ovarian cancer pathological types between patients with different genotypes(P0.05).Conclusion Polymorphism of CYP1A1-MspI gene exisits in patients with ovarian cancer.The age of onset of patients with ovarian cancer is related with CYP1A1-MSPI genotypes;The incidence of epithelium tumor in patients with genotype A is higher than that of other ones.The ratio of non-epithelial tumor in the patients with mutation allele gene C has an increasing tendency.
Genotype frequency
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Parvovirus B19 comprises three distinct genotypes (1, 2, and 3). The distribution of B19 genotypes has not before been examined in South Africa. Two hundred thirty-nine laboratory samples submitted to a diagnostic virology laboratory for parvovirus DNA detection were analyzed retrospectively. Of the 53 PCR-positive samples investigated, 40 (75.4%) were identified as genotype 1 by genotype-specific PCR or consensus NS1 PCR and sequencing and 3 (5.7%) as genotype 2 and 10 (18.9%) as genotype 3 by analysis of NS1 sequences. Furthermore, phylogenetic analysis identified two genotype 1 sequences which were distinct from the previously described genotypes 1A and 1B. Interestingly, a genotype 2 virus was detected in the serum of an 11-year-old child, providing evidence for its recent circulation. This is the first study to demonstrate the concurrent circulation of all three genotypes of B19 in South Africa and the provisional identification of a novel subtype of genotype 1. The implications of parvovirus B19 variation are discussed.
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ABSTRACT The Versant HCV genotype 2.0 assay (line probe assay [LiPA] 2.0), based on reverse hybridization, and the Abbott Realti m e HCV genotype II assay (Realti m e II), based on genotype-specific real-time PCR, have been widely used to analyze hepatitis C virus (HCV) genotypes. However, their performances for detecting HCV genotype 6 infections have not been well studied. Here, we analyzed genotype 6 in 63 samples from the China HCV Genotyping Study that were originally identified as genotype 6 using the LiPA 2.0. The genotyping results were confirmed by nonstructural 5B (NS5B) or core sequence phylogenetic analysis. A total of 57 samples were confirmed to be genotype 6 (51 genotype 6a, 5 genotype 6n, and 1 genotype 6e). Four samples identified as a mixture of genotypes 6 and 4 by the LiPA 2.0 were confirmed to be genotype 3b. The remaining two samples classified as genotype 6 by the LiPA 2.0 were confirmed to be genotype 1b, which were intergenotypic recombinants and excluded from further comparison. In 57 genotype 6 samples detected using the Realti m e II version 2.00 assay, 47 genotype 6a samples were identified as genotype 6, one 6e sample was misclassified as genotype 1, and four 6a and five 6n samples yielded indeterminate results. Nine nucleotide profiles in the 5′ untranslated region affected the performances of both assays. Therefore, our analysis shows that both assays have limitations in identifying HCV genotype 6. The LiPA 2.0 cannot distinguish some 3b samples from genotype 6 samples. The Realti m e II assay fails to identify some 6a and all non-6a subtypes, and it misclassifies genotype 6e as genotype 1.
Hepatitis C
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Antiviral therapy for chronic hepatitis B (CHB) is often required for prolonged periods. We investigated the instance of one HBV genotype switching to another during tenofovir therapy. Of the 67 patients, genotype A was present in 6 (8.9%), D in 43 (65.6%), C in 1 (1.5%), and mixed in 17 (23.8%) patients. Genotype changes were detected in 51 (76.1%) patients on therapy during a follow-up of 192 (range 52–312) weeks. Inter-genotype changes were seen in 17 (33.3%) and intra-genotype in 28 (55%) and both inter- and intra-genotype in 6 of 51 (11.7%) patients. The distribution of genotypes in patients achieving complete virological response was genotype D, 32/43 (74.4%); genotype A, 6/6 (100%); and mixed genotypes, 13/17 (76.47%). The cumulative time of genotype switch among genotype A was 12 months (range 6–18), in genotype D, 12 months (range 6–48), and mixed genotype, 18 months (range 6–24). The type of inter-genotype switch most frequently detected among genotype A1 was from A1 to D1 5/6 (83.3%), followed by mixed to genotype D3 7/13 (54%) and among intra-genotype changes, from D1 to D3 in 14/20 (70%). Pretreatment HBV genotype was the only factor predicting inter-genotype switches with genotype A or mixed genotypes more likely to undergo inter-genotype switches as compared to genotype D patients (OR 66.6 [13.6–327.0, P < 0.001]). Compared to genotype D, genotype A, and mixed genotypes are more inclined to switch while on tenofovir therapy. Genotypes tend to switch and select to a particular type possibly due to constant antiviral drug pressure. J. Med. Virol. 88:1364–1375, 2016. © 2016 Wiley Periodicals, Inc.
Tenofovir
Hepatitis D virus
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ABSTRACT Combinations of 10 Cryptosporidium parvum oocysts, with various ratios of genotype I to genotype II, were isolated and subjected to PCR-restriction fragment length polymorphism analysis. Amplification of both genotypes in these samples ranged from 31 to 74% and yielded no information about the genotype proportions. In addition, since both genotypes were not always detected, amplification of a single genotype is not conclusive evidence that the sample contains only a single genotype.
Cryptosporidium parvum
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