Early Seroconverters Research Articles

Anti-dopamine D2 receptor antibodies in chronic tic disorders.

To investigate the association between circulating anti-dopamine D2 receptor (D2R) autoantibodies and the exacerbation of tics in children with chronic tic disorders (CTDs). One hundred and thirty-seven children with CTDs (108 males, 29 females; mean age [SD] 10y 0mo [2y 7mo], range 4-16y) were recruited over 18 months. Patients were assessed at baseline, at tic exacerbation, and at 2 months after exacerbation. Serum anti-D2R antibodies were evaluated using a cell-based assay and blinded immunofluorescence microscopy scoring was performed by two raters. The association between visit type and presence of anti-D2R antibodies was measured with McNemar's test and repeated-measure logistic regression models, adjusting for potential demographic and clinical confounders. At exacerbation, 11 (8%) participants became anti-D2R-positive ('early peri-exacerbation seroconverters'), and nine (6.6%) became anti-D2R-positive at post-exacerbation ('late peri-exacerbation seroconverters'). The anti-D2R antibodies were significantly associated with exacerbations when compared to baseline (McNemar's odds ratio=11, p=0.003) and conditional logistic regression confirmed this association (Z=3.49, p<0.001) after adjustment for demographic and clinical data and use of psychotropic drugs. There is a potential association between immune mechanisms and the severity course of tics in adolescents with CTDs.

IFN-\u03b1 as a time-sensitive biomarker during Oropouche virus infection in early and late seroconverters

In the present study, patients with acute OROV fever were classified as early seroconverters (IgM/IgG positive at baseline) or late seroconverters (IgM/IgG negative at baseline) and the timeline kinetics of the production of chemokines and cytokines were assessed at 1–3, 4–7, 8–10 and ≥11 days after patients have reported the first symptoms. Regardless immunoglobulin profile, all OROV fever patients presented higher levels of CXCL8, and IFN-α and lower levels of TNF and IL-10 at baseline as compared to healthy donors (HD). Lower levels of CCL2, CXCL10, and IFN-γ and higher levels of CCL2, CXCL10, IL-6, and IL-17A were detected in early and late seroconverters, respectively, as compared to HD. While early seroconverters presented the increasing levels of CCL2 along the timeline, late seroconverters displayed decreasing levels of CCL2, CXCL10, and IL-6 following days of disease onset. Noteworthy was that IFN-α was revealed as universal biomarker of human OROV fever, while CXCL8 & IL-5 and CXCL10 & IL-17 were consistently observed in early and late seroconverters, respectively. Thus, our results suggest that the production of IFN-α, CXCL10, and IL-17 precede the seroconversion bringing novel insights on the immunological events triggered by the OROV disease.

HIV-1 Subtypes and 5'LTR-Leader Sequence Variants Correlate with Seroconversion Status in Pumwani Sex Worker Cohort.

Within the Pumwani sex worker cohort, a subgroup remains seronegative, despite frequent exposure to HIV-1; some of them seroconverted several years later. This study attempts to identify viral variations in 5′LTR-leader sequences (5′LTR-LS) that might contribute to the late seroconversion. The 5′LTR-LS contains sites essential for replication and genome packaging, viz, primer binding site (PBS), major splice donor (SD), and major packaging signal (PS). The 5′LTR-LS of 20 late seroconverters (LSC) and 122 early seroconverters (EC) were amplified, cloned, and sequenced. HelixTree 6.4.3 was employed to classify HIV subtypes and sequence variants based on seroconversion status. We find that HIV-1 subtypes A1.UG and D.UG were overrepresented in the viruses infecting the LSC (P < 0.0001). Specific variants of PBS (Pc < 0.0001), SD1 (Pc < 0.0001), and PS (Pc < 0.0001) were present only in the viral population from EC or LSC. Combinations of PBS [PBS-2 (Pc < 0.0001) and PBS-3 (Pc < 0.0001)] variants with specific SD sequences were only seen in LSC or EC. Combinations of A1.KE or D with specific PBS and SD variants were only present in LSC or EC (Pc < 0.0001). Furthermore, PBS variants only present in LSC co-clustered with PBS references utilizing tRNAArg; whereas, the PBS variants identified only in EC co-clustered with PBS references using tRNALys,3 and its variants. This is the first report that specific PBS, SD1, and PS sequence variants within 5′LTR-LS are associated with HIV-1 seroconversion, and it could aid designing effective anti-HIV strategies.

Disease progression of HIV-1 infection in symptomatic and asymptomatic seroconverters in Osaka, Japan: a retrospective observational study.

BackgroundEstimates of the interval from HIV-1 infection to disease progression may be affected by selection bias, and data concerning asymptomatic early seroconverters are limited. We examined the interval until disease progression in HIV-1 seroconverters in whom the timing of infection could be estimated within 1 year before diagnosis.MethodsSubjects included newly diagnosed patients at Osaka National Hospital between 2003 and 2010 who had either (1) symptomatic acute HIV-1 infection with a negative or intermediate reaction on Western blotting and a positive reaction on an HIV RNA test (symptomatic acute group) or (2) a positive reaction on Western blotting at diagnosis and a <1-year interval from the last negative HIV test until the first positive test. The latter was divided into symptomatic recent or asymptomatic recent groups based on the presence or absence, respectively, of any transient fever between the last negative and first positive tests. Disease progression was defined as a fall in the CD4 count to <350 cells/microL on 2 consecutive tests, the start of anti-HIV therapy, or the onset of AIDS-indicator diseases. Information was retrospectively collected from medical records.ResultsSubjects included 210 patients: 91 in the symptomatic acute group, 72 in the symptomatic recent group, and 47 in the asymptomatic recent group. In the symptomatic acute (0.8 years) and symptomatic recent (2.2 years) groups, the Kaplan-Meier estimate of median interval until disease progression was significantly shorter than that in the asymptomatic recent group (2.9 years). Multivariate analysis by Cox’s proportional hazards test showed that the symptomatic acute group (vs. asymptomatic recent group: hazard ratio: 1.93; 95% confidence interval: 1.14–3.36; p = 0.0140) and a baseline CD4 count of <400 cells/microL (hazard ratio: 3.88; 95% confidence interval: 2.57–5.96; p < 0.0001) were independent prognostic factors associated with early disease progression.ConclusionsSymptomatic seroconversion was associated with early disease progression. Furthermore, the estimated median interval until the CD4 count was <350 cells/microL was only 2.9 years even in patients with asymptomatic seroconversion. These results suggest the importance of early diagnosis in early seroconverters.

HIV-1 co-infection prevalence in two cohorts of early HIV-1 seroconverters in France

Despite anecdotal reports of HIV-1 co-infections and super-infections, few large-scale prevalence studies are available on multiple HIV-1 infection. We systematically searched for HIV-1 co-infections by means of a heteroduplex mobility assay in 660 HIV-1 seroconverters from the two ANRS SEROCO and PRIMO cohorts. Our results strongly suggest that HIV-1 co-infection remains a rare phenomenon in HIV-1 seroconverters infected in France between 1986 and 2004.

Full-Length gag Sequences of HIV Type 1 Subtype C Recent Seroconverters from Pune, India

Although HIV-1 subtype C is the most prevalent subtype worldwide, data on subtype C viruses are rather limited. Very little information is available on the complete HIV-1 subtype C gag sequences from India. We report full-length gag (p55) sequences from six Indian early seroconverters. The samples were collected within few weeks of seroconversion and may represent immunologically naive viruses. The comparison of p55 sequences with other Indian and non-Indian subtype C sequences as well as with nonsubtype C sequences obtained from the Los Alamos database revealed gag as a well-conserved region of the HIV genome (range: 84-95%). The phylogenetic tree indicated that the sequences compared here cluster together within clade C. Two epitopes in the p24 region of the gag gene were subtype C specific while many epitopes in the same region were also present in other clades. The data on HIV-1 subtype C full-length gag sequences would be useful in the design and evaluation of effective subtype C-based HIV vaccines.

Gp120 sequences from HIV type 1 subtype C early seroconverters in India.

A limited number of full-length gp120 sequences are currently available for subtype C HIV-1 from India. Sequence data from HIV-1 subtype C in early seroconverter stage virus are also very limited. With the objective of identifying the sequence variation in early seroconverters, we compared Indian subtype C gp120 sequences obtained from six early seroconverters presented in this study with non-Indian subtype C sequences from other parts of the world obtained from the Los Alamos database and subtype C potential vaccine candidate sequences. All these samples were collected within a few weeks of seroconversion and hence they represent gp120 sequences of currently circulating viral strains in India. The phylogenetic tree indicated that the Indian sequences compared here clustered together within the C clade. The seroconverter sequences presented in the study would surely help in identifying the immunogenic epitopes and could be utilized further for developing effective prophylactic strategies against HIV-1 subtype C for India.

A distinctive clade B HIV type 1 is heterosexually transmitted in Trinidad and Tobago.

HIV-1 transmission worldwide is predominantly associated with heterosexual activity, and non-clade B viruses account for the most spread. The HIV-1 epidemic in Trinidad/Tobago and the Caribbean shares many features with such heterosexual epidemics, including a prominent role for coincident sexually transmitted diseases. This study evaluates the molecular epidemiology of HIV-1 in Trinidad/Tobago during a period when abrupt transition from homosexual to heterosexual transmission occurred in the absence of injecting drug use, concomitant with a rapid rise in HIV-1 prevalence in the heterosexual population. Of 31 viral isolates studied during 1987-1995, all cluster with subtype B reference strains. In the analysis of full env genes from 22 early seroconverters, the Trinidad isolates constitute a significant subcluster within the B subtype. The Trinidad V3 consensus sequence differs by a single amino acid from the prototype B V3 consensus and demonstrates stability over the decade of this study. In the majority of isolates, the V3 loop of env contains a signature threonine deletion that marks the lineage of the Trinidad HIV-1 clade B epidemic from pre-1984. No phenotypic features, including syncitium induction, neutralization profiles, and chemokine receptor usage, distinguish this virus population from other subtype B viruses. Thus, although the subtype B HIV-1 viruses being transmitted in Trinidad are genetically distinguishable from other subtype B viruses, this is probably the result of a strong founder effect in a geographically circumscribed population rather than genetic selection for heterosexual transmission. These results demonstrate that canonical clade B HIV-1 can generate a typical heterosexual epidemic.

Diversity of Full-Length Subtype E HIV Type 1envSequences in Early Seroconvertors from Northern Thailand

Although both HIV-1 subtypes B and E have been identified from infected individuals in Thailand, subtype E is the main form of HIV currently circulating in the country. Full-length gp160 sequences were obtained from 2 early seroconverters from northern Thailand in a study to learn more about the HIV-1 sequences currently being transmitted among recently infected individuals. Subject A01021 was a female prostitute who tested negative for antibodies to HIV-1 in April 1993, then positive in July 1993. Subject E11429 was a male military conscript who tested negative for antibodies to HIV-1 in May 1993, then positive in November 1993. Uncultured peripheral blood mononuclear cells (PBMCs) were collected from these two individuals in January 1994 and about 2500-bp segments containing the full-length gp160 gene were amplified by nested polymerase chain reaction (PCR) using the Expand high-fidelity PCR system. The nucleotide sequences of full-length gp120 from the subjects were subtype E based upon phylogenetic analysis. The gp120 sequences from the 2 seroconverters appeared more diverse than previously published subtype E HIV-1 sequences from Thailand. Overall, however, the subtype E HIV-1 gp120 sequences from Thailand were less diversified compared to the subtype E HIV-1 isolated from people with AIDS in the Central African Republic. Most of the observed amino acid variations were limited to the 5 variable regions in gp120. Therefore, vaccine strategies which elicit immune responses to the conserved regions of HIV-1 env protein will have a greater possibility of success.

Synthetic Peptide ELISAs for Detection of and Discrimination between Group M and Group O HIV Type 1 Infection

We developed and evaluated two peptide-based immunoassays to confirm and discriminate between group M and group O HIV-1 infection. These assays are based on in vitro competition for antibody binding between M and O peptides. The first EIA is based on competition between group M and group O gp41 immunodominant domains and the second on competition between group O and group M V3 regions of gp120. Two panels of sera were used: the first consisted of 109 sera collected from 27 group O- and 92 group M-infected patients in whom the HIV isolates had been genotyped by sequencing or heteroduplex mobility assay. In this panel, the combination of the two assays correctly discriminated 106 samples (100% group O and 96.7% group M samples). The second panel, used for the field evaluation of the two assays, consisted of 157 samples from HIV-1-infected Cameroonian patients, 33 strains having been genotyped. The combination of the two techniques in a serogrouping algorithm discriminated 147 of these samples, 74 being HIV-1 group O and 73 group M. These results always correlated with genotyping results. The 10 sera that were not successfully classified by these assays were from early seroconverters. Altogether, the two assays clearly differentiated 263 of 276 (94.9%) samples in the two panels. On the basis of the genotyping results, the positive predictive value for group discrimination in the two panels was 100% for both GSEIA assays. Our peptide-blocking group-specific EIAs for differentiation and confirmation of HIV-1 group M and group O infection are complementary tools for epidemiological studies and surveillance of HIV-1 group O strain trafficking.

Lack of screening test sensitivity during HIV-1 non-subtype B seroconversions.

To evaluate the serological consequences of HIV-1 group M diversity we studied the ability of screening tests to detect anti-HIV antibodies in early seroconverters infected by different HIV subtypes. Virology Department, Bichat-Claude Bernard Hospital, Paris, France. Symptomatic patients with serial samples and with infective strains characterized by heteroduplex mobility assay. In each case, two sera were selected. The first (pre-seroconversion sample) was the last p24 antigen-positive/Western blot-non-reactive sample. The second (seroconversion sample) was the first Western blot-reactive sample. One second-generation enzyme immunoassay (EIA; Abbott) based on anti-human immunoglobulin (Ig) G-conjugate and three third generation EIA (Abbott; Enzygnost; Genscreen) based on the double antigen sandwich principle, detecting IgM and IgG, were used. Ten patients had subtype B strains and nine had non-B strains (seven were A, one E and one G). The Abbott third-generation test was more sensitive than the second generation test for pre-seroconversion subtype B samples (nine versus four out of 10; P < 0.05), but not for non-B subtypes; only two of the nine non-B sera tested were positive by both EIA. Positivity rates and optical densities differed (P < 0.05) between B and non-B subtypes in all third-generation EIA. There was no significant difference between the subtype B and non-B groups with regard to the interval between the pre-seroconversion sample and the seroconversion sample (subtype B, 6.7 +/- 2.6 days; non-B, 5.2 +/- 1.7 days). No significant difference in positivity rates and optical densities were found between B and non-B subtypes in these seroconversion samples. The shorter time since HIV infection required for sera to become reactive in third-generation EIA screening tests is due to better sensitivity for subtype B strains only. These results stress the importance of strict donor selection, the need to test screening kits against large panels of all subtypes, and the place of p24 antigen testing in closing the window of seroconversion.

The significance of spontaneous hepatitis B e antigen seroconversion in childhood: With special emphasis on the clearance of hepatitis B e antigen before 3 years of age

To investigate the significance of spontaneous hepatitis B e antigen (HBeAg) seroconversion during childhood, 415 hepatitis B surface antigen (HBsAg) carrier children (ages 0 to 15 years) were prospectively followed for 7.1 +/- 2.9 years. Hepatitis B virus (HBV) markers and liver function profiles of each child were tested at least once every 6 months. Among them, 50 were initially anti-HBe positive and 140 seroconverted from HBeAg to anti-HBe during follow-up. Before HBeAg seroconversion, jaundice occurred in 9 and alanine transaminase (ALT) activities elevated in 99 of the 140 seroconverters. Serum ALT returned to normal in all patients within 1 to 5 years of seroconversion. Six had reelevated ALT later after seroconversion. Only 7 (9.7%) of the 72 carrier infants seroconverted before 3 years of age. The peak ALT levels in five of them exceeded 100 IU/L, and two had jaundice before HBeAg seroconversion. One of the early seroconverters developed hepatocellular carcinoma (HCC) at 11 years of age, although his liver function profiles remained normal after HBeAg seroconversion. Liver biopsy specimens from 30 children during the anti-HBe-positive stag e showed inactive cirrhosis in 2 (including one with HCC), chronic hepatitis with marked fibrosis in 1, mild activity and moderate fibrosis in 2, mild activity and mild fibrosis in 9, and minimal histologic changes in the remaining 16. Although most will achieve a normalization of ALT and inactive liver histologic changes, the seroconversion of HBsAg carrier children from HBeAg to anti-HBe is not necessarily an indicator of favorable prognosis; a small proportion of children will develop cirrhosis or even HCC.

The significance of spontaneous hepatitis B e antigen seroconversion in childhood: With special emphasis on the clearance of hepatitis B e antigen before 3 years of age

To investigate the significance of spontaneous hepatitis B e antigen (HBeAg) seroconversion during childhood, 415 hepatitis B surface antigen (HBsAg) carrier children (ages 0 to 15 years) were prospectively followed for 7.1 ± 2.9 years. Hepatitis B virus (HBV) markers and liver function profiles of each child were tested at least once every 6 months. Among them, 50 were initially anti-HBe positive and 140 seroconverted from HBeAg to anti-HBe during follow-up. Before HBeAg seroconversion, jaundice occurred in 9 and alanine transaminase (ALT) activities elevated in 99 of the 140 seroconverters. Serum ALT returned to normal in all patients within 1 to 5 years of seroconversion. Six had reelevated ALT later after seroconversion. Only 7 (9.7%) of the 72 carrier infants seroconverted before 3 years of age. The peak ALT levels in five of them exceeded 100 IU/L, and two had jaundice before HBeAg seroconversion. One of the early seroconverters developed hepatocellular carcinoma (HCC) at 11 years of age, although his liver function profiles remained normal after HBeAg seroconversion. Liver biopsy specimens from 30 children during the anti-HBepositive stage showed inactive cirrhosis in 2 (including one with HCC), chronic hepatitis with marked fibrosis in 1, mild activity and moderate fibrosis in 2, mild activity and mild fibrosis in 9, and minimal histologic changes in the remaining 16. Although most will achieve a normalization of ALT and inactive liver histologic changes, the seroconversion of HBsAg carrier children from HBeAg to anti-HBe is not necessarily an indicator of favorable prognosis; a small proportion of children will develop cirrhosis or even HCC.

Broadly Reactive Antibody-Dependent Cellular Cytotoxic Response to HIV-1 Envelope Glycoproteins Precedes Broad Neutralizing Response in Human Infection

To determine if and when the antibody-dependent cell-mediated cytotoxic (ADCC) response of human serum exhibits broad reactivity across HIV-1 strains, multiple sera were tested for their ability to mediate ADCC against target cells infected with recombinant vaccinia vectors expressing envelope genes of HTLV-IIIB or HTLV-IIIRF. These vectors were found to express the envelope glycoproteins of the two HIV-1 strains and so were appropriate targets for ADCC assays. All the HIV-1-positive sera were able to mediate ADCC against both HTLV-IIIB and HTLV-IIIRF envelope-expressing targets at similar titer. In sera from early seroconverters, the ADCC response was again broadly reactive, even in those sera that exhibited strain-specific neutralizing antibody responses. The ADCC response to natural infection with HIV-1 is therefore broadly reactive and precedes the development of a broad neutralizing antibody response. The broad reactivity of HIV-1-specific ADCC responses may be important for protection against cell-associated virus in vaccine development.

Analysis of factors predicting early seroconversion to anti-HBe in HBeAg-positive chronic hepatitis B

To investigate whether data obtained at the time of diagnosis may serve to predict early seroconversion to anti-HBe in chronic hepatitis B virus infection, we have compared the clinical, pathological and virological features of two groups of patients with untreated HBeAg-positive chronic hepatitis B who showed a markedly different outcome. One group (early seroconverters) included 20 patients who developed a typical seroconversion to anti-HBe within the first year of prospective follow-up. The other group (non-seroconverters) was formed by 21 patients who remained seropositive for HBeAg and still had raised aminotransferase serum levels after at least 2 years of follow-up. The serum aminotransferases, the degree of periportal and lobular lesions, the amount of liver fibrosis and the total score index of histological activity were significantly higher but the amount of HBcAg in liver was smaller in early seroconverters. Stepwise logistic regression analysis demonstrated that the alanine aminotransferase serum levels, the Knodell's index of histological activity and the amount of HBcAg in liver had significant value as independent predictors of early seroconversion. Calculation of the probability of seroconversion for individual cases showed marked differences between the two groups of patients, suggesting that early seroconversion to anti-HBe may be predicted in some patients with chronic hepatitis B.

Development and Early Natural History of HTLV-III Antibodies in Persons With Hemophilia

Antibodies to human T-cell lymphotropic virus type III (HTLV-III) were first detected in 1979 in serum samples from 30 known seropositive patients with hemophilia, over half of whom seroconverted in 1981-1982. Lymphadenopathy was present in 70% who were seropositive more than three years, compared with 10% who were seropositive three years or less. T-helper cell counts were low (307 +/- 64 cells/cu mm) in the early seroconverters, and normal in the late seroconverters. T-suppressor cell counts were not related to the year of seroconversion. The long latency period after seroconversion suggests an ongoing indolent process, rather than an acute infection. It remains to be determined whether this is an aberrant part of the immune response initiated by HTLV-III antigens or the result of a chronic active HTLV-III infection.

Development and early natural history of HTLV-III antibodies in persons with hemophilia

Antibodies to human T-cell lymphotropic virus type III (HTLV-III) were first detected in 1979 in serum samples from 30 known seropositive patients with hemophilia, over half of whom seroconverted in 1981-1982. Lymphadenopathy was present in 70% who were seropositive more than three years, compared with 10% who were seropositive three years or less. T-helper cell counts were low (307 ± 64 cells/cu mm) in the early seroconverters, and normal in the late seroconverters. T-suppressor cell counts were not related to the year of seroconversion. The long latency period after seroconversion suggests an ongoing indolent process, rather than an acute infection. It remains to be determined whether this is an aberrant part of the immune response initiated by HTLV-III antigens or the result of a chronic active HTLV-III infection. (<i>JAMA</i>1985;253:2219-2223)

Primary epstein‐barr virus infections in African infants. II. Clinical and serological observations during seroconversion

AbstractOf 27 Ghanaian infants examined monthly for the first 15 months of life and once more at 21 months, 12 acquired primary Epstein‐Barr virus (EBV) infections by the age of 1 year and 9 others seroconverted during the subsequent period of observation. The seroconversions were not accompanied by significant clinical or physical signs of illness and in none of the infants was a diagnosis of infectious mononucleosis (IM) suspected on the basis of hematologic observations. The 12 early seroconverters, providing the most extensive follow‐up data, showed transient IgM antibody responses to EB viral capsid antigen (VCA) which in some cases initially exceeded the corresponding IgG antibodies in titer. Peak VCA‐specific IgG titers were noted 2 months after seroconversion and were comparable to those seen in IM. Most of the infants developed antibodies to the EBV‐induced early antigen complex which were directed, however, against the R (restricted) component, as observed in Burkitt's lymphoma, and not against the D (diffuse) component, as noted in IM. Low titers of VCA‐specific IgA antibodies emerged in five of the cases. Usually, EBV‐neutralizing antibodies were already present in the first anti‐VCA‐positive serum but antibodies to the EBV‐associated nuclear antigen (EBNA) and antibody‐dependent cell‐mediated cytolysis (ADCC) became detectable only months after seroconversion. No heterophil antibody responses, or at most barely significant ones, were recorded. Attempts to demonstrate EBV in throat swab specimens met with limited success, suggesting a low degree of viral excretion during silent seroconversions. Possible explanations for the differences between clinical, hematologic and serologic responses to primary EBV infections in infancy and later in life are discussed.