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what does seroconversion mean in relation to hiv and aids

Introduction

HIV/AIDS continues to be a major global public wellness crunch with wide social ramifications. In the year 2017, an estimated one.eight million new cases of HIV infection and 0.94 million HIV-related deaths were reported across the world (World Health System [WHO], 2017). Given the UNAIDS 90-90-90 target to end AIDS in 2030 (Brostrom et al., 2014), expansion of the access to HIV testing and comeback in screening algorithms is a key imperative, and the increasing detection of contempo HIV-ane infection in clinical practice has posed to exist a major challenge (Schupbach et al., 2007; Cohen et al., 2010; Branson and Stekler, 2012; Liu et al., 2016; Bottone and Bartlett, 2017; Ning et al., 2018; Toussova et al., 2018). Recent HIV-1 infection, likewise known as early on HIV-ane infection or primary HIV-1 infection, is unremarkably defined as detectable HIV-1 RNA or p24 antigen in serum or plasma in the setting of negative or indeterminate result of HIV-i antibody test including Western blot (WB) (Pilcher et al., 2010). Recent HIV-1 infection can exist confirmed by subsequent HIV antibiotic seroconversion. The identification of recent HIV-one infection is extremely useful for antiretroviral handling and for pathogenetic and epidemiologic studies (Cohen et al., 2010; Hecht et al., 2011).

According to the staging of contempo HIV-1 infection by Fiebig et al. (2003) (Cohen et al., 2011b), the progression of HIV-ane infection can be divided into vi separate stages based on the results of sequential laboratory tests. Of these, the 4th-generation assays for detection of HIV-1 and HIV-2 antibodies (Ab) and HIV-1 p24 antigen (Ag) can exist used to detect HIV infection afterwards the eclipse stage and stage I, while results of WB are negative in stage II and Three, and indeterminate in stage IV. In stage V (day 31–100 post-infection), HIV-ane antibodies that bind to fixed viral proteins would result in WB reactive, while p31 band remains non-reactive (Fiebig et al., 2003; Cohen et al., 2010, 2011b). Several studies have found that the pattern of WB bands is associated with recent HIV-i infection (Schupbach et al., 2007, 2011; Wang et al., 2013) and disease progression (Garland et al., 1996). For case, p31 can be used as a viral marker to distinguish Fiebig stage Five and stage Half dozen (Cohen et al., 2011b). In a study by Sudha et al. (2006), p31 was the most oftentimes missing ring, followed by p55, p66, p51, and gp41. The emergence of HIV-one WB bands at different time-points during the early on infection may reverberate the interaction between the virus and the host. Notwithstanding, data pertaining to seroconversion duration for each HIV-1 antibody are limited and the relation of diverse WB bands with illness progression is not well characterized. In order to farther empathize the window period for appearance of HIV-one antibodies, we retrospectively analyzed the seroconversion fourth dimension of individuals with contempo HIV-one infection in Wuhan, Cathay.

Materials and Methods

Diagnosis of HIV-1 Infection

From 2012 to 2017, plasma or serum specimens were initially screened for HIV antigen and/or antibody at local Centers for Disease Prevention and Control (CDCs), hospitals, blood centers, and other health screening centers in Wuhan, Cathay. The specimens that were reactive on the initial assay were sent to Wuhan CDC for confirmation. All HIV-suspected samples were further screened with ii 4th generation Ag/Ab HIV-ane/2 enzyme immunoassays. Samples with at least i reactive issue in the subsequent screening were confirmed with HIV BLOT 2.2 WB kit (Mp Biomedicals Asia Pacific Pte. Ltd., Singapore). Equally recommended by the manufacturer of WB kit, specimens with two envelope proteins (gp160/gp41 and gp120) plus one of the core proteins (p17, p24, and p55) or one of the enzyme proteins (p31, p51, and p66) were defined as HIV-1 antibody positive; specimens that exhibited HIV-one bands (except p17) even so did not qualify for the minimum criteria for positive result were defined as indeterminate (Linley et al., 2013; Moon et al., 2015; Liu et al., 2016). The WB bands for all specimens were visually verified by at least two experts independently. As per the National Guidelines for Detection of HIV/AIDS in Red china (2015 Version), all subjects with indeterminate HIV-i WB results were asked to undergo re-testing after ii–four weeks. In addition, patients with suspected astute HIV-one infection who showed negative HIV-1 WB consequence were also recommended to undergo repeat testing after 2–4 weeks (Liu et al., 2016).

Data Drove and Assay

All individuals with suspected HIV-1 infection were registered in the Wuhan HIV Management Database. Subjects that underwent echo testing were retrospectively tracked using the unique identification number, especially individuals who showed positive WB results after initial negative or indeterminate WB test outcome. Seroconversion duration of HIV-1 antibody was estimated based on the interval between two sampling dates. Individuals with duration ≥100 days were excluded in social club to eliminate the possibility of multiple exposures.

Statistical Analysis

Where appropriate, information are expressed equally mean ± standard deviation (SD). Statistical analyses were performed with GraphPad Prism (Graphpad Software Inc., San Diego, CA, United states of america). Between-group differences with respect to categorical variables were assessed using the Chi-Squared test; those with respect to continuous variables were assessed using the Student's t-test. P-values <0.05 were considered indicative of statistical significance.

Results

Basic Information

A total of 10,934 HIV-suspected individuals were screened for HIV-1/2 antibodies during the study reference flow (2012–2017). Of these, 6972 patients tested positive for HIV-1 antibody in their beginning test. Amid the patients who initially showed negative or indeterminate WB results, 59 patients and 124 patients have seroconverted to positive WB, respectively. After the exclusion of subjects with seroconversion duration ≥100 days, 40 patients who seroconverted from negative WB and 102 patients who seroconverted from indeterminate WB were included in the analysis of seroconversion fourth dimension (Figure 1). There were no significant differences between the groups that seroconverted from negative WB and indeterminate WB with respect to sex and age (p = 0.1446 and 0.0523, respectively) (Figure 1).

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Figure 1. Schematic illustration of the study design and patient selection criteria. During the study reference menstruation (2012–2017), 10934 individuals with suspected HIV infection were screened with 2 Ag-Ab ELISA kits and confirmed by Western blot in Wuhan CDC. Of these, 59 patients and 124 patients with negative WB and indeterminate WB, respectively, showed seroconversion (including vii patients who initially seroconverted from negative to indeterminate WB and finally to positive WB). After exclusion of patients who seroconverted after ≥100 days, 40 patients with negative WB and 102 patients with indeterminate WB who showed seroconversion were included in the analysis. WB, Western blot; Neg, negative; Ind, indeterminate; Pos, positive; CI, conviction interval. Including not-reactive for two ELISA kits and WB.

Fourth dimension Duration for Seroconversion in Individuals With Negative WB

The fourth dimension duration for seroconversion from negative WB to positive WB ranged from 9 to 91 days with a mean elapsing of 43.90 days (95% confidence interval [CI]: 37.thirty–50.fifty) (Table 1 and Figure 1). Co-ordinate to the stages defined by Fiebig et al. (2003) (Cohen et al., 2011b), the mean duration for people who seroconverted from negative WB to Fiebig stage V with positive WB but without p31 was 39.77 (95% CI: 32.53–47.02) days (Figure two). As the sequential emergence of HIV-one antibodies is a central indicator of recent HIV-i infection (Schupbach et al., 2007, 2012; Wang et al., 2013), we further analyzed the window period for each WB ring. The mean seroconversion fourth dimension (from negative WB to positive) for p66, p51, p31, gp120, gp41, and p17 antibodies was 53.53 (95% CI: 43.54–63.52), 52.64 (95% CI: 38.89–66.38), 58.xi (95% CI: 44.30–71.92), 43.71 (95% CI: 36.22–51.21), 52.38 (95% CI: 44.58–60.18), and 51.eleven (95% CI: 40.36–61.85) days, respectively. As for p66, p31, gp41 and p17 antibodies, the mean seroconversion duration of patients having these bands in the concluding WB test were significantly longer (p < 0.05) than those of patients who lacked these bands (36.78 [95% CI: 28.62–44.95] days for p66 negative, 39.77 [95% CI: 32.53–47.02] days for p31 negative, 34.53 [95% CI: 24.63–44.42] days for gp41 negative, 37.38 [95% CI: 29.63–45.thirteen] days for p17 negative) (Effigy 2).

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Figure two. Comparing of the seroconversion elapsing of different WB bands in HIV-1 positive individuals who seroconverted from negative WB. The time interval (days) between 2 sampling dates of negative WB and positive WB bands, including p66, p51, p31, gp120, gp41, and p17, were calculated; seroconversion rates for subjects with and without the above bands were compared using the Student's t-test (GraphPad Instat Statistical Software). Thick horizontal confined indicate the median, boxes testify quartiles, and whiskers testify full range.

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Table ane. Seroconversion duration for HIV-one antibodies against p31 and p66.

Time Duration for Seroconversion in Individuals With Indeterminate WB

Data pertaining to individuals who seroconverted from indeterminate WB were also analyzed. The mean duration was 42.15 (95% CI: 37.99–46.xxx) days for seroconverting into positive WB (Table 1 and Effigy one) and 37.04 (95% CI: 32.35–41.74) days for seroconverting into Fiebig stage V. Neither was shorter than the elapsing for seroconversion in individuals with negative WB, equally the Fiebig stages I–Iv were relatively cursory with an average time of 3–5 days (Fiebig et al., 2003). With respect to single antibodies, in that location were significant differences betwixt the seroconversion time of individuals with and without p66, p51, or p31 bands in their final WB results (Figure 3). The window periods were 47.87 (95% CI: 43.16–52.57) days for p66, 50.24 (95% CI: 44.68–55.79) days for p51 and 51.91 (95% CI: 44.55–59.28) days for p31, while the mean duration for seroconversion of patients without these bands was 31.20 (95% CI: 24.sixteen–38.24) days, 34.06 (95% CI: 28.57–39.55) days, and 37.04 (95% CI: 32.35–41.74) days, respectively.

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Figure 3. Comparison of the seroconversion duration of different WB bands in HIV-1 positive individuals who seroconverted from indeterminate WB. The time interval (days) betwixt two sampling dates of indeterminate WB and positive WB bands, including p66, p51, p31, gp120, gp41, and p17, were calculated. Seroconversion rates for subjects with and without the above bands were compared using the Student's t-exam (GraphPad Instat Statistical Software). Thick horizontal bars indicate the median, boxes bear witness quartiles, and whiskers show full range.

Of note, no significant deviation was observed with respect to the emergence time of WB bands between patients who seroconverted from negative WB and those who seroconverted from indeterminate WB (Effigy 4). Likewise, seroconversion showed no correlation with the blueprint of bands in the outset WB test (data not shown).

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Figure iv. Comparison of the seroconversion for HIV-1 positive individuals who converted from negative WB and indeterminate WB. The fourth dimension interval (days) betwixt ii sampling dates of negative/indeterminate WB and positive WB bands, including p66, p51, p31, gp120, gp41, and p17, were calculated. Seroconversion duration for subjects with higher up bands who seroconverted from negative and indeterminate WB was compared using the Student'southward t-test (GraphPad Instat Statistical Software). Thick horizontal bars betoken the median, boxes bear witness quartiles, and whiskers bear witness full range. Neg, negative; Ind, indeterminate.

Potential Viral Markers

P31 was recognized as a HIV-1 marker for distinguishing Fiebig stage V and stage Half dozen during contempo HIV-i infection (Fiebig et al., 2003; Cohen et al., 2011b; Tuaillon et al., 2017). In this study, we observed a significant difference between the seroconversion duration of patients with and without p31 ring (p < 0.01), irrespective of the first WB test issue (negative or indeterminate) (Figures 2, iii). The cut-off duration for p31 antibody seroconversion from negative WB and indeterminate WB was about 45 (44.thirty–47.02) days and 43 (41.74–44.55) days, respectively. Interestingly, the p66 antibiotic, like p31, was establish to be a potential viral mark, as its window periods (53.53 [95% CI, 43.54–63.52] days from negative WB and 47.87 [95% CI, 43.16–52.57] days from indeterminate WB) were significantly longer (p < 0.01, Figures two, three) than that for seroconversion of patients without p66 band (36.78 [95% CI, 28.62–44.95] days from negative WB, 31.20 [95% CI, 24.16–38.24] days from indeterminate WB). The cutting-off duration for p66 antibody seroconversion from negative WB and indeterminate WB was virtually 44 (43.54–44.95) days and 42 (38.24–43.16) days, respectively. No significant difference was constitute between the seroconversion time for p31 and p66 antibodies; in addition, seroconversion with respect to p31 and p66 antibodies was concordant in the majority of patients, including 70.00% of individuals who seroconverted from negative WB and 64.70% of individuals who seroconverted from indeterminate WB (Table 1). In contrast, the differences of seroconversion fourth dimension associated with p51, gp41, and p17 antibodies were merely observed among some patients: gp41 and p17 amidst patients who seroconverted from negative WB, while p51 in patients who seroconverted from indeterminate WB. There was no difference associated with gp120 in both groups (p = 0.8827 and 0.7840) (Figures 2, 3).

Discussion

The WB assay detects the HIV-1 antibodies that bind to fixed HIV-1 proteins. Globally, it is the nearly normally used method for clinical confirmation of HIV-ane infection (Centers for Disease Command [CDC], 2014; Liu et al., 2016; Kondo et al., 2018) and positive WB issue is a prerequisite for antiretroviral therapy and laboratory follow-up including CD4 count and HIV-1 viral load test in many low- and middle-income countries. Although HIV-1 nucleic acid testing (NAT) has been recommended for HIV-one screening, particularly for individuals with acute HIV-1 infection and belatedly-stage AIDS (Tang et al., 2008; Patel et al., 2012; Centers for Disease Control [CDC], 2014; Liu et al., 2016), it is non commonly used for diagnosis due to its cost and engineering science threshold. In add-on, according to the diagnostic criteria for HIV/AIDS (WS 293-2008) in Communist china (Shao et al., 2008), confirmation of HIV-1 infection by NAT requires ii positive results with dissimilar sampling times, which prolongs the diagnostic process. Nonetheless, early diagnosis of HIV-ane infection, peculiarly for recent HIV-1 infection, is very of import to forestall the spread of HIV-1 and to facilitate prompt initiation of handling. Clinicians and patients face challenges frequently to estimate window periods (Taylor et al., 2015) and the duration of HIV seroconversion accurately. In this report, we retrospectively analyzed 102 individuals with contempo HIV-1 infection; of these, 40 individuals had originally shown negative WB effect and 102 individuals had shown indeterminate WB event. The mean elapsing for seroconversion was 43.90 (95% CI: 37.30–50.l) days and 42.fifteen (95% CI: 37.99–46.xxx) days, respectively. As the Fiebig phase VI is open up-ended (Fiebig et al., 2003) and typically hard to estimate, nosotros analyzed the duration of seroconversion to stage V, a phase marked past positive WB result without p31 band. The hateful duration of stage V seroconversion for individuals with negative WB and indeterminate WB was 39.77 (95% CI, 32.53–47.02) days and 37.04 (95% CI, 32.35–41.74) days, respectively; these were significantly shorter than that reported past Fiebig et al. (2003). Since patients with suspected HIV infection in this study were tested voluntarily and less ofttimes than that in the other prospective study (Robb et al., 2016), the bodily seroconversion time might be even shorter than the reported results. The difference between our results and those of Fiebig et al. (2003) may be owing to the dissimilar report population (Taylor et al., 2015; Robb et al., 2016), considering the antibody response to the viral poly peptide depends on the genetic background and wellness condition of patients.

In our study, we focused on recent HIV-ane infection and had excluded subjects that had been tested several times only had non seroconverted during the written report period. Both astute/early HIV-1 infection and tardily-phase HIV infection would have been tested equally HIV-one antibodies negative or indeterminate. However, contempo/early on HIV-ane infection is more than mutual than not-symptomatic late-phase HIV infection, and these patients are probable to seroconvert on follow-up within weeks (Hecht et al., 2011; Centers for Illness Command [CDC], 2014). Detection of early HIV-1 infection is a key imperative both from a therapeutic as well as a preventive perspective; studies take shown that intervention during early HIV-1 infection can reduce the size of the HIV-ane reservoir (Loma et al., 2014) and aid minimize the epidemic spread (Hecht et al., 2011; Cohen et al., 2013; Robb et al., 2016). In our previous written report (Liu et al., 2016), newly infected individuals with negative WB result showed college HIV-1 loads than those with indeterminate WB; nevertheless, these were not flagged for re-testing later on 4 weeks based on the current HIV testing algorithm in China. Accurate estimation of seroconversion is very important for HIV-1 prevention through universal testing and treatment strategy (Cohen et al., 2011a, 2012; Powers et al., 2011; Robb et al., 2016).

The pattern of WB bands has been used as a serologic marker of recent HIV-1 seroconversion (Sudha et al., 2006; Schupbach et al., 2007, 2013); in add-on, the number, intensity, and society of emergence of WB bands are associated with the staging of HIV-1 infection (Tuaillon et al., 2017; Huang et al., 2018). In a previous study by the Acute Infection and Early on Disease Research Programme network, p31 antibody was institute absent from 98 newly infected HIV patients (Hecht et al., 2002). Based on this finding, p31 was used as a viral marker to distinguish Fiebig stage V, contempo HIV-1 infection, from stage VI, the early chronic infection (Fiebig et al., 2003; Cohen et al., 2011b; Tuaillon et al., 2017). In this study, not surprisingly, significant differences were observed between the seroconversion duration of subjects with and without p31 antibiotic ring in their terminal WB design, irrespective of whether their initial WB exam result was negative (Figure 2) or indeterminate (Figure 3); these findings provide direct and adequate bear witness to support the Fiebig staging. In improver, p31 seroconversion from negative WB to positive WB occurred over a mean elapsing of 58.xi (95% CI, 44.30–71.92) days, which is much shorter than that in Keating'due south study (Keating et al., 2016); this suggests that the lack of p31 band may characterize HIV infection for a period of less than ane twelvemonth (Tuaillon et al., 2017). Interestingly, antibody against p66, like p31, showed potential equally a viral marker, equally at that place was a pregnant deviation between seroconversion of individuals with and without p66 antibody. Farther analysis showed that p66 band had similar window period as that for p31. To the best of our cognition, this feature of p66 seroconversion has not been reported previously; in improver, it is non even so articulate whether the late emergence of p66 ring is a mutual phenomenon in patients from other regions. However, we propose that the stop point for Fiebig phase V should be set at about day lxx post-infection (40 days after stage IV), based on the seroconversion elapsing of viral markers p31 and p66.

Equally for the other bands, p51, gp41, and p17 only showed differences of seroconversion in a proportion of patients, which supports the previous finding that politician antibodies could be predictors of seroconversion (Duri et al., 2011). We did not observe any meaning departure of seroconversion between individuals with and without gp120 antibody, which is consistent with a recent report (Huang et al., 2018). Gp160 and p24 bands were not included in the analysis because these are the most pop bands (Sudha et al., 2006) and commonly became positive earlier than other bands (Hecht et al., 2011).

In summary, nosotros retrospectively analyzed the seroconversion duration among subjects with recent HIV-1 infection who seroconverted from negative WB or indeterminate WB into positive WB. Our data provide direct evidence for the window period of each HIV-one antibody and suggest that antibody against p66 (like p31) may also serve equally a viral marker for distinguishing Fiebig stage 5 and VI at 24-hour interval 70 post-infection. Additional studies involving a larger sample size roofing multiple geographic and genetic backgrounds are needed to clarify the role of p66 as well as other WB bands in the progression of HIV-1 infection.

Data Availability

The datasets for this manuscript are non publicly available considering the datasets included the patients' information, which could non be made publicly available online. Requests to access the datasets should be directed to M-QL, liumq33@hotmail.com.

Ethics Statement

Written informed consent and data pertaining to demographic characteristics were collected at the time of the first HIV examination. The report was approved past the Institutional Review Board of Wuhan CDC.

Author Contributions

M-QL designed the written report. W-HK and M-QL wrote the manuscript. PL and M-QL analyzed the information. All authors collected the information and contributed to the writing and proofreading of this manuscript.

Funding

This study was supported by the Hubei Province Health and Family unit Planning Scientific Research Projection (No: WJ2019M014 to Chiliad-QL).

Conflict of Involvement Argument

The authors declare that the research was conducted in the absenteeism of any commercial or fiscal relationships that could be construed every bit a potential conflict of interest.

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Source: https://www.frontiersin.org/articles/10.3389/fmicb.2019.01322/full