Antibody responses to lytic and latent human herpesvirus 8 antigens among HIV-infected patients in central China

Human herpesvirus 8 (HHV8) is an important opportunistic infection of HIV/AIDS. However, very little is known about antibody seropositivities to HHV8 lytic and latent antigens among HIVinfected patients in China. Therefore, a cross-sectional study was conducted to explore HHV8 serostatus among 316 HIV-infected patients in a rural area of central China. The antibody seropositivity to HHV8 ORF65 (lytic) and LANA (latent) antigens was 12.7% and 10.4%, respectively. Patients who were naïve to antiretroviral therapy (ART) were more likely to be seropositive for antibodies to ORF65 (OR: 3.79; 95% CI: 1.71–8.42) and LANA (OR: 3.77; 95% CI: 1.55–9.14) than patients receiving ART. Patients having CD4+ cell counts less than 200 cells/mm3 were more likely to be seropositive for LANA antibody (OR: 3.53; 95% CI: 1.44–8.64) and to have lower LANA antibody titer (p = 0.007). They were also more likely to be seropositive for ORF65 antibody (OR: 2.12; 95% CI: 0.94–4.78) and to have a lower ORF65 antibody titer (p = 0.065), though the difference was marginally significant. No associations between other viral coinfections studied and antibody seropositivity to either latent or lytic HHV8 antigens were identified. Study findings suggest that antibody responses to both lytic and latent HHV8 antigens among HIV patients in China were fairly high and were associated with immunodeficiency status and ART

Conformational Entropy as a Means to Control the Behavior of Poly(diketoenamine) Vitrimers In and Out of Equilibrium.

Control of equilibrium and non-equilibrium thermomechanical behavior of poly(diketoenamine) vitrimers is shown by incorporating linear polymer segments varying in molecular weight (MW) and conformational degrees of freedom into the dynamic covalent network. While increasing MW of linear segments yields a lower storage modulus at the rubbery plateau after softening above the glass transition (Tg ), both Tg and the characteristic time of stress relaxation are independently governed by the conformational entropy of the embodied linear segments. Activation energies for bond exchange in the solid state are lower for networks incorporating flexible chains; the network topology freezing temperature decreases with increasing MW of flexible linear segments but increases with increasing MW of stiff segments. Vitrimer reconfigurability is therefore influenced not only by the energetics of bond exchange for a given network density, but also the entropy of polymer chains within the network

Evolution of subtype C HIV-1 Env in a slowly progressing Zambian infant

BACKGROUND: Given the high prevalence of mother to child infection, the development of a better understanding of African subtype C HIV-1 transmission and natural evolution is of significant importance. In this study, we genotypically and phenotypically characterized subtype C viruses isolated over a 67-month follow-up period from an in utero-infected Zambian infant. Changes in genotype and phenotype were correlated to alterations of the host humoral immune response. RESULTS: A comparison of baseline maternal and infant samples indicated that the infant sequences are monophyletic and contain a fraction of the diversity observed in the mother. This finding suggests that selective transmission occurred from mother to child. Peaks in infant HIV-1 Env genetic diversity and divergence were noted at 48 months, but were not correlated with changes in co-receptor usage or syncytia phenotype. Phylogenetic analyses revealed an accumulation of mutations over time, as well as the reappearance of ancestral lineages. In the infant C2-V4 region of Env, neither the median number of putative N-glycosylation sites or median sequence length showed consistent increases over time. The infant possessed neutralizing antibodies at birth, but these decreased in effectiveness or quantity with time. De novo humoral responses were detected in the child after 12 months, and corresponded with an increase in Env diversity. CONCLUSION: Our study demonstrates a correlation between HIV-1 Env evolution and the humoral immune response. There was an increase in genetic diversification in the infant viral sequences after 12 months, which coincided with increases in neutralizing antibody titers. In addition, episodes of viral growth and successive immune reactions in the first 5–6 years were observed in this slow progressor infant with delayed onset of AIDS. Whether this pattern is typical of slow progressing subtype C HIV-1 infected infant needs to be further substantiated

Genetic Variation in Mother-Child Acute Seroconverter Pairs from Zambia

Objective: To characterize the envelope (env) glycoprotein of HIV-1 in mother-infant pairs (MIP) that underwent near simultaneous or acute-phase seroconversion, we examined the env sequence of the transmitted viruses and compare viral evolution within the pair. Design: Three MIP from a Zambian cohort that seroconverted at the same sampling time were identified and followed longitudinally. Methods: The V1-V5 region of the HIV-1 env gene was sequenced for each sample collected. Phylogenetic and population genetics analyses were carried out to subtype the viruses, estimate relationships among viral genotypes, and compare molecular evolution between the viral populations. Results: Genetic analyses demonstrated a close intrapair relationship between viral sequences from each MIP. Transmission involved several closely related viral genotypes and did not result in a reduction in viral diversity. Amino acid changes were not evenly distributed along env V1-V5 but concentrated in concordant areas within each MIP. Several positions under positive selection were shared between the MIP viruses. Interestingly, selective pressure on the virus was higher in the infants than in the mothers. Conclusions: In contrast to most cases of perinatal transmission of HIV-1 from chronically infected mothers, there is no evidence of a genetic bottleneck in the transmitted viruses in these three instances of acute seroconversion. The longitudinal changes in the amino acids are in similar positions in env for the MIP, suggesting shared evolutionary constrains among the closely related viruses infecting the MIP; such constrains may lead to similar genetic changes in the virus in two different hosts

Seroprevalence of Human Herpesvirus 8 among Zambian Women of Childbearing Age without Kaposi’s Sarcoma (KS) and Mother-Child Pairs with KS

The seroprevalence of human herpesvirus 8 (HHV-8) among a group of Zambian women of reproductive age and among mother-child pairs in which either one of them has Kaposi’s sarcoma (KS) was determined. A cross-sectional group of 378 pregnant women was randomly recruited into the study, and 183 (48.4%) had HHV-8 antibodies. Among the human immunodeficiency virus (HIV)-1–infected women, 51.1% were HHV-8–seropositive, whereas of HIV- 1–negative women, 47.3% were HHV-8–seropositive. In addition, 21 women index patients with KS and 5 young children index patients with KS were studied. All children with KS had mothers who were HHV-8–seropositive, while not all children whose mothers had KS were infected with HHV-8. Our study suggests that there is a high HHV-8 seroprevalence among Zambian women, and the rate is almost the same in HIV-1–positive and –negative women. This high seroprevalence may be a contributing factor toward the increased frequency of KS in this population

Was Kaposi’s sarcoma-associated herpesvirus introduced into China via the ancient Silk Road? An evolutionary perspective

Kaposi’s sarcoma-associated herpesvirus (KSHV) has become widely dispersed worldwide since it was first reported in 1994, but the seroprevalence of KSHV varies geographically. KSHV is relatively ubiquitous in Mediterranean areas and the Xinjiang Uygur Autonomous Region, China. The origin of KSHV has long been puzzling. In the present study, we collected and analysed 154 KSHV ORF-K1 sequences obtained from samples originating from Xinjiang, Italy, Greece, Iran and southern Siberia using Bayesian evolutionary analysis in BEAST to test the hypothesis that KSHV was introduced into Xinjiang via the ancient Silk Road. According to the phylogenetic analysis, 72 sequences were subtype A and 82 subtype C, with C2 (n = 56) being the predominant subtype. The times to the most recent common ancestors (tMRCAs) of KSHV were 29,872 years (95% highest probability density [HPD], 26,851–32,760 years) for all analysed sequences and 2037 years (95% HPD, 1843–2229 years) for Xinjiang sequences in particular. The tMRCA of Xinjiang KSHV was exactly matched with the time period of the ancient Silk Road approximately two thousand years ago. This route began in Chang’an, the capital of the Han dynasty of China, and crossed Central Asia, ending in the Roman Empire. The evolution rate of KSHV was slow, with 3.44 × 10−6 substitutions per site per year (95% HPD, 2.26 × 10−6 to 4.71 × 10−6), although 11 codons were discovered to be under positive selection pressure. The geographic distances from Italy to Iran and Xinjiang are more than 4000 and 7000 kilometres, respectively, but no explicit relationship between genetic distance and geographic distance was detected

Human Herpesvirus 8 Seroprevalence, China

To summarize the seroprevalence of human herpesvirus 8 (HHV-8) in mainland China, we conducted a systematic review and meta-analysis based on available literature. Data show that differences in HHV-8 prevalence vary considerably among different ethnic groups and geographic regions. Blood-borne transmission could be a potential route for HHV-8 infection in China

How early can myocardial iron overload occur in Beta thalassemia major?

BACKGROUND: Myocardial siderosis is the most common cause of death in patients with beta thalassemia major(TM). This study aimed at investigating the occurrence, prevalence and severity of cardiac iron overload in a young Chinese population with beta TM. METHODS AND RESULTS: We analyzed T2* cardiac magnetic resonance (CMR), left ventricular ejection fraction (LVEF) and serum ferritin (SF) in 201 beta TM patients. The median age was 9 years old. Patients received an average of 13 units of blood per year. The median SF level was 4536 ng/ml and 165 patients (82.1%) had SF>2500 ng/ml. Myocardial iron overload was detected in 68 patients (33.8%) and severe myocardial iron overload was detected in 26 patients (12.6%). Twenty-two patients ≤10 years old had myocardial iron overload, three of whom were only 6 years old. No myocardial iron overload was detected under the age of 6 years. Median LVEF was 64% (measured by CMR in 175 patients). Five of 6 patients with a LVEF<56% and 8 of 10 patients with cardiac disease had myocardial iron overload. CONCLUSIONS: The TM patients under follow-up at this regional centre in China patients are younger than other reported cohorts, more poorly-chelated, and have a high burden of iron overload. Myocardial siderosis occurred in patients younger than previously reported, and was strongly associated with impaired LVEF and cardiac disease. For such poorly-chelated TM patients, our data shows that the first assessment of cardiac T2* should be performed as early as 6 years old

Characterization of HIV-1 subtype C envelope glycoproteins from perinatally infected children with different courses of disease

BACKGROUND: The causal mechanisms of differential disease progression in HIV-1 infected children remain poorly defined, and much of the accumulated knowledge comes from studies of subtype B infected individuals. The applicability of such findings to other subtypes, such as subtype C, remains to be substantiated. In this study, we longitudinally characterized the evolution of the Env V1–V5 region from seven subtype C HIV-1 perinatally infected children with different clinical outcomes. We investigated the possible influence of viral genotype and humoral immune response on disease progression in infants. RESULTS: Genetic analyses revealed that rapid progressors (infants that died in the first year of life) received and maintained a genetically homogeneous viral population throughout the disease course. In contrast, slow progressors (infants that remained clinically asymptomatic for up to four years) also exhibited low levels variation initially, but attained higher levels of diversity over time. Genetic assessment of variation, as indicated by dN/dS, showed that particular regions of Env undergo selective changes. Nevertheless, the magnitude and distribution of these changes did not segregate slow and rapid progressors. Longitudinal trends in Env V1–V5 length and the number of potential N-glycosylation sites varied among patients but also failed to discriminate between fast and slow progressors. Viral isolates from rapid progressors and slow progressors displayed no significant growth properties differences in vitro. The neutralizing activity in maternal and infant baseline plasma also varied in its effectiveness against the initial virus from the infants but did not differentiate rapid from slow progressors. Quantification of the neutralization susceptibility of the initial infant viral isolates to maternal baseline plasma indicated that both sensitive and resistant viruses were transmitted, irrespective of disease course. We showed that humoral immunity, whether passively acquired or developed de novo in the infected children, varied but was not predictive of disease progression. CONCLUSION: Our data suggest that neither genetic variation in env, or initial maternal neutralizing activity, or the level of passively acquired neutralizing antibody, or the level of the de novo neutralization response appear to be linked to differences in disease progression in subtype C HIV-1 infected children