Functional properties of the HIV-1 subtype C envelope glycoprotein associated with mother-to-child transmission

Understanding the properties of viruses capable of establishing infection during perinatal transmission of HIV-1 is critical for designing effective means of limiting transmission. We previously demonstrated that the newly transmitted viruses (in infant) were more fit in growth, as imparted by their envelope glycoproteins, than those in their corresponding mothers. Here, we further characterized the viral envelope glycoproteins from six mother-infant transmission pairs and determined whether any specific envelope functions correlate with HIV-1 subtype C perinatal transmission. We found that most newly transmitted viruses were less susceptible to neutralization by their maternal plasma compared to contemporaneous maternal viruses. However, the newly transmitted variants were sensitive to neutralization by pooled heterologous plasma but in general were resistant to IgG1 b12. Neither Env processing nor incorporation efficiency was predictive of viral transmissibility. These findings provide further insight into the characteristics of perinatally transmissible HIV-1 and may have implications for intervention approaches.     

Diversity of the HIV-1 long terminal repeat following mother-to-child transmission

A study of the human immunodeficiency virus Type 1 (HIV-1) 5' long terminal repeat (LTR) was performed to determine the extent of variation found within the LTR from 19 mother-infant pairs in Tanzania and to assess whether the LTR is useful in distinguishing maternal sequences that were transmitted to infants. HIV-1 subtypes A, C, and D as well as intersubtype recombinant LTR sequences were detected in mothers and infants. The LTR subtype was 100% concordant between mothers and their infants. Diversity calculations showed a significant reduction in LTR variation in infants compared to their mothers. However, the overall magnitude of LTR variation was less than that found in the env gene from the same individuals. These data suggest a selective constraint active upon the 5' long terminal repeat that is distinct from immune selective pressure(s) directed against HIV-1 structural genes. Detection of maternal LTR variants that were transmitted to infants may yield important information concerning nonstructural determinants of HIV-1 transmission from mother to infant.     

Relationship of Antibody to Outcome in Neonatal Herpes Simplex Virus Infections

Neutralizing antibody titers to herpes simplex virus type 1 (HSV-1) and HSV-2 were measured at birth in normal infants and uninfected infants of mothers with genital HSV infections during pregnancy and at the onset of infection in 5 infants with mild infections and 11 infants with severe infections. Thirty-eight percent of premature and 29% of term infants had neutralization titers of <1:5. High titers ([unk]1:40) were found in 55% of infants of mothers with primary infections during pregnancy and in 76% of infants of mothers with recurrent infections. The mean titers to HSV-1 and -2 in 5 infected infants with mild infections were 1:56 and 1:65 at the time of onset of infection, whereas the mean titers in 11 infants with severe infections were 1:11 and 1:12. Six natally exposed infants who remained asymptomatic were also studied and had a mean titer to HSV-1 of 1:85 and to HSV-2 of 1:69. Therefore, infants with high titers of transplacentally derived antibody had a more favorable outcome than infants with lower titers. Ninety-five percent of the infants of mothers with recurrent infections had a Rawls index of more than 85, suggesting that the antibody response was to HSV-2. However, low levels of antibody with this type specificity failed to protect four infants from infection with HSV-2. Augmentation of the neutralization titer to HSV-2 by the amount of complement present in cord serum was less than twofold. The study suggests that the quantity of antibody derived transplacentally affects the outcome of infection after natal exposure to herpes simplex virus. Complete neutralization of virus by antibody may occur in some infants, and prolongation of the incubation period and modification of the infection may occur in others.     

Resistance of recent measles virus wild-type isolates to antibody-mediated neutralization by vaccinees with antibody

The neutralization capacity of sera from Luxembourgian adolescent vaccinees and from Nigerian women with measles-induced immunity to a number of measles virus strains was compared. Although both cohorts were matched for their hemagglutination inhibition and standard neutralization titers, 12 of the 22 late convalescent sera, and only 6 of 24 vaccinees neutralized all viruses. Similarly, only 2 of 20 viruses were not neutralized by at least 75% of late convalescent sera, in comparison to 10 of 20 viruses that resisted neutralization by at least 75% of the vaccinees. The more resistant viruses were not limited to a certain clade. One Nigerian virus was resistant to neutralization by 30% of the late convalescent women and by 75% of vaccinees. These results suggest that qualitative differences in neutralizing antibodies may reduce further protection of infants by passively acquired immunity against wild-type viruses when vaccinated girls become mothers.     

Genetic analysis of small ruminant lentiviruses following lactogenic transmission

Lactogenic transmission plays an important role in the biology of lentiviruses such as HIV and SIV or the small ruminant lentiviruses (SRLV). In this work we analyzed the characteristics of viruses that goats, naturally infected with two strains of SRLV, transmitted to their kids. The spectrum of viral genotypes transmitted was broader and the efficiency of transmission greater compared to their human and simian counterparts. The newly described A10 subgroup of SRLV was more efficiently transmitted than the B1 genotype. The analysis of a particular stretch of the envelope glycoprotein encompassing a potential neutralizing epitope revealed that, as in SIV, the transmitted viruses were positively charged in this region, but, in contrast to SIV, they tended to lack a glycosylation site that might protect against antibody neutralization. We conclude that the physiology of the ruminant neonatal intestine, which permits the adsorption of infected maternal cells, shaped the evolution of these particular lentiviruses that represent a valid model of lactogenic lentivirus transmission.     

Compartmentalization of HIV-1 between breast milk and blood of HIV-infected mothers

HIV-1 variants in breast milk and peripheral blood have been compared in three HIV-1 infected mothers. Analysis of DNA and RNA env C2-V3 sequences showed a differential distribution of HIV variants between the two compartments. The major provirus variant found in breast milk corresponds to a minor variant in the blood of two mothers. In the third mother, the predominant proviral variant detected in breast milk was not represented in the HIV-1 blood population. The major RNA variant in breast milk was not represented in the blood of two mothers. The predominant RNA variant in breast milk and blood was however the same for the third mother. Unexpectedly, the pattern of free virus variants in breast milk of three mothers did not correspond to that of the proviral form, suggesting that free viruses do not derive from infected cells in breast milk. The observation of a compartmentalization of HIV-1 between peripheral blood and breast milk emphasizes that postnatal transmission of HIV occurs with variants that may not be predicted from the analysis of circulating viral populations.     

Effect of pregnancy on proteoglycan-induced progressive polyarthritis in BALB/c mice: remission of disease activity

Proteoglycan-induced arthritis is a murine autoimmune model displaying many similarities to human rheumatoid arthritis and ankylosing spondylitis, as has been documented by clinical, immunological and histopathological studies. Since the onset of arthritis correlates with the serum antibody level to mouse cartilage proteoglycan (PG), it is believed that these autoreactivc antibodies may play crucial roles in the pathological mechanisms of PG-induced arthritis. We have found that fertility in these PG-induced arthritic mice had been reduced but, unlike collagen-induced arthritis, had not been completely lost. Moreover, pregnancy had a beneficial effect upon the clinical symptoms with very little or no influence on scrum antibody levels. Although fertility was retained and arthritic mothers delivered healthy offspring, the birth frequency was significantly less than in non-arthritic age-matched controls. Furthermore, the presence of anti-PG autoantibodies (predominantly IgG1 subclass) transmitted from arthritic mothers to infants transplacentally and by milk during the lactation period did not render these offspring either resistant or more sensitive to subsequent induction of arthritis. Subsequent immunization of infants with ‘arthritogenic’ PG revealed an unaltered susceptibility to arthritis induction.     

The neutralization sensitivity of viruses representing human immunodeficiency virus type 1 variants of diverse subtypes from early in infection is dependent on producer cell, as well as characteristics of the specific antibody and envelope variant

Neutralization properties of human immunodeficiency virus (HIV-1) are often defined using pseudoviruses grown in transformed cells, which are not biologically relevant HIV-1 producer cells. Little information exists on how these viruses compare to viruses produced in primary lymphocytes, particularly for globally relevant HIV-1 strains. Therefore, replication-competent chimeras encoding envelope variants from the dominant HIV-1 subtypes (A, C, and D) obtained early after infection were generated and the neutralization properties explored. Pseudoviruses generated in 293T cells were the most sensitive to antibody neutralization. Replicating viruses generated in primary lymphocytes were most resistant to neutralization by plasma antibodies and most monoclonal antibodies (b12, 4E10, 2F5, VRC01). These differences were not associated with differences in envelope content. Surprisingly, the virus source did not impact neutralization sensitivity of most viruses to PG9. These findings suggest that producer cell type has a major effect on neutralization sensitivity, but in an antibody dependent manner.     

Transmission of cell-free and cell-associated HIV-1 through breast-feeding

BACKGROUND: Transmission through breast-feeding is an important cause of infant HIV-1 infections in developing countries; however, its mechanism remains largely unknown. We have explored the association between cell-free virus (CFV) and cell-associated virus (CAV) levels in breast milk (BM), as reflected by viral RNA and proviral DNA, respectively, and the risk of infant HIV-1 infection after 6 weeks postpartum. METHODS: Sixty-one HIV-positive mothers who transmitted HIV-1 by BM were matched to 61 HIV-positive nontransmitting mothers based on their infant's age at sample collection. CFV and CAV were quantified in a single milk specimen per mother preceding the infant's first HIV-positive result. RESULTS: After adjusting for maternal CD4 cell counts and disease stage, each 10-fold increase in CFV or CAV load was associated with an almost 3-fold increase in BM transmission. Whereas CAV load was predictive of transmission before and after 9 months postpartum, CFV was a significant predictor of transmission occurring only after 9 months. Phylogenetic analyses of the C2 to C5 env region showed that 85% of infants (11 of 13 infants) harboring viruses that clustered with CFV in their mother's milk were infected after 9 months postpartum. CONCLUSION: A reduction in milk CAV and CFV loads might significantly decrease HIV-1 transmission by breast-feeding.     

In vitro selection of influenza B viruses with reduced sensitivity to neuraminidase inhibitors

We and others have previously isolated influenza B viruses with reduced sensitivity to neuraminidase (NA) inhibitors (oseltamivir and zanamivir) from patients who were never exposed to these drugs. It was unclear whether the NA substitutions found in these influenza B isolates arose spontaneously or were caused by selective pressure. Here, we obtained influenza B viruses with reduced NA inhibitor sensitivity by in vitro selection with NA inhibitors. We found that these viruses possessed the same NA substitutions as those previously found in viruses isolated from untreated patients. These results suggest that these NA substitutions were selected in patients who were treated with an NA inhibitor and that the resistant variants were then transmitted to others.     

Mother-to-infant transmission of multiple blood-borne viral infections from multi-infected mothers

Infants born from mothers with multiple blood-borne viral infections are at risk of multiple transmissions. Whether the risk of transmission of multiple infections increases with the number of viruses infecting the mother is still unknown. The aim of this study was to describe the risk of mother-to-infant transmission of multiple infections from multi-infected mothers. Sixty-four pregnant women infected by at least two viruses among human immunodeficiency virus-type 1 (HIV-1), hepatitis C virus, TT virus, and GB virus type C, together with their 64 infants, were studied. Maternal blood samples were collected in the third trimester of pregnancy and all infants were prospectively followed for evaluation of transmission within 3 months after birth and two times in the subsequent 24 months. Transmission of single and of dual infection from mothers infected by two viruses was, respectively, 10/40 (25%) and 5/40 (12.5%) and from mothers infected by three viruses 9/20 (45%) and 2/20 (10%). One (25%) infant infected by one virus was born from the four mothers infected by four viruses. Transmission of single or dual infection was not significantly associated with the number of viruses infecting the mother (P = 0.9) in the linear regression analysis. Present study suggests the absence of a synergistic effect from viral interactions toward mother-to-infant transmission of multiple infections and supports the hypothesis that transmission from multi-infected mothers is the result of the specific interaction between each virus and the host. These observations may be of clinical relevance in perinatal counseling.     

The Role of superantigens in virus infection

Murine mammary tumor viruses are retroviruses which encode superantigens capable of stimulating T cells via superantigen-reactive T-cell receptor Vβ chains. Murine mammary tumor viruses are transmitted to the suckling offspring through the milk. We have established that B cell-deficient pups which were foster-nursed by virus-secreting mice do not transfer infectious murine mammary tumor viruses to their offspring. No murine mammary tumor virus proviruses could be detected in the spleen and mammary tissue of these mice. We conclude that B cells are essential for the completion of the viral life cyclein vivo. This indicates that B cells are infected first and that viral amplification takes place only if infected B cells present the murine mammary tumor virus superantigen on their surface, which, in turn, results in activation of T cells expressing the appropriate T-cell receptor Vβ chains. These activated T cells secrete factors which stimulate B cells, enabling viral replication.     

Prospective cohort study of mother‐to‐infant infection and clearance of hepatitis C in rural Egyptian villages

Although persistent transmission of hepatitis C virus (HCV) from infected mothers to their infants is reported in 4–8%, transient HCV perinatal infection also occurs. This prospective cohort study determined perinatal HCV infection‐ and early and late clearance‐rates in 1,863 mother‐infant pairs in rural Egyptian villages. This study found 15.7% and 10.9% of pregnant women had HCV antibodies (anti‐HCV) and HCV‐RNA, respectively. Among 329 infants born of these mothers, 33 (10.0%) tested positive for both anti‐HCV and HCV‐RNA 2 months following birth—29 (12.5%) having HCV‐RNA positive mothers and 4 (with transient infections) having mothers with only anti‐HCV. Fifteen remained HCV‐RNA positive at one and/or 2 years (persistent infections), while 18 cleared both virus and antibody by 1 year (transient infections). Among the 15 persistent cases, 7 cleared their infections by 2 or 3 years. At 2‐ to 6‐ and at 10‐ to 12‐month maternally acquired anti‐HCV was observed in 80% and 5% of infants, respectively. Four perinatally infected and one transiently infected infant were confirmed to be infected by their mothers by the sequence similarity of their viruses. Viremia was 155‐fold greater in mothers of infants with persistent than mothers of infants with transient infections. Maternal‐infant transmission of HCV is more frequent than generally reported. However, both early and late clearance of infection frequently occurs and only 15 (4.6%) and 8 (2.4%) infants born of HCV‐RNA positive mothers had detectable HCV‐RNA at one and 2–3 years of age. Investigating how infants clear infection may provide important information about protective immunity to HCV. J. Med. Virol. 81:1024–1031, 2009. © 2009 Wiley‐Liss, Inc.     

Heterogeneity analysis of the hepatitis B virus genome in intrauterine infection

There are many factors leading to intrauterine infection with hepatitis B virus (HBV). These factors include viral structure, HBV mutations, HBV DNA level, placenta barrier, immune status of the mother, and susceptibility of the fetus. The purpose of this study was to investigate the possible relationship between intrauterine infection with and HBV mutations of the genome of the virus. In this study, HBsAg-positive mothers were divided into two groups: intrauterine infection group and non-infection group according to whether the newborn infants were infected or not. The intrauterine infection group included four pairs of mother and their newborn infants infected in utero, and non-infection group included five HBsAg-positive mothers. HBV sequences from the two groups were analyzed and compared. The predominant strains in the mothers and infants from the intrauterine infection group were not completely consistent. This suggested that both HBV predominant strains and minority strains in the mothers could infect their infants through intrauterine transmission. Some HBV mutations probably related to intrauterine infection were examined and it was found that the frequencies of mutations were low in isolates of the virus of infants from the intrauterine infection group and high in the non-infection group. These results suggest that some strains of HBV from the mother may be transmitted selectively to the fetus in utero because of viral heterogeneity. The strains without screened mutations such as P21L in the pre-S1 region may infect the fetus more readily.     

Mutation analysis of hepatitis B virus promoters in chronically infected children

Summary. Hepatitis B viral (HBV) infection in early childhood is one of the leading causes of chronic hepatitis and liver cirrhosis that eventually lead to hepatic carcinoma. Despite the nationwide immunization programs to curtail the vertical transmission of HBV, childhood HBV infection through mothers is still occurring in Korea. As one of the efforts to understand the childhood HBV infection in Korea, four HBV promoter sequences in the sera of the chronically infected children were analyzed. Children harbored diverse viral variants as most of the chronically infected adult patients, but the deletion mutations were rare. The dominant viral sequences in the children were highly similar to the ones in the respective mothers, indicating that the maternal viruses were most likely transmitted to the children. The mutations in X, S1, S2/S promoters did not seem to show any correlation to the severity of the disease nor ages of the children. The mutations that showed some correlation to the severity of the disease were the mutations in C promoter, but the mutations did not seem to be vertically transmitted. Finally, the children with the elevated ALT/AST levels tended to have more child-specific variants suggesting that the accumulation of host-specific mutations might be associated with the development of clinical symptoms.     

Biological characterization of plaque-size variants of yellow fever virus in mosquitoes and mice

We isolated plaque-size variants of a South American strain of yellow fever virus, and compared their ability to infect orally and be transmitted by vector Aedes aegypti mosquitoes with that of the uncloned, parental virus. We analyzed the same clonal isolates in mouse virulence experiments. No significant differences could be demonstrated in the capacities of the variants to infect and be transmitted by mosquitoes or in mouse virulence tests. The 17D vaccine virus (derived from the African Asibi strain) was, however, markedly attenuated in mosquitoes; also, a variant virus (Asibi strain) derived by continuous passage in HeLa cells (and attenuated for monkeys and mice) was markedly attenuated in mosquitoes when compared with its parent virus. The results suggest that vector competence and mouse virulence are similar in plaque-size variants of the South American strain of yellow fever virus. However, if vigorous and appropriate selection pressures are applied (as established by the derivation of the 17D vaccine and HeLa passaged viruses), attenuated variants can be discovered; their role and prevalence within a virus population in nature is unknown.     

Mother-to-infant transmission occurs more frequently with GB virus C than hepatitis C virus

Summary.  A total of 107 hepatitis C virus (HCV)-infected pregnant women were screened for GB virus C (GBV-C) RNA in their sera, and 11 (10.3%) were positive. Among 11 infants born to these HCV/GBV-C co-infected mothers, GBV-C RNA was detected in 7 (63.6%) while HCV RNA was found in 1 (9.1%) within 1 year after birth: this difference was statistically significant (p = 0.023). The mothers of infected infants had significantly higher serum titers of GBV-C RNA than those of uninfected infants: 10^6.7±0.5 vs 10^4.0±1.0 copies/ml in average (p=0.001). The baby in whom HCV RNA was found was also positive for GBV-C RNA, and had an elevation in serum transaminase levels, whereas all the other GBV-C infected infants showed no evidence for hepatitis. A family study, performed on 2 of the 7 infected cases, revealed that all the elder siblings of the index infants were also GBV-C RNA-positive. Nucleotide sequence of GBV-C RNA, amplified by PCR from an NS3 region, was completely identical between the mother and the infant within each family, but varied significantly across different families. These results suggest that GBV-C is more easily transmitted from mother to infant than HCV, although hepatitis is not caused thereby. Aaccepted August 26, 1997 Received July 30, 1997     

Genetic variability of the V1 and V2 env domains of SIVcpz-ant and neutralization pattern of plasma viruses in a chimpanzee infected naturally.

Specific neutralizing epitope changes have been observed in a chimpanzee infected naturally with SIVcpz, which differ from HIV-1 infecting humans. To characterize further these changes, a longitudinal study of env genomic sequence variation of SIVcpz-ant isolates was undertaken in this animal. The V1 and V2 regions of the env were determined to arise from specific recombination events. To determine whether recombination of the V1 and V2 domains was possibly associated with the emergence of neutralization escape viruses, envelope sequences and gene length polymorphisms from PBMC and plasma viral variants were studied over a 7-year period. PBMCs and plasma-associated infectious virus titers as well as plasma RNA viral loads were monitored longitudinally. The first 5 viruses isolated from the plasma were found to be neutralization escape variants. Sequence analysis of their V1 and the V2 regions indicated that a 20 amino acid stretch of the V1 region had undergone recombination and was also associated with the emergence of isolates eliciting strong neutralization responses. These findings support the hypothesis that recombination of the V1 and V2 regions of the envelope play a role in neutralization escape of SIVcpz in chimpanzees infected naturally. Furthermore, the data confirm that the neutralizing antibody response plays an important role in the decline of plasma infectious virus titers in HIV-1 related SIVcpz nonpathogenic infection.     

Intrauterine Growth Retardation of Unknown Etiology. I. Serum Complement and Circulating Immune Complexes in Mothers and Infants

ABSTRACT: Complement (C) and circulating immune complexes (CIC) levels were measured in 22 full-term pregnant women and 15 of their small-for-gestational-age (SGA) offspring in order to seek evidence supporting an immunological etiology for placental lesions related to idiopathic intrauterine growth retardation. We used 19 normal full-term pregnant women and 18 of their infants with birthweight above the 25th centile of the ponderal curve as a control population for this study. C levels were significantly lower in mothers of SGA infants than in controls (146.6 ± 46.6 and 183.6 ± 36.6 respectively, p < 0.01). CIC were present in the sera of 5 out of 22 mothers of the SGA group and in 3 out of the 15 infants sera. No CIC were found in the sera of mothers or infants from the control group. Placental lesions were observed in 14 out of the 22 (64%) cases studied in the SGA group and in 1 of 11 (9%) of the controls. Two placentas from SGA infants showed acute atherosis, and deposits of IgM and C₃ were found in their vessel walls. These data are in favor of an immunological mechanism for intrauterine growth retardation of unknown etiology.     

Quasispecies characters of hepatitis B virus in immunoprophylaxis failure infants

Hepatitis B vaccination prevents 80–95% of transmission and reduces the incidence of HBV in children. The variations in the a determinant of HBV surface antigen (HBsAg) have been reported to be the most prevalent cause for vaccine or antibody escape. There is a conflicting evidence on as to whether escape mutants arise de novo in infected infants or whether the mutants, that have preexisted maternally, subsequently undergo selective replication in the infant under immune pressure. Here, we report that nearly 65% (55 of 85) vaccination failure in child patients has no amino acid substitution in a determinant as seen by Sanger sequencing. We further employed an Illumina sequencing platform-based method to detect HBV quasispecies in four immunoprophylaxis failure infants and their mothers. In our data, the substitution rate of amino acid located at a determinant is relatively low (<?10%), I/T126A, C124S, F134Y, K141Q, Q129H, D144A, G145V, and N146K, which showed no statistical difference to their mothers, proving that these vaccine escape mutants preexist maternally as minor variants. Besides that, bioinformatical analysis showed that the binding affinity of high variation epitopes (amino acid divergence in mother and their infants >?20%) to related HLA molecules was generally decreased, these traces of immune escape suggesting that immune pressure was present and was effective in all samples.