阻断乙型肝炎病毒母婴传播方案探讨

目的探讨阻断乙型肝炎病毒母婴传播的有效方法。方法将乙型肝炎病毒携带孕妇,根据她们的不同情况和就诊的不同时期分为6组,Ms组为乙肝表面抗原阳性乙肝e抗原阴性的孕妇,根据就诊的不同时期分为Ms1组、Ms2组、Ms3组。Mse组为乙肝表面抗原和乙肝e抗原双阳性孕妇。MF组为孕妇与配偶均为乙型肝炎病毒携带者。F组为孕妇为非乙型肝炎病毒携带者配偶为乙型肝炎病毒携带者的孕妇。各组采用不同的方法阻断乙型肝炎病毒的垂直传播。结果 Ms1组230例中有22例母亲孕期用过乙肝免疫球蛋白（占本组总数9.6%）。Ms2组：372例中有37例母亲孕期用过乙肝免疫球蛋白（占本组总数9.9%）。Ms3组287例中有4例母亲孕期检测乙型肝炎病毒脱氧核糖核酸阳性用过HBIG（占本组总数1.4%）,与Ms1组和Ms2组母亲用乙肝免疫球蛋白率9.6%和9.9%比较经统计学处理差异都非常显著（χ2=17.850,P=0.000）;（χ2=20.311,P=0.000）。Mse组32例母亲在孕期都用过乙肝免疫球蛋白（占本组总数100%）。MF组72例中有20例母亲在孕期用过乙肝免疫球蛋白（占本组总数27.7%）。F组：48例中3例母亲在孕期用过乙肝免疫球蛋白（占本组总数6.2%）;32例母亲在孕期用过乙肝疫苗接种（占本组总数66.6%）。各组共1041例新生儿生后24h内静脉血乙肝抗原抗体定性检测：乙肝表面抗原和乙肝e抗原均为阴性。生后3个月至1岁随访检测婴儿静脉血1041例乙肝抗原定性乙肝表面抗原和乙肝e抗原仍均为阴性。结论孕妇或配偶为乙型肝炎病毒携带者,如乙肝e抗原阳性或乙型肝炎病毒脱氧核糖核酸阳性孕妇孕期需要注射乙肝免疫球蛋白阻断乙型肝炎病毒传播,否则不需要。父母为乙型肝炎病毒携带者,如新生儿生后检测乙型肝炎病毒抗原检测阳性需要注射乙肝免疫球蛋白,否则不需要。所有新生儿必须接种乙肝疫苗。     

Plasmodium Falciparum malaria and perinatally acquired human immunodeficiency virus type 1 infection in Kinshasa, Zaire. A prospective, longitudinal cohort study of 587 children

BACKGROUND. It is uncertain whether Plasmodium falciparum malaria is more frequent or more severe in children with perinatally acquired human immunodeficiency virus type 1 (HIV-1) infection and whether P. falciparum infection accelerates the progression of HIV-related disease. METHODS. We conducted a prospective, longitudinal cohort study in Kinshasa, Zaire. Two hundred sixty children 5 to 9 months of age who had been born to HIV-1-seropositive mothers and 327 children of the same age who had been born to seronegative mothers were monitored intensively for malaria over a 13-month period. All episodes of fever were evaluated with blood smears for malaria, and children found to be infected with P. falciparum were treated with a standard regimen of oral quinine. RESULTS. A total of 2899 fevers were evaluated, with 271 cases of malaria identified. No statistically significant differences were found in the incidence, severity, or response to therapy of malaria among four well-defined groups of children: those with the acquired immunodeficiency syndrome (AIDS), those who were HIV-1-seropositive throughout the study, those who were born to HIV-1-seropositive mothers but reverted to seronegative, and those who were seronegative throughout the study. During the 13-month period the incidence of malaria in the 36 children with HIV infection in whom AIDS developed was lower, although not significantly so, than in the 37 in whom AIDS did not. CONCLUSIONS. In this study malaria was not more frequent or more severe in children with progressive HIV-1 infection and malaria did not appear to accelerate the rate of progression of HIV-1 disease.     

Differences in perinatal transmission among human immunodeficiency virus type 1 genotypes

OBJECTIVE: To determine whether genotypes from human immunodeficiency virus type 1 (HIV-1) subtypes A, C, or D or intersubtype recombinants have the same probability of being transmitted from mother to child. METHODS: We determined the HIV-1 genetic subtype and maternal risk factors of 51 matched transmitting and nontransmitting mothers from Tanzania. The HIV-1 gag (p24-p7) and env (C2-C5) nucleotide sequences were used for genotype classification, and matched logistic regression analysis was used to assess differences among genotypes. RESULTS: Mothers infected with HIV-1 subtype A (odds ratio, 3.8; 95% CI, 0.8-24.7%), HIV-1 subtype C (odds ratio, 5.1; 95% CI, 1.3-30.8%), or HIV-1 intersubtype recombinant viruses (odds ratio, 5.3; 95% CI, 1.2-33.4%) were more likely to transmit HIV-1 to their infants than mothers infected with HIV-1 subtype D. Lower CD4 cell counts at enrollment were associated with transmission, but CD4 cell counts within each genotype did not explain differences in transmission among HIV-1 genotypes. CONCLUSION: We have shown that HIV-1 genotypes might be associated with differential risk for vertical transmission. These findings provide the first evidence that HIV-1 genetic subtypes may play a role in rates of vertical transmission in an African setting.     

In-utero transmission of quasispecies among human immunodeficiency virus type 1 genotypes

Samples from infants infected in-utero by the human immunodeficiency virus type 1 (HIV-1) subtypes A, C, D, and recombinants from Dar es Salaam, Tanzania, were examined for the presence of viral genetic quasispecies. HIV-1 envelope diversity was measured on peripheral blood mononuclear cells collected within the first 48 h of life from 53 infants. Phylogenetic analysis of C2-C5 envelope nucleotide sequences was used for HIV-1 subtype classification. Forty-two of 53 samples (79%) showed a heteroduplex mobility assay (HMA) suggestive of transmission of a single quasispecies, while 21% showed infection with multiple quasispecies. No differences among HIV-1 subtypes were found in the proportion of single to multiple quasispecies transmitted in-utero (Likelihood ratio test, P = 0.83), nor were differences found among single to multiple quasispecies transmitted and maternal viral load (Mann-Whitney test, P = 0.44). This suggests that differences in perinatal transmission between subtypes we previously observed in this cohort could not be associated with the likelihood for multiple independent infections during in-utero infections.     

A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia

We evaluated a multicenter cohort of 1219 subjects with hemophilia or related disorders prospectively, focusing on 319 subjects with documented dates of seroconversion to human immunodeficiency virus type 1 (HIV-1). The incidence rate of the acquired immunodeficiency syndrome (AIDS) after seroconversion was 2.67 per 100 person-years and was directly related to age (from 0.83 in persons 1 to 11 years old up to 5.66 in persons 35 to 70 years old; Ptrend = 0.00003). The annual incidence of AIDS ranged from zero during the first year after seroconversion to 7 percent during the eighth year, with eight-year cumulative rates (+/- SE) of 13.3 +/- 5.3 percent for ages 1 to 17, 26.8 +/- 6.4 percent for ages 18 to 34, and 43.7 +/- 16.4 percent for ages 35 to 70. Serial immunologic and virologic markers (total numbers of CD4 lymphocytes, presence of serum interferon or HIV-1 p24 antigen, and low or absent serum levels of anti-p24 or anti-gp120) predicted a high risk for the subsequent development of AIDS. Adults 35 to 70 years old had a higher incidence of low CD4 counts than younger subjects (P less than or equal to 0.005), whereas adolescents had a low rate of anti-p24 loss (P = 0.0007) and subjects 1 to 17 years old had a lower incidence of AIDS after loss of anti-p24 (P = 0.03). These findings not only demonstrate that the risk of AIDS is related directly to age but also suggest that older adults are disproportionately affected during the earlier phases of HIV disease, that adolescents may have a low replication rate of HIV, and that children and adolescents may tolerate severe immunodeficiency better because they have fewer other infections or because of some unmeasured, age-dependent cofactor or immune alteration in the later phase of HIV disease.     

A prospective study of infants born to women seropositive for human immunodeficiency virus type 1. HIV Infection in Newborns French Collaborative Study Group

Assessment of the risks of transmission of infection with human immunodeficiency virus type 1 (HIV-1) from mother to newborn is difficult, partly because of the persistence for up to a year of maternal antibodies transmitted passively to the infant. To determine the frequency of perinatal transmission of HIV infection, we studied from birth 308 infants born to seropositive women, 62 percent of whom were intravenous drug abusers. Of 117 infants evaluated 18 months after birth, 32 (27 percent) were seropositive for HIV or had died of the acquired immunodeficiency syndrome (AIDS) (n = 6); of the 32, only 2 remained asymptomatic. Another 76 infants (65 percent) were seronegative and free of symptoms, whereas 9 (8 percent) were seronegative but had symptoms suggestive of HIV-1 infection. The infants infected with HIV-1 did not differ from the others at birth with respect to weight, height, head circumference, or rate of malformations, but as compared with newborns who were seronegative at 18 months, their serum IgM levels were higher (78 +/- 81 mg per deciliter vs. 38 +/- 39 mg per deciliter; P less than 0.03) and their CD4 lymphocyte counts were lower (2054 +/- 1221 per cubic millimeter vs. 2901 +/- 1195 per cubic millimeter; P less than 0.006). Neither maternal risk factors nor the route of delivery was a predictor of seropositivity at 18 months; however, 5 of the 6 infants who were breast-fed became seropositive, as compared with 25 of 99 who were not (P less than 0.01). We conclude that approximately one third of the infants born to seropositive mothers will have evidence of HIV-1 infection or of AIDS by the age of 18 months, and that about one fifth of this group will have died.     

Rapid screening for early detection of mother-to-child transmission of human immunodeficiency virus type 1.

The testing of dried blood spots (DBSs) for the presence of human immunodeficiency type 1 (HIV-1) proviral DNA by PCR was first described in 1991. The technology has proven to be particularly valuable for resolving the infection status in HIV-1-indeterminate infants born to HIV-1-seropositive mothers. To broaden the applicability of DBS PCR, we adapted it to a standardized, commercially available microwell plate amplification and detection kit, Amplicor HIV-1, produced by Roche Diagnostic Systems. The microwell assay is rapid and easy to perform and uses equipment that is readily available in routine diagnostic laboratories. The high level of performance of the assay was demonstrated in 1,168 duplicate tests performed on 584 DBSs from 178 uninfected and 100 HIV-1-infected individuals, including 56 children with perinatally acquired HIV-1. Of 12 infants who were followed prospectively from birth, 3 (25%) were infected in utero (PCR positive at birth) and 9 (75%) were infected intrapartum (PCR negative, culture negative at birth). Overall, HIV-1 DNA was identified in 3 of 11 (27.3%) DBSs collected from infected infants during the first 4 days of life, 8 of 9 (88.9%) DBSs collected between 10 and 15 days postpartum, and 166 of 167 (99.4%) DBSs collected after 15 days of age. All 320 DBSs from uninfected children were PCR DNA negative. These findings indicate that use of the Roche microwell DBS PCR assay provides a powerful new approach for large-scale perinatal screening programs and population-based studies of vertical transmission.     

Immunoprecipitation of human immunodeficiency virus type 2 glycoproteins by sera positive for human immunodeficiency virus type 1.

Analysis by radioimmunoprecipitation of serum samples from 27 different human immunodeficiency virus type 1 (HIV-1)-infected individuals residing in Chile showed that the sera of 26% of these individuals also react with glycoprotein gp125 of HIV type 2 (HIV-2). This cross-reaction seems to reflect a qualitative difference among infected individuals, because the titer of antibodies against gp120 of HIV-1 in the cross-reacting samples did not differ significantly from that in the non-cross-reacting samples. Most of the HIV-1-seropositive sera, including many that did not react with gp125 of HIV-2, reacted with gp140, the precursor of HIV-2 glycoproteins. The observed cross-reactions allowed us to distinguish three groups of HIV-1-infected individuals: (i) those whose sera react with both gp140 and gp125, (ii) those whose sera react with gp140, and (iii) those whose sera react with neither of these glycoproteins. The possible cause and significance of these differences is under study.     

Perinatal transmission of the human immunodeficiency virus type 1 to infants of seropositive women in Zaire

To examine perinatal transmission of the human immunodeficiency virus type 1 (HIV-1) in Zaire, we screened 8108 women who gave birth at one of two Kinshasa hospitals that serve populations of markedly different socioeconomic status. For up to one year, we followed the 475 infants of the 466 seropositive women (5.8 percent of those screened) and the 616 infants of 606 seronegative women matched for age, parity, and hospital. On the basis of clinical criteria, 85 of the seropositive women (18 percent) had the acquired immunodeficiency syndrome (AIDS). The infants of seropositive mothers, as compared with those of seronegative mothers, were more frequently premature, had lower birth weights, and had a higher death rate in the first 28 days (6.2 vs. 1.2 percent; P less than 0.0001). The patterns were similar at the two hospitals. Twenty-one percent of the cultures for HIV-1 of 92 randomly selected cord-blood samples from infants of seropositive women were positive. T4-cell counts were performed in 37 seropositive women, and cord blood from their infants was cultured. The cultures were positive in the infants of 6 of the 18 women with antepartum T4 counts of 400 or fewer cells per cubic millimeter, as compared with none of the infants of the 19 women with more than 400 T4 cells per cubic millimeter (P = 0.02). One year later, 21 percent of the infants of the seropositive mothers had died as compared with 3.8 percent of the control infants (P less than 0.001), and 7.9 percent of their surviving infants had AIDS. We conclude that the mortality rates among children of seropositive mothers are high regardless of socioeconomic status, and that perinatal transmission of HIV-1 has a major adverse effect on infant survival in Kinshasa.     

Toll-like receptor 9 polymorphisms influence mother-to-child transmission of human immunodeficiency virus type 1

Background  

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns and play a crucial role in the host's innate immune response. Genetic variations in TLR genes may influence host-viral interactions and might impact upon the risk of mother-to-child transmission (MTCT) of Human Immunodeficiency Virus type 1 (HIV-1). The aim of this study was to investigate the influence of genetic variants of TLR 9 gene on MTCT.     

Cellular latency of human immunodeficiency virus type 1.

The infection of humans by human immunodeficiency virus type 1 is characterized by a prolonged stage of clinical quiescence. This clinically asymptomatic period may be based, in part, on the development of cell populations within the body that maintain human immunodeficiency virus type 1 in a state of latency. Recent advances in the understanding of the molecular mechanisms involved in various forms of cellular latency of human immunodeficiency virus type 1 have begun to shed light on the variable period of asymptomatic infection. The elucidation of cellular retroviral latency, in vivo, will also be critical to the design of novel therapeutic approaches with which to combat human immunodeficiency virus type 1 infections.     

Variability of human immunodeficiency virus type 1

The variability of human immunodeficiency virus type 1 (HIV-1) is very high. To date, three distinct lineages of HIVs, type 1 group M, type 1 group O and type 2 are described, suggesting at least three different zoonotic infections. HIV-1 group M is responsible for the global epidemic of AIDS. At least ten subtypes of HIV-1 group M, labelled A through J, have been discovered. Viral sequences from both the gag and the env gene, particularly a part of gp 120 referred to as the V3 region have been used to identify subtypes of HIV-1 group M. The nucleotide distance between viruses of different subtypes is on average 30% for the env gene. The various subtypes are geographically distributed throughout the world. Some of the subtypes were identified as recombinant or mosaic viruses. The existence of different subtypes of HIV-1 have major implication for vaccination. They may also influence the diagnosis of HIV infection. To date, it is unclear whether subtypes of HIV-1 differ with respect to transmissibility or pathogenicity.     

Molecular investigation of transmission of human immunodeficiency virus type 1 in a criminal case

Very few criminal cases involving human immunodeficiency virus type 1 (HIV-1) transmission have been described. We report on an HIV-1 transmission case with a child being infected by an HIV-1-positive man. The objective was to determine through molecular epidemiology and phylogenetic analyses whether HIV-1 from the HIV-1-positive man could be the source of infection in the HIV-1-positive child, as claimed by the authorities. We conducted genetic analysis of three different parts of the HIV-1 genome (gag, pol, and env) by PCR, direct-sequencing, and phylogenetic analyses. We used maximum likelihood, maximum parsimony, and neighbor-joining methods for the phylogenetic analyses to investigate whether the sequences from the man and the child were related. We found that the viral sequences from the man and the child formed separate clusters in all of the phylogenetic analyses compared to the local controls. A unique amino acid deletion was identified in the C2-V3-C3 region of the env gene in the virus from the man and the child. These results were used in the criminal court to elucidate whether the virus from the man was related to the virus from the child. In summary, the results from the phylogenetic analyses, the sequence distances between the virus from the man and the virus from the child, and the identification of the unique molecular fingerprint in the env gene together indicated that the virus from the man and the virus from the child were epidemiologically linked.     

Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group

BACKGROUND AND METHODS: We examined the influence of viral load in relation to other risk factors for the heterosexual transmission of human immunodeficiency virus type 1 (HIV-1). In a community-based study of 15,127 persons in a rural district of Uganda, we identified 415 couples in which one partner was HIV-1-positive and one was initially HIV-1-negative and followed them prospectively for up to 30 months. The incidence of HIV-1 infection per 100 person-years among the initially seronegative partners was examined in relation to behavioral and biologic variables. RESULTS: The male partner was HIV-1-positive in 228 couples, and the female partner was HIV-1-positive in 187 couples. Ninety of the 415 initially HIV-1-negative partners seroconverted (incidence, 11.8 per 100 person-years). The rate of male-to-female transmission was not significantly different from the rate of female-to-male transmission (12.0 per 100 person-years vs. 11.6 per 100 person-years). The incidence of seroconversion was highest among the partners who were 15 to 19 years of age (15.3 per 100 person-years). The incidence was 16.7 per 100 person-years among 137 uncircumcised male partners, whereas there were no seroconversions among the 50 circumcised male partners (P<0.001). The mean serum HIV-1 RNA level was significantly higher among HIV-1-positive subjects whose partners seroconverted than among those whose partners did not seroconvert (90,254 copies per milliliter vs. 38,029 copies per milliliter, P=0.01). There were no instances of transmission among the 51 subjects with serum HIV-1 RNA levels of less than 1500 copies per milliliter; there was a significant dose-response relation of increased transmission with increasing viral load. In multivariate analyses of log-transformed HIV-1 RNA levels, each log increment in the viral load was associated with a rate ratio of 2.45 for seroconversion (95 percent confidence interval, 1.85 to 3.26). CONCLUSIONS: The viral load is the chief predictor of the risk of heterosexual transmission of HIV-1, and transmission is rare among persons with levels of less than 1500 copies of HIV-1 RNA per milliliter.     

Contribution of immune activation to the pathogenesis and transmission of human immunodeficiency virus type 1 infection

The life cycle of human immunodeficiency virus type 1 (HIV-1) is intricately related to the activation state of the host cells supporting viral replication. Although cellular activation is essential to mount an effective host immune response to invading pathogens, paradoxically the marked systemic immune activation that accompanies HIV-1 infection in vivo may play an important role in sustaining phenomenal rates of HIV-1 replication in infected persons. Moreover, by inducing CD4+ cell loss by apoptosis, immune activation may further be central to the increased rate of CD4+ cell turnover and eventual development of CD4+ lymphocytopenia. In addition to HIV-1-induced immune activation, exogenous immune stimuli such as opportunistic infections may further impact the rate of HIV-1 replication systemically or at localized anatomical sites. Such stimuli may also lead to genotypic and phenotypic changes in the virus pool. Together, these various immunological effects on the biology of HIV-1 may potentially enhance disease progression in HIV-infected persons and may ultimately outweigh the beneficial aspects of antiviral immune responses. This may be particularly important for those living in developing countries, where there is little or no access to antiretroviral drugs and where frequent exposure to pathogenic organisms sustains a chronically heightened state of immune activation. Moreover, immune activation associated with sexually transmitted diseases, chorioamnionitis, and mastitis may have important local effects on HIV-1 replication that may increase the risk of sexual or mother-to-child transmission of HIV-1. The aim of this paper is to provide a broad review of the interrelationship between immune activation and the immunopathogenesis, transmission, progression, and treatment of HIV-1 infection in vivo.     

RNA packaging signal of human immunodeficiency virus type 1.

Cells infected with a recombinant vaccinia virus carrying the gag and pol regions of the human immunodeficiency virus type 1 genome (Vac-gag/pol) released human immunodeficiency virus (HIV)-like particles containing HIV-specific RNA. However, cells infected with another recombinant vaccinia, Vac-gag/pol-dP, derived through the deletion of an 85-base region (nucleotide positions 679-763) of the HIV genome between the primer binding site and the gag initiation codon of Vac-gag/pol, produced HIV-like particles devoid of the HIV-specific RNA. This 85-base deletion was suggested to cause the collapse of a stable stem-loop structure of 46 bases (751-796) around the gag initiation codon. To examine the role of the stem-loop structure in the packaging of RNAs, we constructed a vaccinia vector plasmid that carried this 46-base sequence followed by the Sendai virus nucleocapsid (NP) gene. When both Vac-gag/pol-dP and this plasmid were introduced into cells, HIV-like particles released from the cells contained the NP gene RNA. However, another vaccinia vector plasmid, which carried the 46-base sequence in the midst of the NP gene, could not supply RNA for incorporation into HIV-like particles. Computer analysis of this plasmid sequence suggested that the 46-base sequence cannot form the stem-loop structure. These findings suggest that the stem-loop structure formed by the 46-base sequence is crucial as a packaging signal.