Maternal HIV-1 DNA load and mother-to-child transmission

While many factors contribute to mother-to-child transmission (MTCT) of HIV-1, maternal plasma HIV-1 RNA viral load (RNA-VL) has been consistently found as the main risk factor, including when antiretroviral prophylaxis was used to prevent MTCT. However the predictive value of RNA-VL is poor. A recent study of HIV-1-positive pregnant women who did not receive antiretroviral prophylaxis reported an association between HIV-1 DNA viral load (DNA-VL) and MTCT that was stronger than the association between RNA-VL and MTCT. We sought to determine if HIV-1 DNA-VL was independently associated with MTCT of HIV in a population of women who received zidovudine prophylaxis during pregnancy and whose infants received zidovudine after birth. Patients were 33 non-breastfeeding transmitting (TR) and 33 nontransmitting mothers (NTR) from Perinatal HIV Prevention Trial (PHPT-1), a multicenter clinical trial conducted in Thailand comparing zidovudine prophylaxis durations to prevent MTCT. TR and NTR mothers were matched according to baseline RNA-VL. Maternal peripheral blood mononuclear cell (PBMC)-associated HIV-1 DNA was extracted from whole blood, and DNA-VL was established by quantitative real-time polymerase chain reaction. We found that TR had a significantly higher cell-associated HIV-1 DNA viral load than did NTR. Median TR DNA-VL was 2.54 log(10) copies per microgram PBMC DNA, while it was 2.28 log(10) copies per microgram PBMC DNA in NTR (Wilcoxon p = 0.02). In summary, HIV-1 DNA viral load was associated with MTCT in a population of women who received antiretroviral prophylaxis during pregnancy, independently from RNA viral load.     

Transmission of HIV-1 in the face of neutralizing antibodies

In most cases of HIV-1 transmission, only a subset of variants is transmitted from the index case to the newly infected individual. Understanding the characteristics of these transmitted variants may aid in developing new methods to halt the spread of HIV-1. Studies evaluating the genotypic and antigenic properties of transmitted variants have provided insights into how the selective pressures applied during different modes of transmission uniquely imprint the infecting viruses. In the setting of sexual transmission, variants with increased neutralization sensitivity appeared to be selected during transmission in discordant subtype C-infected couples, although transmitted variants from different risk groups and HIV-1 subtypes did not demonstrate increased neutralization sensitivity, suggesting this may not be a consistent feature of transmitted variants. Studies of both mother to child transmission (MTCT) and superinfection, where preexisting NAbs are present at the time of exposure, provide opportunities to analyze whether the breadth and potency of the NAb response influence the incidence of new infections. MTCT resulted in selection for variants that were resistant to maternal antibodies, suggesting that maternal antibodies can protect the baby from those variants that are susceptible to the antibodies present. There are some data to suggest that poor neutralizing antibody (NAb) responses are present in cases of superinfection, although these data are preliminary. Defining the characteristics of the viruses transmitted in the presence and absence of NAbs as well as defining the NAb responses that fail to protect from infection during MTCT and superinfection may provide critical insights into the antibody responses that are needed for effective vaccines and other prophylactic therapeutics.     

Exposure to HIV-1 during delivery and mother-to-child transmission

BACKGROUND: The correlation between the presence of HIV-1 in maternal cervicovaginal secretions and in the infant's oro-pharyngal secretions at birth, and mother-to-child HIV transmission (MTCT) were examined to obtain a better understanding of its mechanism. METHODS: Women without medical and obstetrical complications, living within a reasonable distance of the government hospital in Mombasa, Kenya, were recruited after informed consent. Maternal and infant characteristics were collected. Polymerase chain reaction was used to detect HIV-1 in cervico-vaginal and oro-pharyngal secretions. Infants were tested for HIV-1 by polymerase chain reaction within 48 h and at 6 weeks after delivery. RESULTS: Between April 1998 and April 1999, 228 woman-infant pairs were included in the study. HIV-1 DNA in cervico-vaginal secretions was independently associated with HIV-1 maternal viral load and with infant birth-weight, whereas HIV-1 RNA was associated with maternal viral load and maternal age. HIV-1 DNA in the oropharyngal secretions was also independently associated with maternal viral load. MTCT rate at the age of 6 weeks was 23.6%. Intrapartum and early postpartum HIV transmission was independently associated with maternal viral load [adjusted odds ratio (OR), 1.6; 95% confidence interval (CI),1.0-2.7], detection of HIV-1 RNA in cervico-vaginal secretions (adjusted OR, 3.2; 95% CI, 1.5-7.3) and of HIV-1 DNA in oro-pharyngeal secretions (adjusted OR, 3.2; 95% CI, 1.1-9.0). DISCUSSION: As far as is known, this is the first study showing that infant exposure to HIV-1 in the birth canal and the presence of HIV-infected cells in the infant's oropharyngeal cavity are independently associated with intrapartum and early postpartum MTCT. It supports the hypothesis that MTCT could occur through the oral route.     

Preventing mother-to-child transmission of HIV-1 in Africa in the year 2000

OBJECTIVES: Various approaches to preventing mother-to-child transmission (MTCT) of HIV have recently been, or are being, evaluated in developing countries, especially in Africa. New findings from these trials are now becoming available, the implications of which, for population-based intervention programmes, need urgent consideration. METHOD: A critical review of 18 randomized trials and other relevant studies from developing and industrialized countries. RESULTS: Most African results relate to trials of antiretroviral agents (ARV). They demonstrate efficacy in reducing transmission in the first 6 months of life with short regimens of zidovudine (ZDV), with or without lamivudine (3TC), and nevirapine (NVP) alone. Preliminary results suggest the long-term efficacy of zidovudine. Antiseptic and nutritional interventions have been shown to reduce maternal and infant mortality and morbidity but not MTCT of HIV. HIV confidential voluntary counselling and testing for pregnant women, a short regimen of peripartum ARV with alternatives to breastfeeding such as early weaning or breast milk substitutes from birth currently represent the best option to reduce MTCTof HIV in Africa. However, the prevention of postnatal transmission requires further research, particularly in view of the consequences of different feeding options and the possibility of post-perinatal exposure prophylaxis of newborns with ARV. Issues relating to the implementation of currently validated strategies are discussed.     

Presence of HIV-1 neutralizing IgA antibodies in primary HIV-1 infected patients

The initial control of viral replication during primary HIV-1 infection is dominated by CD8+ T-cell mediated responses. Neutralizing IgG to autologous virus is first detected in serum weeks after this response when the viraemia has already declined. However, the mucosal and systemic HIV-1 neutralizing IgA response during primary HIV-1 infection in patients treated with HAART has not been studied previously. The presence of HIV-1 neutralizing IgA antibodies in serum (n=10 patients) and semen (n=6 patients) samples was tested against a laboratory adapted HIV-1 isolate and against primary HIV-1 isolates, representing different clades and phenotypes. The patients received HAART during the study period and were followed from primary HIV-1 infection and up to 72 weeks. Overall, HIV-1 neutralizing IgA activity could be demonstrated in serum from 5 of 10 primary HIV-1 infected patients at inclusion, although the response was restricted to only 1 of the 4 tested isolates. In semen samples, HIV-1 neutralizing IgA activity was seen in 2 of 5 patients against at least 1 of the HIV-1 isolates. In conclusion, a restricted but early neutralizing IgA response can be detected in serum and semen in primary infected patients treated with HAART.     

Advances and research directions in the prevention of mother-to-child HIV-1 transmission

Although substantial progress has been made in preventing mother-to-child HIV-1 transmission in the past decade, critical research questions remain. Two perinatal epidemics now exist. In more-developed countries, integration of prenatal HIV-1 counselling and testing programmes into an existing antenatal infrastructure, availability of effective antiretroviral prophylaxis, and access to infant formula have resulted in new perinatal infections becoming rare. However, identification of missed prevention opportunities, the causes of prophylaxis failure, and the potential effects of in-utero antiretroviral exposure have become a priority. In less-developed countries, antenatal care is limited, testing programmes are almost non-existent, effective interventions remain unimplemented, and prevention of postnatal transmission through breastmilk while maintaining adequate infant nutrition is a major dilemma. The challenge for the next decade is to simultaneously address questions relevant to both epidemics while bridging the gap in prevention of perinatal transmission between more-developed and less-developed countries.     

Domestic violence and prevention of mother-to-child transmission of HIV-1

OBJECTIVES: To determine the prevalence of life-time domestic violence by the current partner before HIV-1 testing, its impact on the uptake of prevention of mother-to-child transmission (PMTCT) interventions and frequency after testing. DESIGN: A prospective cohort. METHODS: Antenatally, women and their partners were interviewed regarding physical, financial, and psychological abuse by the male partner before HIV-1 testing and 2 weeks after receiving results. RESULTS: Before testing, 804 of 2836 women (28%) reported previous domestic violence, which tended to be associated with increased odds of HIV-1 infection [univariate odds ratio (OR) 1.7, 95% confidence interval (CI) 1.3-2.2; P < 0.0001, adjusted OR 1.2, 95% CI 0.9-1.6; P = 0.1], decreased odds of coming with partners for counseling (adjusted OR 0.7, 95% CI 0.5-1.0; P = 0.04), and decreased odds of partner notification (adjusted OR 0.7, 95% CI 0.5-1.1; P = 0.09). Previous domestic violence was not associated with a reduced uptake of HIV-1 counseling, HIV-1 testing, or nevirapine. After receiving results, 15 out of 1638 women (0.9%) reported domestic violence. After notifying partners of results, the odds of HIV-1-seropositive women reporting domestic violence were 4.8 times those of HIV-1-seronegative women (95% CI 1.4-16; P = 0.01). Compared with women, men reported similar or more male-perpetrated domestic violence, suggesting a cultural acceptability of violence. CONCLUSION: Domestic violence before testing may limit partner involvement in PMTCT. Although infrequent, immediate post-test domestic violence is more common among HIV-1-infected than uninfected women. Domestic violence prevention programmes need to be integrated into PMTCT, particularly for HIV-1-seropositive women.     

Centralized HIV-1 envelope immunogens and neutralizing antibodies

Centralized HIV-1 genes (consensus, most recent common ancestor and center of the tree) have recently been explored for induction of broadly reactive immune responses to overcome the extraordinary genetic diversity among HIV-1 strains. Although all of these strategies are based on artificial sequences predicted by computer programs, they retain biological function, and use the CCR5 co-receptor for entry into target cells as transmitted HIV-1 Envs. Results from laboratory animals indicate that centralized immunogens are superior to many wild-type immunogens for inducing cross-subtype T and B cell immune responses. Structural modifications have improved the ability of consensus Envs to elicit antibody responses that neutralize a spectrum of HIV-1 Env pseudoviruses. However, the more difficult to neutralize tier 2 Env pseudoviruses are generally not neutralized well by anti-consensus Env antibodies, indicating the need for further modifications, new formulations, or additional strategies to generate antibodies that neutralize a full spectrum of transmitted HIV-1 strains.     

AIDS following mother-to-child transmission of HIV-2

Mother-to-child infection with HIV-2 is thought to be rare, and there have been few previous reports of transmission by this route. Reports of morbidity associated with HIV-2 infection in children are also rare. We describe eight children born to mothers who were infected with HIV-2; five developed AIDS, and three were still seropositive at 17-49 months of age. The only apparent route of HIV-2 transmission was from mother to child, except for one child who had been transfused. Three of the children with AIDS died, all having decreased CD4+ lymphocytes and mitogen responses. Further studies are needed to determine the prevalence and natural history of mother-to-child transmission of HIV-2.     

Development of HIV-1 group-specific neutralizing antibodies after seroconversion.

OBJECTIVE: To study the induction of group-specific (gs) neutralizing antibodies to HIV-1 after seroconversion. DESIGN AND METHODS: Serum samples taken sequentially from seven Dutch homosexual men and four British haemophiliacs (anonymous sample, therefore sex not known) before and after seroconversion were tested for neutralizing antibodies effective against five diverse HIV-1 strains. Strains of HIV-1 tested included isolates from the United States, Europe and Africa. RESULTS: The gs neutralizing antibody response varied between individuals. Only five of the 11 individuals studied produced detectable neutralizing antibodies to laboratory-adapted HIV-1 strains (for example, IIIB) within 32 weeks of seroconversion. Most individuals initially produced antibodies effective against US/European isolates; the response then generally broadened to include the more diverse strains, i.e., African. CONCLUSIONS: These results suggest that the gs neutralizing target for HIV-1 is poorly immunogenic in vivo and is probably not highly conserved among diverse HIV-1 strains.     

Cost-effectiveness of cesarean section delivery to prevent mother-to-child transmission of HIV-1

OBJECTIVE: To evaluate costs and outcomes of cesarean section performed before onset of labor and before rupture of membranes (elective cesarean section) compared to vaginal delivery among HIV-infected women. DESIGN: Cost-effectiveness and cost-benefit analysis. Participants and setting: Pregnant HIV-infected women in the US who refrain from breastfeeding. INTERVENTION: Elective cesarean section versus vaginal delivery by antiretroviral therapy regimen. Main outcome measures: Pediatric HIV cases avoided, years of life saved, and direct medical costs for maternal interventions and pediatric HIV treatment. RESULTS: Elective cesarean section (versus vaginal delivery) was cost-effective among women receiving zidovudine prophylaxis (US$1131 per case avoided, US$17 per year of life saved) and combination antiretroviral therapy (US$112693 per case avoided, US$1697 per year of life saved), and cost saving among women receiving no antiretroviral therapy during pregnancy (benefit-cost ratio of 2.23). Although elective cesarean section remained cost-effective, results were sensitive to variations in vertical transmission rates and to pediatric HIV treatment costs. Population-based analyses indicated that elective cesarean section could prevent 239 pediatric HIV cases annually with a savings of over US$4 million. CONCLUSIONS: Elective cesarean section is a cost-effective intervention to prevent vertical transmission of HIV among women receiving various antiretroviral therapy regimens, who refrain from breastfeeding.     

Broadly neutralizing antibodies and their significance for HIV-1 vaccines

Despite extensive efforts, a preventive HIV vaccine has not yet been obtained and remains the main challenge in the field of AIDS research. Empirical approaches which have proved successful for many vaccines are not sufficient to tackle HIV-1 and new strategies to design effective preventive AIDS vaccines are critical. To this aim, further understanding of the mechanisms of action of neutralizing antibodies is required. In this review we summarize our current knowledge on the structure of the gp160 viral envelope and the dynamics of viral entry, the evolution of humoral response in HIV-infected patients and the mechanisms of viral escape. Finally, we describe the few neutralizing antibodies with activity against a broad spectrum of circulating HIV strains and their relevance in the design of new candidates to HIV-1 vaccines.     

Genetic diversity of HIV-1 in western Kenya: subtype-specific differences in mother-to-child transmission

BACKGROUND: Little is known about the impact of HIV-1 group M subtypes on mother-to-child transmission (MTCT) of HIV-1 in African settings where multiple HIV-1 group M subtypes are co-circulating. OBJECTIVE: To assess the role of subtype variation on MTCT. METHODS: HIV-1-infected women attending an antenatal clinic in western Kenya were enrolled for a prospective study (1996-2000) of MTCT. HIV-1 subtype analysis of p24gag and gp41env identified potential recombinants, and their role in MTCT was determined. RESULTS: Among 414 women for whom HIV-1 subtype and HIV transmission status were available, MTCT occurred in 80 (19.3%). MTCT rates were higher among women with subtype D compared with subtype A in either the gp41 region [31.6 versus 16.1%, relative risk (RR) 2.0, P=0.002] or p24 region (29.9 versus 18.0%, RR 1.7, P=0.02). Discordant subtype combinations were identified in 103 of the women (25.9%), and were associated with higher rates of MTCT (28.2 versus 17.0%, RR 1.7, P=0.01). In multivariate analysis, women with subtype combinations D/D, D/A, and A/D had an increased risk of MTCT (adjusted odds ratios 3.5, 2.5, 6.2; P=0.005, 0.05, and 0.0003, respectively) compared with A/A women after adjustment for maternal HIV viral load, placental malaria infection, episiotomy or perineal tear, and low birthweight. CONCLUSION: MTCT appears to be more common among mothers infected with subtype D compared with subtype A. Such differences in MTCT frequency may be caused by altered cellular tropism for placental cell types.     

CC and CXC chemokines in breastmilk are associated with mother-to-child HIV-1 transmission

INTRODUCTION: CC and CXC chemokines may play a role in mother-to-child HIV-1 transmission by blocking HIV-1 binding to chemokine receptors and impeding viral entry into cells. METHODS: To define correlates of breastmilk chemokines and associations with infant HIV-1 acquisition, chemokines in breastmilk and infant HIV-1 infection risk were assessed in an observational, longitudinal cohort study. We measured MIP-1alpha, MIP-1beta, RANTES, and SDF-1 in month 1 breastmilk specimens from HIV-1-infected women in Nairobi and HIV-1 viral load was calculated in maternal plasma and breastmilk at delivery and 1 month postpartum. Infant infection status was determined at birth and months 1, 3, 6, 9, and 12. RESULTS: Among 281 breastfeeding women, 60 (21%) of their infants acquired HIV-1 during follow-up, 39 (65%) of whom became infected intrapartum or after birth. MIP-1alpha, MIP-1beta, RANTES, and SDF-1 were all positively correlated with breastmilk HIV-1 RNA (P<0.0005). Women with clinical mastitis had 50% higher MIP-1alpha and MIP-1beta levels (P<0.001 and P=0.006, respectively) and women with subclinical mastitis (breastmilk Na(+)/K(+)>1) had approximately 70% higher MIP-1alpha, MIP-1beta and RANTES (P<0.002 for all) compared to women without mastitis. Independent of breastmilk HIV-1, increased MIP-1beta and SDF-1 were associated with reduced risk of infant HIV-1 (RR=0.4; 95% CI 0.2-0.9; P=0.03 and RR=0.5; 95% CI=0.3-0.9; P=0.02, respectively) and increased RANTES was associated with higher transmission risk (RR=2.3; 95% CI 1.1- 5.3; P=0.04). CONCLUSIONS: These observations suggest a complex interplay between virus levels, breastmilk chemokines, and mother-to-child HIV-1 transmission and may provide insight into developing novel strategies to reduce infection across mucosal surfaces.     

Assessment of mother-to-child HIV-1 and HIV-2 transmission: an AIDS reference laboratory collaborative study

Objective

A prospective study was carried out to assess HIV‐1 and HIV‐2 mother‐to‐child transmission (MTCT) rates in Portugal between 1999 and 2005 by analysing the proportion of diagnosed infected children born to HIV‐positive mothers.

Materials and methods

Serial blood samples were collected from 1315 children at risk of HIV‐1 infection, 131 children at risk of HIV‐2 infection and six children at risk of both HIV‐1 and HIV‐2 infections attending 25 Health Institutions. HIV proviral DNA was detected by nested polymerase chain reaction (PCR) and statistical analysis was performed using spss .

Results

DNA PCR using HIV‐1 and HIV‐2 long terminal repeat (LTR) primers amplified 92.5% and 75% of maternal HIV infections, respectively. Overall, MTCT occurred in 3.4% [95% confidence interval (CI) 2.5–4.6%] of HIV‐1 and 1.5% (95% CI 0.2–5.4%) of HIV‐2 mother–child pairs. A significant decrease in HIV‐1 MTCT was observed with time, from 7.0% (95% CI 2.6–14.6%) in 1999 to 0.5% (95% CI 0.0–2.5%) in 2005. HIV MTCT was associated with an absence of antiretroviral therapy in infected pregnant women (P<0.0001). Of the 48 infected children (46 with HIV‐1 and two with HIV‐2), the schedule of blood sample collection was followed for only 26 children. In 14 (53.8%) of those 26 children the infections were diagnosed in the first sample collected before they were 48 h old, suggesting in utero transmission. Despite the national recommendations for antenatal HIV testing, a high overall proportion (22.2% for HIV‐1 and 44.3% for HIV‐2) of mothers did not access any MTCT prevention measures, mostly because of late diagnosis in pregnancy. A small but significant proportion of HIV‐2 infection was found in mothers with no identifiable link with West Africa.

Conclusion

HIV‐2 transmission rates are low (1.5% in this study), and this may have led to a lower uptake of interventions, but in the absence of interventions transmission does occur. HIV‐1 transmission was also associated with a lack of intervention, mostly as a result of late presentation. Use of primers restricted to a single sequence led to false‐negative maternal results in a significant proportion of cases. In part this may have been attributable to very low HIV DNA loads as well as primer template mismatches. HIV infection was not documented in children born to mothers with negative HIV DNA PCR results.     

Persistence of K103N-containing HIV-1 variants after single-dose nevirapine for prevention of HIV-1 mother-to-child transmission

K103N-containing human immunodeficiency virus (HIV)-1 variants are selected in some women who receive single-dose (SD) nevirapine (NVP) for prevention of HIV-1 mother-infant transmission. We examined the persistence of K103N in women who received SD NVP prophylaxis. K103N was detected using the LigAmp assay (assay cutoff, 0.5% K103N). K103N was detected at 6-8 weeks in 60 (41.7%) of 144 women. Fading (lack of detection) of K103N was documented in 16 women by 2 years, 43 women by 3 years, and 55 women by 4 and 5 years. Slower fading was independently associated with HIV-1 subtype (D>A) and higher pre-NVP viral load.     

Prevalence,incidence, and mother-to-child transmission of HIV-1 in rural South Africa

Simple, robust approaches are needed to monitor prevalence, incidence, and mother-to-child transmission of HIV-1 in rural Africa. We have designed a method that uses antibody and viral RNA testing of dried blood spots obtained from mother-infant pairs attending routine immunisation clinics. In our study, prevalence and incidence of HIV-1 was highest in young women in their late teens and early twenties. In children born to infected mothers, prevalence increased from 14% in infants younger than 6 weeks of age to 24% at 3-6 months. The blood-spot approach is an effective method for surveillance of HIV-1 in women and children, and for early identification of incidence of this infection in women of child-bearing age.