HIV-1 genetic variability: implications for the development of HIV vaccines.
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AIDS Vaccines↗
Biomedical subjects
W L Heyward
Publications and source records attributed to W L Heyward.
Establishment of WHO-sponsored field sites for HIV vaccine evaluation in developing countries.
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AIDS Vaccines↗
HIV vaccine development: from basic research to human trials.
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AIDS Vaccines↗
HIV preventive vaccines. Progress to date.
The major conceptual problem for HIV vaccine development has been the lack of information on immune responses known to correlate with protection against HIV infection in humans. In this regard, studies on the natural history of HIV infection and AIDS, especially of people with apparent resistance to HIV infection and of patients with HIV infection who have long term survival without disease progression, may provide important information for vaccine development. In addition, a major concern for the development of broadly effective vaccines has been the extensive genetic variability which is characteristic of HIV. In spite of these unknowns, the first generation of HIV candidate vaccines has been developed and evaluated. HIV candidate vaccines based on the subunit recombinant envelope concept (gp120 or gp160) have been shown to protect chimpanzees from HIV infection on challenge, and have now been evaluated in humans in phase I and phase II trials. These products are well tolerated, and capable of inducing neutralising antibodies, but not cytotoxic T lymphocytes. A second vaccine concept, currently in phase I trials, is based on live recombinant vectors, especially using poxvirus vectors followed by boosting with subunit recombinant envelope vaccines. This concept is theoretically very attractive because preliminary data suggest that these vaccines induce both humoral and cell-mediated immunity. However, no published information is available on the ability of live recombinant vector vaccines to protect chimpanzees from HIV infection. The next step in HIV vaccine development is to proceed carefully to expanded phase II and phase III trials to assess the protective efficacy of these candidate vaccines in humans. These trials will be extremely complex from the logistical, scientific and ethical points of view, and will require close collaboration between clinical, basic science and behavioural researchers, national and international organisations, and the pharmaceutical industry.
AIDS Vaccines↗
The World Health Organization Network for HIV Isolation and Characterization: summary of a pilot study.
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Genetic Variation↗
Elevated concentrations of plasma omega-3 polyunsaturated fatty acids among Alaskan Eskimos.
Eskimos living in rural southwestern Alaska depend on fish and marine mammals as major sources of subsistence food. Fatty acid concentrations in 80 Yupik Eskimos living in either a coastal or river village of southwestern Alaska were compared with those of non-Native control subjects. Concentrations of total plasma omega-3 fatty acids, eicosapentaenoic acid (20:5 omega-3), and docosahexaenoic acid (22:6 omega-3) were 4.3, 13, and 6.8 times higher, respectively, in Native participants than in non-Native control subjects. Concentrations of these fatty acids were higher in coastal-village than in river-village participants; concentrations paralleled consumption of marine mammal oil and marine fish. The ratios of eicosapentaenoic to arachidonic acid for adult coastal- and river-village participants were 1.16 and 0.70, respectively, 14 and 9 times those of non-Native adults, respectively. There was no increase in the mean bleeding times of Native participants of either village.
Adolescent↗
Mortality in HIV-1-seropositive women, their spouses and their newly born children during 36 months of follow-up in Kinshasa, Zaïre.
OBJECTIVE: To calculate 3-year mortality rates in HIV-1-seropositive and HIV-1-seronegative mothers, their newborn children and the fathers of these children. DESIGN: Longitudinal cohort study of HIV-1-seropositive, age and parity-matched HIV-1-seronegative pregnant women, their newborn babies and the fathers of these children. SETTING: Obstetric ward and follow-up clinic at a large municipal hospital in Kinshasa, Zaïre. PARTICIPANTS: A total of 335 newborn children and their 327 HIV-1-seropositive mothers and 341 newborn children and their 337 HIV-1-seronegative mothers and the fathers of these children. MAIN OUTCOME MEASURES: Rates of vertical HIV-1 transmission and maternal, paternal and early childhood mortality. RESULTS: The lower and upper bounds of vertical transmission were 27 and 50%, respectively. The 3-year mortality rate was 44% in children with vertically acquired HIV-1 infection, 25% in children with HIV-1-seropositive mothers and indeterminant HIV-1 infection status, and 6% in uninfected children with HIV-1-seronegative mothers. HIV-1-seropositive women who transmitted HIV-1 infection to their most recently born child had lost a greater number of previously born children (mean, 1.5 versus 0.5; P < 0.05), were more likely to have had AIDS at delivery (25 versus 12%; P < 0.01) and were more likely to die during follow-up (22 versus 9%; P < 0.01) than HIV-1-seropositive women who did not transmit HIV-1 infection to their newborn child. Twenty-five out of 239 (10.4%) fathers of children with HIV-1-seropositive mothers, not lost to follow-up, died compared with three out of 310 (1%) fathers of children with HIV-1-seronegative mothers (P < 0.01). CONCLUSIONS: Families in Kinshasa, Zaïre, in which the mother was HIV-1-seropositive experienced a five to 10-fold higher maternal, paternal and early childhood mortality rate than families in which the mother was HIV-1-seronegative.
Acquired Immunodeficiency Syndrome↗
AIDS orphans in Kinshasa, Zaïre: incidence and socioeconomic consequences.
OBJECTIVE: To determine the incidence, morbidity, mortality, and socioeconomic consequences of becoming an AIDS orphan (a child with an HIV-1-seropositive mother who has died) in Kinshasa, Zaïre. DESIGN: A longitudinal cohort study was undertaken between 1986 and 1990. Within this cohort, a nested case-control study of AIDS orphans was performed. AIDS orphan cases were children with an HIV-1-seropositive mother who had died. Two groups of control children were identified. The first group of control children were age-matched children with HIV-1-seropositive mothers who were alive at the time of death of the AIDS orphan case mother. The second group of control children were children with HIV-1-seronegative mothers who were also alive at the time of death of the AIDS orphan case mother. SETTING: Obstetric ward and follow-up clinic at two large municipal hospitals in Kinshasa, Zaïre. PARTICIPANTS: A total of 466 HIV-1-seropositive women, their children, and the fathers of these children; 606 HIV-1-seronegative women, their children, and the fathers of these children. MAIN OUTCOME MEASURES: AIDS orphan incidence, HIV-1 vertical transmission rate, morbidity, mortality and socioeconomic indicators of the consequences of becoming an AIDS orphan. RESULTS: The AIDS orphan incidence rate was 8.2 per 100 HIV-1-seropositive women-years of follow-up. Vertical transmission of HIV-1 was higher in AIDS orphan cases (41%) than in control children with HIV-1-seropositive mothers (26%; P < 0.05). Among children without vertically acquired HIV-1 infection, morbidity rates and indices of social and economic well-being were similar in AIDS orphans and control children. Five out of 26 (19%) AIDS orphan cases died during follow-up, compared with three out of 52 (6%) control children (P < 0.05). CONCLUSION: During a 3-year follow-up period, children with HIV-1-seropositive mothers had a considerable risk of becoming an AIDS orphan. However, the presence of a concerned extended family appeared to minimize any adverse health and socioeconomic effects experienced by orphan children.
Acquired Immunodeficiency Syndrome↗
High HIV-1 incidence in young women masked by stable overall seroprevalence among childbearing women in Kinshasa, Zaïre: estimating incidence from serial seroprevalence data.
OBJECTIVE: To describe the dynamics of the HIV-1 epidemic in childbearing women in Kinshasa, Zaïre, by estimating incidence from serial seroprevalence studies. METHODS: In 1986 and 1989, 5937 and 4623 pregnant women, respectively, were screened for HIV-1 in Kinshasa. We estimated age-specific incidence from two seroprevalence surveys by using a birth-year cohort analysis and adjusting for differences in mortality and fertility between HIV-1-infected and uninfected women. Mortality and fertility data were measured in a cohort of women recruited from the survey in 1986 and followed until 1989. RESULTS: While the overall HIV-1 seroprevalence changed little (5.8% in 1986 and 6.5% in 1989; P = 0.17), the prevalence increased in birth-year cohorts of women under 25 years of age in 1989 from 3.2 to 6.2% (P < 0.001), but decreased for women above 25 years of age from 6.9 to 6.7% (P = 0.7). In addition, new HIV infections between 1986 and 1989 were balanced by a higher mortality and lower fertility observed in HIV-infected women. After adjusting for these effects, we estimated an overall 3-year cumulative HIV-1 incidence of 2.8 per 100 uninfected women [95% confidence interval (CI), 1.4-4.2]. The highest incidence, 5.7 per 100 (95% CI, 3.5-8.0), was in women aged 20-24 years in 1989. CONCLUSION: Despite an overall relatively stable HIV-1 prevalence in childbearing women in Kinshasa between 1986 and 1989, approximately 40% of all HIV-1 infections detected in the 1989 survey occurred between 1986 and 1989, and 60% occurred in women under 25 years of age in 1989.
Adult↗
Preparation for phase III HIV vaccine efficacy trials: methods for the determination of HIV incidence.
OBJECTIVE: Accurate estimates of HIV incidence that reflect the effect of non-vaccine interventions (education, counselling, condom promotion, and possibly sexually transmitted disease treatment) and that may be provided in a Phase III vaccine efficacy trial, are needed so that vaccine trial population sample sizes can be accurately determined. In order to avoid delays in the implementation of efficacy trials, well characterized cohorts must also be developed and available to participate in such trials. We reviewed the potential study populations, the epidemiologic methods for the determination of HIV incidence (using open cohort, closed cohort, and seroprevalence data methods), and the need for the development of population cohorts in preparation for Phase III HIV vaccine efficacy trials. SETTING: Phase III trials in developed and developing countries. METHODS: Comparison of open and closed cohorts and those using seroprevalence data to estimate HIV incidence. RESULTS: Open and closed cohorts each have disadvantages and advantages. However, the open cohort may be more suitable for determining estimates of HIV incidence that reflect non-vaccine interventions and for the development of a well characterized cohort available to participate in efficacy trials. CONCLUSION: Careful preparation of research infrastructures and population cohorts will help ensure the successful conduct of scientifically and ethically sound HIV vaccine efficacy trials in the future.
AIDS Vaccines↗
Lack of association between anti-V3 loop antibody and perinatal HIV-1 transmission in Kinshasa, Zaire, despite use of assays based on local HIV-1 strains.
Maternal antibodies against the V3 loop principal neutralizing domain (PND) have been reported to protect against perinatal HIV-1 transmission. To study this association in an African city with a long-standing HIV epidemic and no established "consensus sequence" for the V3 loop region of gp120, we determined the DNA sequence for the V3 region of HIV-1 from 13 HIV-1-infected residents of Kinshasa, Zaire, and developed peptide enzyme immunoassays (EIAs) reflecting the V3 loop PND for those HIV-1 strains. Using the most broadly reactive locally derived V3 loop peptide in a limited-antigen EIA, there was no significant difference in the perinatal HIV-1 transmission risk between 64 women with anti-V3 loop antibody (transmission risk, 30%) and 104 women without anti-V3 loop antibody (transmission risk, 25%; p = 0.5); this finding was unchanged after we controlled for maternal AIDS and low birth weight. Although we used assays for V3 loop antibody based on local HIV-1 strains and evaluated a large number of mother-child pairs, we found no evidence that maternal anti-V3 loop PND antibody protects against perinatal HIV-1 transmission.
Amino Acid Sequence↗
Genital types of papillomavirus in children of women with HIV-1 infection in Kinshasa, Zaire.
Increasing evidence indicates that infection with genital types of human papillomavirus (HPV) can occur prior to the onset of sexual activity, possibly by perinatal transmission. Evidence is also accumulating that women infected with the human immunodeficiency virus (HIV) more frequently express HPV. We conducted this study to measure HPV prevalence in HIV-seropositive and -seronegative women in Kinshasa, Zaire and in their children. We collected cervico-vaginal lavage specimens from 80 mothers (52 HIV-seropositive and 28 HIV-seronegative at the time of delivery) and oropharyngeal and perineal specimens from their 81 3-year old children (21 HIV-seropositive and 60-seronegative). We used the ViraPap and ViraType assay to test specimens for HPV DNA by the dot-blot technique. Detection of HPV in the mother was highly associated with HIV: 20 HIV-seropositive women and one seronegative woman had HPV DNA. Ten children had HPV DNA. However, detection of HPV in the children was not associated with the mothers' HPV or HIV status or with the child's own HIV status. These findings document a substantial prevalence in young children of HPV DNA types that are linked to genital-tract neoplasia in adults, but do not specifically support a hypothesis of mother-to-child transmission of genital HPV types.
DNA, Viral↗
Accurate detection of maternal antibodies to HIV in newborn whole blood dried on filter paper.
OBJECTIVE: The testing of neonatal blood specimens dried on filter paper for maternal HIV antibodies, using an enzyme immunoassay (EIA) with confirmation of repeatedly reactive specimens by immunoblot (IB), was first described in 1987. It has been used to conduct large, unlinked, anonymous HIV seroprevalence surveys for surveillance of HIV in child-bearing women in several countries. We directly assessed the sensitivity and specificity of this combination of tests to detect maternal HIV antibodies. SETTING: Serum samples obtained from mothers delivering at a major hospital in Kinshasa, Zaire were screened for HIV antibody using the rapid assay HIVCHEK. DESIGN: Plasma from HIVCHEK-positive women and age-matched negative controls were tested by enzyme-linked immunosorbent assay (ELISA); repeatedly reactive specimens were confirmed by Western blot (WB). Two days after delivery, whole blood was obtained from each newborn by heel-stick, dried on filter paper, and tested by EIA. Repeatedly reactive specimens were confirmed by IB. MAIN OUTCOME MEASURE: The serologic status of neonatal filter-paper specimens was compared with that of corresponding maternal plasma. RESULTS: The testing of neonatal filter-paper specimens using EIA, with confirmatory testing of repeatedly reactive specimens using IB, was 100.0% sensitive [of the 192 ELISA-positive and WB-positive maternal plasma specimens, 192 of the corresponding newborn filter-paper specimens were EIA-positive and IB-positive; 95% confidence interval (CI), 98.1-100]. The detection of maternal HIV antibodies was 99.6% specific using this combination of tests (of the 281 ELISA-negative or ELISA-positive but WB-negative maternal plasma samples, 280 of the corresponding newborn filter-paper specimens were EIA-negative or EIA-positive but IB-negative; 95% CI, 98.0-100). CONCLUSIONS: Maternal HIV antibodies can be detected accurately by testing neonatal blood dried on filter paper, using EIA with confirmation of repeatedly reactive specimens by IB. This approach can facilitate the determination of HIV seroprevalence in child-bearing women in countries with neonatal screening programs, or where serum or plasma is difficult to obtain.
Democratic Republic of the Congo↗
Impact of HIV counseling and testing among child-bearing women in Kinshasa, Zaïre.
OBJECTIVE: To determine the impact of HIV counseling and testing among child-bearing women. STUDY SETTING: Mama Yemo Hospital in Kinshasa, Zaïre. PARTICIPANTS AND INTERVENTIONS: After informed consent, 187 HIV-seropositive and 177 HIV-seronegative child-bearing women received pre- and post-test counseling for HIV infection. MAIN OUTCOME MEASURES: Participant knowledge of HIV/AIDS and plans for notifying partners of serologic status and contraceptive use at the time of counseling, and actual partner involvement and contraception use 12 months later. RESULTS: During pre-test counseling, participant knowledge of HIV infection was high, although 30% of women were unaware of perinatal HIV transmission, and 50% did not know that HIV infection could be asymptomatic. At post-test counseling, 70% of mothers (47% of HIV-seropositive, 94% of HIV-seronegative) intended to notify their partners and have joint counseling and testing, although after 12 months, only 2.2% of all women and 7.9% of those who desired assistance to notify their partner returned with their partners for joint counseling and testing. Similarly, 86% planned to use birth control (61% condoms), with HIV-seropositive women more likely to prefer condoms than HIV-seronegative women (71 versus 53%; P < 0.001). After 12-months, however, only 20% of HIV-seropositive women reported condom use, and the frequency of pregnancy in both groups was approximately equal. CONCLUSIONS: HIV counseling and testing led to higher rates of contraceptive and condom use, although the actual level was lower than the intended use. To further reduce the risk of heterosexual and perinatal HIV transmission in families with an HIV-infected woman, counseling should also include their male partners.
Adult↗
Genital papillomavirus infection and cervical dysplasia--opportunistic complications of HIV infection.
Certain human genital papillomaviruses (HPV) are strongly associated with cervical dysplasia and cancer. Evidence is accumulating that HPV infection and ano-genital cancers are more common in patients with the acquired immunodeficiency syndrome. The objective of our study was to evaluate the extent to which HPV infection and associated cervical disease constitute opportunistic complications of human immunodeficiency virus (HIV) infection in a population of sexually promiscuous, HIV-infected women in Kinshasa, Zaire. In 1989 we obtained Pap smears and cervicovaginal lavage specimens for HPV DNA testing from 47 HIV-seropositive and 48 HIV-seronegative prostitutes who were part of a cohort under observation since 1988. Thirty-eight percent of the HIV-seropositive and 8% of the seronegative women (odds ratio = 6.8; p = 0.001) had HPV DNA detected by either ViraType, a dot-blot assay which detects specific genital HPV types, or low-stringency Southern blot, which detects all HPV types. Eighty-two women (86%) had an interpretable Pap smear; 11 of 41 (27%) HIV-seropositive women and one of 41 (3%) seronegative women had cervical intra-epithelial neoplasia (CIN) (odds ratio = 14.7; p = 0.002). HIV seropositivity, HPV infection and CIN were highly associated. Eight (73%) of 11 seropositive women with CIN had HPV detected. Both HPV infection and cervical cancer may emerge as opportunistic complications of HIV infection in populations in which HIV, HPV and cervical cancer are common.
DNA, Viral↗
HIV infection and breast-feeding: policy implications through a decision analysis model.
OBJECTIVES: (1) To develop a comprehensive decision analysis model to compare mortality associated with HIV transmission from breast-feeding with the mortality from not breast-feeding in different populations and (2) to perform sensitivity analyses to illustrate critical boundaries for guiding research and policy. METHODS: Using a decision tree, mortality rates were estimated for all children, children born to mothers infected during pregnancy, and children born to mothers who were uninfected at delivery. Given various assumptions about child mortality rates, relative risks of mortality among children who are not breast-fed compared with those who are (R), rates of HIV transmission from breast-feeding, HIV prevalence, and HIV incidence, scenarios were created and sensitivity analysis used to delineate critical boundaries. RESULTS: Our model shows that only in situations where R is approximately < or = 1.5 and HIV incidence/prevalence is high (prevalence > 10%, incidence > 5%) would universal breast-feeding result in equal or higher mortality compared with non-breast-feeding. Among populations in many developing countries, where there is a high relative risk of mortality if breast-feeding is not practiced, if R > 3, overall mortality is almost always lower among children who are breast-fed, even by HIV-infected mothers. In situations where maternal HIV status is known, the decision whether to breast-feed is largely dependent on the magnitude of additional mortality risk if the child is not breast-fed. The model illustrates the importance of distinguishing between population and individual recommendations. CONCLUSIONS: Based on available data, the model supports current World Health Organization and Centers for Disease Control recommendations on HIV infection and breast-feeding. Given the importance of breast-feeding and the global impact of HIV infection, more research is needed, especially to clarify the range of HIV transmission rates from breast-feeding and to expand specific assessments of relative risks for different areas of the world.
Breast Feeding↗
Clustering of hepatocellular carcinoma in Alaska Native families.
Alaska Natives have a high incidence of hepatocellular carcinoma (HCC), with regional, ethnic, village, and familial clustering. During 1969-1988, 15 of the 45 incident cases of HCC in Alaska Natives occurred in 5 families. This report presents epidemiologic, virologic, and immunogenetic data on these 5 families. The results of hepatitis B virus (HBV) serologic testing indicates that HBV infection was an important factor in 4 of the 5 families. Human lymphocyte antigen (HLA) testing was performed in 3 families. The HLA results are reviewed in relationship to the familial clustering of HCC.
Adolescent↗
Evidence of marked sexual behavior change associated with low HIV-1 seroconversion in 149 married couples with discordant HIV-1 serostatus: experience at an HIV counselling center in Zaire.
To determine the effect of an HIV-1 counselling program on 149 married Zairian couples with discordant HIV-1 serology, the rates of HIV-1 seroconversion and reported condom utilization have been observed during 382.4 person-years of follow-up (minimum follow-up time per couple of 6 months). Before determination of HIV-1 serostatus and counselling, less than 5% of these couples had ever used a condom. One month after notification of HIV-1 serostatus and counselling, 70.7% of couples reported using condoms during all episodes of sexual intercourse. At 18 months follow-up, 77.4% of the 140 couples still being followed reported continued use of condoms during all episodes of sexual intercourse. At the time of notification of HIV-1 serostatus, 18 couples experienced acute psychological distress. Home-based counselling by trained nurses resolved these difficulties in all but three couples who subsequently divorced. Intensive counselling following notification of HIV-1 serostatus led to low rates of HIV-1 seroconversion (3.1% per 100 person-years of observation) in Zairian married couples with discordant HIV-1 serostatus who voluntarily attended an HIV counselling center.
Adult↗