Asymmetric representation of aversive prediction errors in Pavlovian threat conditioning.

Survival in biological environments requires learning associations between predictive sensory cues and threatening outcomes. Such aversive learning may be implemented through reinforcement learning algorithms that are driven by the signed difference between expected and encountered outcomes, termed prediction errors (PEs). While PE-based learning is well established for reward learning, the role of putative PE signals in aversive learning is less clear. Here, we used functional magnetic resonance imaging in humans (21 healthy men and women) to investigate the neural representation of PEs during maintenance of learned aversive associations. Four visual cues, each with a different probability (0, 33, 66, 100%) of being followed by an aversive outcome (electric shock), were repeatedly presented to participants. We found that neural activity at omission (US-) but not occurrence of the aversive outcome (US+) encoded PEs in the medial prefrontal cortex. More expected omission of aversive outcome was associated with lower neural activity. No neural signals fulfilled axiomatic criteria, which specify necessary and sufficient components of PE signals, for signed PE representation in a whole-brain search or in a-priori regions of interest. Our results might suggest that, different from reward learning, aversive learning does not involve signed PE signals that are represented within the same brain region for all conditions.

Immunogenetic influences on acquisition of HIV-1 infection: consensus findings from two African cohorts point to an enhancer element in IL19 (1q32.2).

Numerous reports have suggested that immunogenetic factors may influence human immunodeficiency virus (HIV)-1 acquisition, yet replicated findings that translate between study cohorts remain elusive. Our work aimed to test several hypotheses about genetic variants within the IL10-IL24 gene cluster that encodes interleukin (IL)-10, IL-19, IL-20 and IL-24. In aggregated data from 515 Rwandans and 762 Zambians with up to 12 years of follow-up, 190 single-nucleotide polymorphisms passed quality control procedures. When HIV-1-exposed seronegative subjects (n=486) were compared with newly seroconverted individuals (n=313) and seroprevalent subjects (n=478) who were already infected at enrollment, rs12407485 (G>A) in IL19 showed a robust association signal in adjusted logistic regression models (odds ratio=0.64, P=1.7 × 10(-4) and q=0.033). Sensitivity analyses demonstrated that (i) results from both cohorts and subgroups within each cohort were highly consistent; (ii) verification of HIV-1 infection status after enrollment was critical; and (iii) supporting evidence was readily obtained from Cox proportional hazards models. Data from public databases indicate that rs12407485 is part of an enhancer element for three transcription factors. Overall, these findings suggest that molecular features at the IL19 locus may modestly alter the establishment of HIV-1 infection.

Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.

BACKGROUND: Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. METHODS: We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. RESULTS: A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. CONCLUSIONS: Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)

Inhibiting Human Aversive Memory by Transcranial Theta-Burst Stimulation to the Primary Sensory Cortex.

BACKGROUND: Predicting adverse events from past experience is fundamental for many biological organisms. However, some individuals suffer from maladaptive memories that impair behavioral control and well-being, e.g., after psychological trauma. Inhibiting the formation and maintenance of such memories would have high clinical relevance. Previous preclinical research has focused on systemically administered pharmacological interventions, which cannot be targeted to specific neural circuits in humans. Here, we investigated the potential of noninvasive neural stimulation on the human sensory cortex in inhibiting aversive memory in a laboratory threat conditioning model. METHODS: We build on an emerging nonhuman literature suggesting that primary sensory cortices may be crucially required for threat memory formation and consolidation. Immediately before conditioning innocuous somatosensory stimuli (conditioned stimuli [CS]) to aversive electric stimulation, healthy human participants received continuous theta-burst transcranial magnetic stimulation (cTBS) to individually localized primary somatosensory cortex in either the CS-contralateral (experimental) or CS-ipsilateral (control) hemisphere. We measured fear-potentiated startle to infer threat memory retention on the next day, as well as skin conductance and pupil size during learning. RESULTS: After overnight consolidation, threat memory was attenuated in the experimental group compared with the control cTBS group. There was no evidence that this differed between simple and complex CS or that CS identification or initial learning were affected by cTBS. CONCLUSIONS: Our results suggest that cTBS to the primary sensory cortex inhibits threat memory, likely by an impact on postlearning consolidation. We propose that noninvasive targeted stimulation of the sensory cortex may provide a new avenue for interfering with aversive memories in humans.

The Relationship Between Sexual Behavior Stigma and Depression Among Men Who have Sex with Men and Transgender Women in Kigali, Rwanda: a Cross-sectional Study.

To evaluate the role of sexual behavior stigma as a determinant of depressive symptoms among men who have sex with men (MSM) and transgender women (TGW) in Kigali, Rwanda. MSM/TGW aged ≥18 years were recruited using respondent-driven sampling (RDS) between March-August, 2018. Mental health was assessed using the Patient Health Questionnaire (PHQ-9). Sexual behavior stigma from friends and family, healthcare workers, and community members was assessed using a validated instrument. Multinomial logistic regression models were used to determine the association between sexual behavior stigma and depressive symptoms and depression. Secondary analyses further compared depression and depressive symptoms among MSM and TGW. Among the 736 participants included, 14% (106/736) identified as TGW. Depression 8.9% (RDS-adjusted, 7.6%; 95% CI, 4.6-10.6) and mild/moderate symptoms of depression 26.4% (RDS-adjusted, 24.1%; 95% CI, 19.4-28.7) were common and higher among TGW compared to MSM (p < 0.001). Anticipated (41%), perceived (36%), and enacted (45%) stigmas were highly prevalent, and were also significantly higher among TGW (p < 0.001). In multivariable RDS-adjusted analysis, anticipated (relative risk ratio (RRR), 1.88; 95% CI, 1.11-3.19) and perceived (RRR, 2.06; 95% CI, 1.12-3.79) stigmas were associated with a higher prevalence of depressive symptoms. Anticipated (RRR, 4.78; 95% CI, 1.74-13.13) and enacted (RRR, 3.09; 95% CI, 1.61-5.93) stigmas were also associated with a higher prevalence of depression. In secondary analyses, the significant differences between MSM and TGW were lost after adjusting for stigma. These data demonstrate a high burden of depressive symptoms and depression among MSM/TGW in Kigali. Conceptually, stigma is a likely antecedent of mental health stress among MSM and TGW suggesting the potential utility of scaling up stigma mitigation interventions to improve the quality of life and mental health outcomes among sexual and gender minority communities in Rwanda.

Measuring learning in human classical threat conditioning: Translational, cognitive and methodological considerations.

Threat conditioning is a laboratory model of associative learning across species that is often used in research on the etiology and treatment of anxiety disorders. At least 10 different conditioned responses (CR) for quantifying learning in human threat conditioning are found in the literature. In this narrative review, we discuss these CR by considering the following questions: (1) Are the CR indicators of amygdala-dependent threat learning? (2) To what components of formal learning models do the CR relate? (3) How well can threat learning be inferred from the CR? Despite a vast literature, these questions can only be answered for some CR. Among the CR considered, heart period, startle eye-blink and Pavlovian-to-instrumental transfer are most clearly related to amygdala-dependent threat learning. Formal learning models have mostly been studied for skin conductance responses, which are likely to reflect threat prediction and its uncertainty. Startle eye-blink and pupil size appear to best differentiate CS+/CS-, although few direct comparisons between CR exist. We suggest future directions for improving the quantification of threat conditioning.

The demographic profile of sero-discordant couples enrolled in clinical research in Rwanda and Zambia.

This paper examines the demographic profile of two cohorts of sero-discordant couples enrolled in research activities at two clinical research sites in Kigali, Rwanda and Lusaka, Zambia and compares their background characteristics by country, gender and sero-status. Differences between the two cohorts represent economic and cultural differences between the two countries. Recruitment procedures appear to be successful in reaching the intended audience - couples from poor urban communities - and we suggest that similar recruitment strategies could be adopted to reach other population groups in other settings. The profiles of sero-discordant couples highlight several potential intervention points, and call for attention to be focused towards prevention efforts aimed at young women and their male partners.

Dopaminergic Drug Effects on Probability Weighting during Risky Decision Making.

Dopamine has been associated with risky decision-making, as well as with pathological gambling, a behavioral addiction characterized by excessive risk-taking behavior. However, the specific mechanisms through which dopamine might act to foster risk-taking and pathological gambling remain elusive. Here we test the hypothesis that this might be achieved, in part, via modulation of subjective probability weighting during decision making. Human healthy controls (n = 21) and pathological gamblers (n = 16) played a decision-making task involving choices between sure monetary options and risky gambles both in the gain and loss domains. Each participant played the task twice, either under placebo or the dopamine D2/D3 receptor antagonist sulpiride, in a double-blind counterbalanced design. A prospect theory modelling approach was used to estimate subjective probability weighting and sensitivity to monetary outcomes. Consistent with prospect theory, we found that participants presented a distortion in the subjective weighting of probabilities, i.e., they overweighted low probabilities and underweighted moderate to high probabilities, both in the gain and loss domains. Compared with placebo, sulpiride attenuated this distortion in the gain domain. Across drugs, the groups did not differ in their probability weighting, although gamblers consistently underweighted losing probabilities in the placebo condition. Overall, our results reveal that dopamine D2/D3 receptor antagonism modulates the subjective weighting of probabilities in the gain domain, in the direction of more objective, economically rational decision making.

Molecular investigation of recurrent tuberculosis in patients from Rwanda.

SETTING: Pulmonary tuberculosis (TB) patients enrolled in four provinces of Rwanda. OBJECTIVE: To determine the cause of recurrent TB. DESIGN: Serial Mycobacterium tuberculosis isolates obtained from patients with recurrent TB from January 2002 to September 2005 were genotyped by spoligotyping and mycobacterial interspersed repetitive unit-variable number of tandem repeat (MIRU-VNTR) typing. Drug resistance was determined by phenotypic susceptibility testing and sequencing of rpoB, katG, inhA and embB genes. RESULTS: Among 710 culture-positive TB patients enrolled in the study, initial drug susceptibility testing results were available for 638. Sixty-nine of these had multidrug-resistant (MDR) TB and 569 were non-MDR-TB. Among the MDR-TB patients, 22 had follow-up isolates after cure (n = 12) or chronic infection (n = 10). The DNA patterns of sequential isolates from 4 of the 12 previously cured MDR-TB patients were different, indicating re-infection. DNA patterns of isolates from the remaining 8 previously cured and 10 chronic MDR-TB patients were identical, suggesting reactivation and treatment failure, respectively. Among the non-MDR-TB patients, disease recurrence was observed in one case; this was determined to be due to reactivation after initial mixed infection. CONCLUSION: These results document a high treatment failure/reactivation rate for MDR-TB and suggest that re-infection within 2 years may not be a common cause of recurrent TB in this setting.

Evaluation of the resazurin microtiter assay for rapid detection of ofloxacin resistance in M. tuberculosis.

OBJECTIVE: To evaluate the performance of the colorimetric resazurin microtiter assay (REMA) method for the detection of ofloxacin resistance. METHODS: A panel of 120 multidrug-resistant Mycobacterium tuberculosis strains was tested blindly by the REMA method and compared with the results obtained using the BACTEC 460 method. RESULT: A very good correlation was observed between the two methods. CONCLUSION: The REMA method is simple, rapid and can be an inexpensive alternative procedure for the rapid detection of anti-tuberculosis drug resistance in laboratories with limited resources.

Characterization of CD8+ T lymphocytes in chronic HIV-1 subtype A infection in Rwandan women.

We examined CD8+ T lymphocyte characteristics in Rwandan women who have survived HIV-1 subtype A infection for 8-13 years without antiretroviral therapy. HIV-1 subtype A gag-specific IFN-gamma expressing CD8+ T lymphocytes were detectable in PBMC from 5 of 7 women and there was a strong positive association (r = 0.9262; p < 0.001) between these cells and plasma viral load. CD8+ T cells of these HIV-positive women produced more RANTES and MIP-1beta than cells from HIV-negative donors. However, extremely low levels of perforin (0.88 +/- 0.93%) were produced by CD8+ T lymphocytes from the infected women compared with HIV-negative controls (42.86 +/- 11.0%; p < 0.001). The percentages of CD8+ CD45RA+ perforin+ and CD8+ CD45RA+ CD27-lymphocytes were also much lower in the HIV-infected women compared with HIV-negative controls. Therefore, the inability of CD8+ T cells to control HIV may, in part, be dependent on insufficient generation of effectors from HIV-specific CD8+ T cells. Also, the lack of perforin in CD8+ T cells is linked with persistent CD27 expression, suggesting impaired maturation and impairment in cytolytic activity in chronic HIV-1 infection.

Antiretroviral treatment in Africa.

PIP: Demand for treatment with antiretroviral (ARV) drugs increased in Africa in the wake of the July 1996 AIDS Conference in Vancouver, during which combination ARV treatment including protease inhibitors was shown to dramatically improve the quality and length of life for people with AIDS. However, 1 year after the Vancouver Conference, ARV drugs remain scarce in Africa. Most people treated with antivirals in Africa try to acquire their drugs by ordering them through friends outside Africa or by travelling to Europe or the US. ARV treatment is becoming more complicated and treatment strategies change rapidly. The imbalance between the high price of ARV treatment and the scarcity of resources, competing health care needs, and the continent's weak health care systems all impede the introduction of large-scale ARV treatment in Africa. Nonetheless, if neither governments, organizations, nor industry provide ARV, HIV-infected people, their families, and physicians may try to obtain them through informal channels. Poor quality ARV may then be procured, sold at extremely high prices, and inadequately administered. Indications for ARV treatment, indications of ARV as preventive therapy, and requirements to introduce ARV are discussed.^ieng

Estimating the seroincidence of HIV-1 in the general adult population in Kigali, Rwanda.

OBJECTIVE: To estimate the seroincidence of HIV-1 infection in the general adult population of Kigali, Rwanda. DESIGN: Repeated standardized cross-sectional studies. SETTING: Two urban prenatal clinics. PATIENTS: A total of 4486 consecutive pregnant women consulting in 1989 and 1990. MAIN OUTCOME MEASURES: Prevalence of HIV-1 antibodies. RESULTS: HIV seropositivity increased by 3-5% annually over this period, indicating that it has not reached a plateau in this sentinel population. The percentage infection rates, calculated using two complementary methods, were 26.2-30.7% in 1990. Extrapolating these results to the general population of Kigali, we estimate that 2300-3800 new infections in young women and 3600-6100 new infections in young men occur annually among the total population of 350,000 in Kigali. CONCLUSIONS: A new HIV infection occurred in an adult every 50-90 min, on average, in Kigali during 1989-1990, while every 6-7 h a baby with maternally acquired HIV infection was born. Our HIV surveillance system, which is based on prenatal sentinel posts, is a useful tool for monitoring the progression of the HIV epidemic in Kigali.

PIP: This study aimed to estimate the seroincidence of HIV-1 infection in the general adult population of Kigali, Rwanda, by examining a total of 4486 consecutive pregnant women consulting in 1989 and 1990 at 2 urban prenatal clinics. Via repeated standardized cross-sectional studies the authors aimed to measure prevalence of HIV-1 antibodies. HIV seropositivity increased by 3-5% annually over this sentinel population. The percentage infection rates, calculated using 2 complementary methods, were 26.2-30.7 in 1990. Extrapolating these results to the general population of Kigali, the authors estimate that 2300-3800 new infections in young women and 3600-6100 infections in young men occur annually among the total population of 350,000 in Kigali. A new HIV infection occurred in an adult every 50 through 90 minutes, on average, in Kigali, during 1989 and 1990, while every 6 to 7 hours a baby with maternally acquired HIV infection was born. This HIV surveillance system, which is based on prenatal sentinel posts, is a useful tool for monitoring the progression of the HIV epidemic in Kigali.

Beta 2-microglobulin as a predictor of death in HIV-infected women from Kigali, Rwanda.

OBJECTIVE: To determine if beta 2-microglobulin (beta 2M) predicts death among HIV-infected African women. DESIGN: Nested case-control study. SETTING: Kigali, Rwanda. PARTICIPANTS: Two hundred and five seroprevalent women known to be HIV-infected since 1986-1987; 67 of whom died of HIV disease (cases) and 138 were alive (controls) as of November 1991. In addition, 128 women who seroconverted between 1986 and 1991. MAIN OUTCOME MEASURES: HIV serology, clinical signs and symptoms of HIV disease, hematology variables, and beta 2M concentration. RESULTS: beta 2M concentration increased over time (P < 0.001) in the seroprevalent women and seroconvertors. The average rate of beta 2M increase in women who died was 0.5 compared with 0.3 mg/l/year in the vital, seroprevalent women (P = 0.07). The strongest independent predictors of death were the rate of change of beta 2M (mg/l/year) [odds ratio (OR), 3.4; 95% confidence interval (CI), 1.7-6.8] and baseline beta 2M concentration (mg/l) [OR, 1.6; 95% CI, 1.2-2.1]. The rate of death for women with beta 2M concentration > or = 7.0 mg/l and a rate of change of beta 2M > or = 0.4 mg/l/year was 7.3 times higher than for women with beta 2M concentration < 7.0 mg/l and a rate of change of beta 2M of < 0.4 mg/l/year (95% CI, 3.1-17.2). The estimated median time from seroconversion to death assuming a constant rate of change of beta 2M was 10.6 years (95% CI, 9.9-11.2) for this cohort of HIV-infected women. CONCLUSIONS: Elevated beta 2M and a high rate of beta 2M increase were strongly associated with mortality among HIV-infected African women. Based on survival estimates using the rate of change of beta 2M, HIV-infected African women have similar survival compared with HIV-infected adults in the United States.

Seroincidence of HIV-1 infection in African women of reproductive age: a prospective cohort study in Kigali, Rwanda, 1988-1992.

OBJECTIVE: To estimate the seroincidence of HIV-1 infection among women of reproductive age in Kigali, Rwanda. DESIGN: Fixed prospective cohort followed for 36 months between November 1988 and June 1992, as part of an ongoing study of mother-to-child transmission of HIV-1. SETTING: Centre Hospitalier, Kigali, Rwanda. SUBJECTS: A total of 216 HIV-seronegative women were enrolled at delivery between November 1988 and June 1989. METHODS: A blood sample was obtained at delivery to test for HIV antibodies (by enzyme-linked immunosorbent assay and Western blot). Serum was tested every 3 months during follow-up. Incidence density rates of HIV seroconversion were estimated. RESULTS: The follow-up rate after 3 years was 89%, assessed by the maximum person-years method. The seroincidence density rate was 3.5 per 100 women-years (95% confidence interval, 1.9-5.0). It decreased linearly from 7.6 during the first 6-months postpartum to 2.5 per 100 women-years during the last 6 months of the third year of follow-up. Maternal age did not affect HIV incidence rates. We examined the role of the cohort, counselling, and the first 6-month postpartum effects on this estimate. CONCLUSION: This fixed cohort provided an overall estimation of the HIV infection incidence rate and its dynamics. These figures could be used for programming future HIV preventive vaccine efficacy trials in Rwanda.

PIP: The objective was to estimate the seroincidence of HIV-1 infection among women of reproductive age in Kigali, Rwanda. A fixed prospective cohort followed a total of 216 HIV-seronegative women for 36 months between November 1988 and June 1992 at Centre Hospitalier, Kigali, Rwanda. A study of mother-to-child transmission of HIV-1 has been going on at the Centre Hospitalier de Kigali since November 1988. A group of HIV-seronegative women matched by maternal age and parity was consecutively selected as a comparison group. The mean maternal age was 25.1 years (SD, 4.5 years), and the total number of pregnancies was 2.7 (SD, 1.8). A blood sample was obtained at delivery to test for HIV antibodies (by enzyme-linked immunosorbent assay and Western blot). Serum was tested every 3 months during follow-up. The follow-up rate after 3 years was 89.2% (577/646.75), assessed by the maximum person-years method. 20 seroconversions were documented during the first 36 months of follow-up among the 216 women seronegative at inclusion, yielding a cumulative incidence of 11.2%. The largest number of seroconversions (8/20; 40%) was observed in the first 6 months of the postpartum period. The seroincidence density rate was 3.5/100 women-years (95% confidence interval, 1.9-5.0). It decreased linearly from 7.6 during the first 6-months postpartum to 2.5 per 100 women-years during the last 6 months of the third year of follow-up (P = 0.01). Maternal age did not affect HIV incidence rates. We examined the role of the cohort, counseling, and the first 6-month postpartum effects on this estimate. The study confirms that pregnant women may represent a population in which the HIV seroincidence is high and concentrated in the immediate postpartum period. Pregnant women should become a potential target group for future large scale vaccination trials and programs with adequate follow-up. These figures could be used for programming future HIV preventive vaccine efficacy trials in Rwanda.

Antibodies to V3 loop peptides derived from chimpanzee lentiviruses and the divergent HIV-1ANT-70 isolate in human sera from different geographic regions.

OBJECTIVE: To study the spread of antibodies to V3 loop peptides of two chimpanzee lentiviruses and the divergent HIV-1ANT-70 isolate (group O) in human sera from different geographic regions, and to compare this with reactions to peptides from known North American (subtype B) and Zaïrean (subtype D) strains. METHODS: A total 2495 HIV-1-antibody-positive sera from nine countries were tested by enzyme-linked immunosorbent assay for antibodies to the V3 loop of 10 HIV/SIV isolates (including MN, SF2, HXB2, RF, MAL, ELI, Z6 and ANT-70 for HIV-1, and cpz-gab and cpz-ant for SIV). RESULTS: In each country, the highest prevalences were observed against the MN peptide (58.8-91.7%). Seroreactivity to other peptides from subtype B were generally lower. Prevalences of antibodies to V3 peptides derived from Zaïrean strains belonging to subtype D were generally lower than to subtype B. Relative high prevalences of sera reactive with the SIVcpz-gab V3 peptide were observed. The lowest rates were seen in Brazil (4.2%) and Belgium (25.7%). Among the African countries, the prevalence rates varied between 30.1 and 67.6%. Prevalence to the V3 loop derived from the SIVcpz-ant strains was much lower. Prevalence of sera reactive to the ANT-70 V3 loop peptide was very low, and the highest rates were observed in Cameroon (10.2%), Niger (6%) and Gabon (4.6%). Only the sera reactive to the ANT-70 V3 loop peptide from Cameroon and Gabon were confirmed on a specific HIVANT-70 Western blot (i.e., presence of antibodies to the envelope protein gp 120). CONCLUSIONS: The extent to which different V3 peptide reactivity patterns reflect the circulation of different HIV-1 strains in a particular population is not yet clear. However, V3 peptide serology using the very specific V3 peptide of the HIVANT-70 is a good indicator of the very aberrant group O in a particular population.

Effect of HIV-1 infection on pregnancy outcome in women in Kigali, Rwanda, 1992-1994. Pregnancy and HIV Study Group.

OBJECTIVE: To study the effect of HIV-1 infection on pregnancy outcome in women provided with antenatal services including malaria and sexually transmitted disease (STD) treatment in Kigali, Rwanda. SUBJECTS AND METHODS: Pregnant women attending the antenatal clinic ward of the Centre Hospitalier de Kigali in their last 3 months of pregnancy were tested for HIV antibody after consent had been obtained. All HIV-1-infected women were included and compared with HIV-negative women of same age and parity. Until delivery, each woman enrolled had a monthly follow-up including malaria and STD aetiological diagnosis and treatment. At the time of delivery, obstetrical and neonatal characteristics were recorded. Mothers and their children were followed until 6 weeks postpartum. RESULTS: By mid-August 1993, 384 HIV-positive and 381 HIV-negative women had been enrolled and by the end of November 1993, 729 women (95.3%; 364 HIV-positive and 365 HIV-negative) had delivered 725 livebirths, including eight and six twins, respectively; 10 stillbirths were recorded amongst HIV-positive women and eight amongst HIV-negative women (P=0.60). Excluding twins, premature birth (< 37 completed weeks of gestation) was observed in 22.7% of infants born to HIV-positive women versus 14.1% of those born to HIV-negative women; low birth weight (< 2500 g) was observed in 25.5% of infants born to HIV-positive women versus 14.8% of those born to HIV-negative women. Low birth weight was significantly more frequent in full-term infants born to HIV-positive mothers than to HIV-negative mothers. No significant difference in low birth weight rate was observed in preterm infants. Death occurred in 5.1% of children during the perinatal period without statistically significant difference between the two groups. HIV-positive women were more likely to have a postpartum haemorrhage. CONCLUSION: In the context of high HIV prevalence, maternal HIV infection is associated with adverse obstetrical and neonatal outcomes even when treating STD and malaria.

An assessment of the timing of mother-to-child transmission of human immunodeficiency virus type 1 by means of polymerase chain reaction.

To approximate the contributions of in utero, intrapartum, and postnatal transmission of human immunodeficiency virus type-1 (HIV-1) and to evaluate polymerase chain reaction (PCR) as a diagnostic tool for pediatric HIV infection, blood was collected at birth (cord blood), and at 3, 6-12, and 13-24 months in 218 children born to HIV-1-seropositive mothers in Kigali, Rwanda. Proviral DNA was detected by a double PCR using two sets of three primers (gag, pol, and env). Pediatric HIV-1 infection was defined according to serological and clinical criteria. The probability of having a positive PCR at a given time was calculated by a nonparametric method. Among children with unequivocal evidence of infection (n = 47), it was 30.5% on cord blood and 80.6% at 3 months. Thus, in children born to HIV-1-infected mothers, the estimated rate of transmission in the late postnatal period is 4.9%, and the rate of transmission in the intrapartum plus postnatal periods is 17.6%. Among 117 HIV-1-uninfected children born to HIV-1-infected mothers, six (5%) had a false-positive PCR on cord blood. These results should be taken into account in designing intervention trials aimed at reducing mother-to-child transmission of HIV-1.

TAPI polymorphisms in several human ethnic groups: characteristics, evolution, and genotyping strategies.

Genetic variations in the locus encoding the transporter associated with antigen processing, subunit 1 (TAP1), were systematically studied using samples from Caucasians, Africans, Brazilians, and compared with data from chimpanzees. PCR-amplified genomic sequences corresponding to the 11 exons were analyzed by single-strand conformation polymorphism (SSCP) and sequencing. Six nonsynonymous and 2 synonymous single nucleotide polymorphisms (SNPs) were found to be common in one ethnic group or another, and they involved codons 254 (Gly-GGC/Gly-GGT) in exon 3, 333 (Ile-ATC/Val-GTC) in exon 4, 370 (Ala-GCT/Val-GTT) in exon 5, 458 (Val-GTG/Leu-TTG) in exon 6, 518 (Val-GTC/Ile-ATC) in exon 7, 637 (Asp-GAC/Gly-GGC), 648 (Arg-CGA/Gln-CAA) and 661 (Pro-CCG/Pro-CCA) in exon 10. At each SNP site the sequence listed first was predominant in all ethnic groups. Several SNPs segregated on the same chromosome regardless of populations and species. Together, the SNPs produced 5 major human TAP1 alleles, 4 of which matched the officially recognized alleles *0101, *02011, *0301, and *0401; the 5th allele differed from each of those by at least 4 SNPs. Overall, TAP1*0101 was the predominant allele in all ethnic groups, with frequencies ranging from 0.667 in Zambians to 0.808 in US Caucasians. The TAP1*0401 frequency showed the greatest difference between Africans (0.221-0.254) and Caucasians (0.033), with Brazilians (0.058) fitting in the middle. Consistent with earlier work based on Caucasians and gorillas, *0101 appeared to be the newest human TAP1 allele, suggesting a dramatic spread of *0101 into all human populations examined. Characterization of TAP1 polymorphisms allowed the design of a PCR-based genotyping scheme that targeted 7 SNP sites and required 2 separate genotyping techniques.

Novel alleles at the lymphotoxin alpha (LTalpha) locus mark extended HLA haplotypes in native Africans.

Genetic variations at the closely related tumor necrosis factor alpha (TNFalpha or TNF) and lymphotoxin alpha (LTalpha, formerly TNFbeta) loci have been well documented in various human populations, and several haplotypes spanning the MHC class I and class II loci are known to carry specific TNF alleles. Genotyping of the TNFc microsatellite within the first intron of LTalpha in 285 Rwandans and 319 Zambians revealed two predominant alleles, c1 at frequencies of 0.598 and 0.683 and c2 at 0.384 and 0.307, respectively. Overall, the distribution of TNFc genotypes containing the major alleles conformed well to the Hardy-Weinberg equilibrium in both cohorts. Two previously unrecognized minor TNFc alleles were also detected: the first, designated c0, was found in 10 native Africans and was the only allele present in 10 chimpanzees; the second, designated c3, was seen in 6 other African patients. Further genotyping at loci for HLA class I, class II, and for transporters associated with antigen processing, subunit 1 (TAP1) in those 16 individuals suggested a tight, stable extended haplotype involving c0 and 26Asn (LTalpha)-TNF3 (TNF promoter -238A and -308G)-DRB1*1503-DQB1*0602-TAP1.2 (333Val)-TAP1.4 (637Gly). The c3 allele was observed on another extended haplotype with 26Thr (LTalpha)-TNF1 (TNF promoter -238G and -308G)-DQB1*0102-DQB1*0501-TAP1*0101 (333Ile and 637Asp). The c3-tagged haplotype further extended to Cw*15 at the HLA class I C locus, but no specific A or B alleles could be unambiguously assigned. Positive associations between c2 homozygosity and HIV-1 seronegative status in both Rwandans and Zambians (odds ratio = 2.03 and 2.00, p = 0.04 and 0.07, respectively) had little effect on the haplotype assignments. These findings suggest a preferential expansion of the human TNFc dinucleotide (CT/AG) repeat sequence and further imply the existence of two extended MHC lineages that have not been disrupted by recombinations.