HTLV-1 sweet-talks its way into cells.
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Biological Transport↗
Biomedical subjects
Julie Overbaugh
Publications and source records attributed to Julie Overbaugh.
Predictors of early mortality in a cohort of human immunodeficiency virus type 1-infected african children.
BACKGROUND: Pediatric human immunodeficiency virus type 1 (HIV-1) infection follows a bimodal clinical course with rapid progression in 10-45% of children before the age of 2 years and slower progression in the remainder. A prospective observational study was undertaken to determine predictors of mortality in HIV-1-infected African infants during the first 2 years of life. METHODS: Infants in a perinatal cohort identified to be HIV-1-infected by DNA PCR were followed monthly to 1 year, then quarterly to 2 years or death. RESULTS: Among 62 HIV-1-infected infants, infection occurred by the age of 1 month in 56 (90%) infants, and 32 (52%) died at median age of 6.2 months. All infant deaths were caused by infectious diseases, most frequently pneumonia (75%) and diarrhea (41%). Univariate predictors of infant mortality included maternal CD4 count <200 cells/microl [hazard ratio (HR), 3.4; P = 0.008], maternal anemia (HR = 3.7; P = 0.005), delivery complications (HR = 2.7; P = 0.01), low birth weight (HR = 4.1; P = 0.001), weight, length and head circumference </=5th percentile at age 1 month (HR = 3.7, P = 0.003; HR = 5.8, P < 0.001; and HR = 10.4, P < 0.001, respectively), formula-feeding (HR = 4.0; P = 0.01), infant CD4% </=15% (HR = 5.5; P = 0.01), infant CD4 count <750 (HR = 9.7; P = 0.006) and maternal death (HR = 2.9, P = 0.05). In multivariate analysis, maternal CD4 count <200 (HR = 2.7; P = 0.03) and delivery complications (HR = 3.4; P = 0.005) were independently associated with infant mortality. CONCLUSIONS: Advanced maternal HIV disease, maternal anemia, delivery complications, early growth faltering, formula-feeding and low infant CD4 were predictors of early mortality in African HIV-1-infected infants. In resource-poor settings, these predictors may be useful for early identification and treatment of high risk infants.
Africa↗
A real-time PCR-based method to independently sample single simian immunodeficiency virus genomes from macaques with a range of viral loads.
The generation of a diverse population of viral variants is a hallmark of simian immunodeficiency virus (SIV) infection. In order to address what role this diversity plays in disease progression, accurate sampling of the viral population is necessary. However, traditional PCR-based methods often rely on amplification of multiple genomes in one reaction, leading to resampling of viral genomes and potential errors in the estimations of viral diversity, especially when sequences from only one or a small number of PCRs are examined and/or viral copy number is low. Here we describe a method to amplify one viral envelope gene per PCR, thereby avoiding resampling. For this purpose we developed a highly accurate real-time PCR method to quantify SIV copy number, then used a single SIV template in a sensitive, high-fidelity full-length envelope PCR. Using this method, we have estimated the intra-animal viral diversity for a cohort of five pig-tailed macaques (Macaca nemestrina) infected with SIVMne variants, which displayed a broad range of viral loads at setpoint.
Amino Acid Sequence↗
Characterization of virus infectivity and cell-free capsid assembly of SIVMneCL8.
We have previously described a cell-free system that reconstitutes immature capsid assembly of Gag polypeptides from viruses belonging to three major primate lentiviral lineages, including HIV-1, HIV-2 and SIVagm. Studies described here examine a member of the SIVmac/Mne lineage, SIVMneCL8, using assays for virus production and infectivity as well as cellular events in capsid formation. We report that SIVMneCL8, a molecular clone with properties typical of transmitted viral variants, is less infectious per unit p27 Gag than another member of the SIVmac/Mne lineage, SIVmac239. SIVMneCL8 Gag polypeptides are arrested at an early stage of capsid assembly in the cell-free system. Additionally, SIVMneCL8 Gag polypeptides associate minimally with the host factor human HP68. This is the first report of a primate lentivirus that does not complete capsid assembly in the cell-free system.
Animals↗
Human immunodeficiency virus type 1 (HIV-1) diversity at time of infection is not restricted to certain risk groups or specific HIV-1 subtypes.
African women frequently acquire several genetically distinct human immunodeficiency virus type 1 (HIV-1) variants from a heterosexual partner, whereas the acquisition of multiple variants appears to be rare in men. To determine whether newly infected individuals in other risk groups acquire genetically diverse viruses, we examined the viral envelope sequences in plasma samples from 13 women and 4 men from the United States infected with subtype B viruses and 10 men from Kenya infected with non-subtype B viruses. HIV-1 envelope sequences differed by more than 2% in three U.S. women, one U.S. man, and one Kenyan man near the time of seroconversion. These findings suggest that early HIV-1 genetic diversity is not exclusive to women from Africa or to infection with any particular HIV-1 subtype.
Female↗
Longitudinal analysis of human immunodeficiency virus type 1 RNA in breast milk and of its relationship to infant infection and maternal disease.
Transmission of human immunodeficiency virus type 1 (HIV-1) via breast-feeding can occur throughout lactation. Defining both fluctuation in breast-milk virus level over time and how breast-milk virus correlates with mother-to-child transmission is important for establishing effective interventions. We quantified breast-milk HIV-1 RNA levels in serial samples collected from 275 women for up to 2 years after delivery. Higher maternal plasma virus load, lower maternal CD4 T cell count, and detection of HIV-1 DNA in maternal genital secretions were significantly associated with elevated breast-milk HIV-1 RNA. Within women who breast-fed, median virus load in colostrum/early milk was significantly higher than that in mature breast milk collected 14 days after delivery (P< or =.004). Breast-feeding mothers who transmitted HIV-1 to their infants had both significantly higher breast-milk viral RNA throughout lactation and more-consistent viral shedding, compared with mothers who did not transmit HIV-1. In breast-feeding women, a 2-fold-increased risk of transmission was associated with every 10-fold increase in breast-milk virus load (95% confidence interval, 1.3-3.0; P<.001). These results indicate that the risk of infant infection from breast-feeding is influenced by breast-milk virus load, which is highest early after delivery.
Breast Feeding↗
Breast-milk infectivity in human immunodeficiency virus type 1-infected mothers.
Human immunodeficiency virus type 1 (HIV-1) is transmitted through blood, genital secretions, and breast milk. The probability of heterosexual transmission of HIV-1 per sex act is.0003-.0015, but little is known regarding the risk of transmission per breast-milk exposure. We evaluated the probability of breast-milk transmission of HIV-1 per liter of breast milk ingested and per day of breast-feeding in a study of children born to HIV-1-infected mothers. The probability of breast-milk transmission of HIV-1 was.00064 per liter ingested and.00028 per day of breast-feeding. Breast-milk infectivity was significantly higher for mothers with more-advanced disease, as measured by prenatal HIV-1 RNA plasma levels and CD4 cell counts. The probability of HIV-1 infection per liter of breast milk ingested by an infant is similar in magnitude to the probability of heterosexual transmission of HIV-1 per unprotected sex act in adults.
Adult↗
Comparison of human immunodeficiency virus type 1 viral loads in Kenyan women, men, and infants during primary and early infection.
Steady-state levels of human immunodeficiency virus type 1 (HIV-1) RNA in plasma reached at approximately 4 months postinfection are highly predictive of disease progression. Several studies have investigated viral levels in adults or infants during primary and early infection. However, no studies have directly compared these groups. We compared differences in peak and set point plasma HIV-1 RNA viral loads among antiretrovirus-naive Kenyan infants and adults for whom the timing of infection was well defined. Peak and set point viral loads were significantly higher in infants than in adults. We did not observe any gender-specific differences in viral set point in either adults or infants. However, infants who acquired HIV-1 in the first 2 months of life, either in utero, intrapartum, or through early breast milk transmission, had significantly higher set point HIV-1 RNA levels than infants who were infected after 2 months of age through late breast milk transmission or adults who were infected through heterosexual transmission.
Acute Disease↗
Short-term effect of zidovudine on plasma and genital human immunodeficiency virus type 1 and viral turnover in these compartments.
The effect of zidovudine on plasma and genital human immunodeficiency virus type 1 (HIV-1) was determined in 42 antiretroviral-naive HIV-1-seropositive women in Nairobi. After 7 days of zidovudine treatment, HIV-1 RNA levels decreased by 0.5 to 1.1 log(10) in plasma and genital secretions. HIV-1 RNA half-life following zidovudine treatment was 4.7, 1.3, and 0.9 days in plasma, cervix, and vagina, respectively, and significantly shorter in genital secretions than in plasma (P < 0.001). Defining the short-term effect of zidovudine on plasma and genital HIV-1 is important for improving perinatal HIV-1 interventions.
Cervix Uteri↗
Early- and intermediate-stage variants of simian immunodeficiency virus replicate efficiently in cells lacking CCR5.
Primate lentiviruses are thought to use the chemokine receptor CCR5 as the major coreceptor for entry into cells. Here we show that some variants of simian immunodeficiency virus (SIV) replicate efficiently in peripheral blood mononuclear cells (PBMCs) lacking a functional CCR5. There were differences in the replication patterns of sequential variants that evolved during SIVMne infection; the late-stage pathogenic variants were unable to replicate in PBMCs lacking CCR5, whereas the early- and intermediate-stage viruses replicated as well in PBMCs lacking CCR5 as they did in cells with wild-type CCR5. The coreceptor specificities of these sequential variants were compared using indicator cell lines expressing known SIV coreceptors. Among the known SIV coreceptors, there were none that were functional for the early and intermediate variants but not the late-stage variants, suggesting that the coreceptor used for replication in PBMCs may be a coreceptor that has not yet been described. Because some variants replicate with high efficiency in peripheral blood cells using this as yet uncharacterized cellular receptor, this coreceptor may be important for viral entry of some target cell populations in the host.
Animals↗
Infection with multiple human immunodeficiency virus type 1 variants is associated with faster disease progression.
Human immunodeficiency virus type 1 (HIV-1)-infected individuals develop a genetically diverse virus population over time, but often only a limited number of viral variants are transmitted from a chronic carrier to a newly infected person. Interestingly, many women but few men are infected by multiple HIV-1 variants from a single partner. To determine whether the complexity of the infecting virus population influences clinical outcome, we examined viral diversity in the HIV-1 envelope sequences present at primary infection in 156 women from Kenya for whom we had follow-up data on viral RNA levels and CD4 T-cell counts. Eighty-nine women had multiple viral genotypes, while 67 women had a single genotype at primary infection. Women who acquired multiple viral genotypes had a significantly higher viral load (median, 4.84 versus 4.64 log(10) copies/ml, P = 0.04) and a significantly lower CD4(+)-T-cell count (median, 416 versus 617 cells/mm(3), P = 0.01) 4 to 24 months after infection compared to women who were infected with a single viral genotype. These studies suggest that early HIV-1 genetic diversity is linked to faster disease progression.
Base Sequence↗
Measuring the infectiousness of persons with HIV-1: opportunities for preventing sexual HIV-1 transmission.
Methods to reduce sexual transmission of HIV-1 are urgently needed to slow the global HIV-1 epidemic. These methods should include interventions that minimize susceptibility in uninfected populations at risk, as well as interventions that decrease the infectiousness of HIV-1 infected individuals. Surprisingly few interventions to prevent HIV-1 transmission have been targeted at persons who are already infected, although such interventions could have a significant impact on population-wide HIV-1 spread. This review summarizes current knowledge of factors that influence HIV-1 infectiousness, with special attention on the role of genital tract HIV-1 as a surrogate marker of infectiousness. Epidemiologic studies have demonstrated good agreement between factors associated with increased HIV-1 transmission and increased HIV-1 genital tract shedding. Treatment of sexually transmitted diseases and initiation of antiretroviral therapy have been shown to reduce HIV-1 shedding and thus are promising interventions that may reduce HIV-1 transmission. Unresolved issues related to optimal measurement techniques for genital HIV-1, promises and limitations of antiretroviral therapy and vaccines to reduce infectiousness, and other intervention strategies still in development are reviewed.
Communicable Disease Control↗
Association between cervical shedding of herpes simplex virus and HIV-1.
OBJECTIVE: To investigate the association between the cervical shedding of herpes simplex virus (HSV) and HIV-1. DESIGN: A cross-sectional study on 200 women seropositive for both HSV-2 and HIV-1 was conducted in a family planning clinic at the Coast Provincial General Hospital, Mombasa, Kenya. MAIN OUTCOME MEASURES: Quantities of HSV DNA (types 1 and 2) and HIV-1 RNA as well as the presence or absence of HIV-1 proviral DNA in cervical secretions were determined and compared. RESULTS: There was a significant correlation between the quantities of HSV DNA and HIV-1 RNA in the cervical secretions of HSV-shedding women (Pearson's r = 0.24, P = 0.05). A 10-fold increase in the quantity of cervical HSV DNA was associated with 1.35-fold higher cervical HIV-1-RNA levels (95% CI 1.00-1.81; P = 0.05), and with 1.36-fold greater odds of detection of HIV-1 proviral DNA (95% CI 1.05-1.75; P = 0.02). CONCLUSION: Higher levels of cervical HSV were associated with higher levels of expressed HIV-1 and with the more frequent detection of HIV-1-infected cells in cervical secretions. Prospective studies are needed to explore further the association between non-ulcerative cervical HSV reactivation and HIV-1 shedding. Such a relationship may have important implications for interventions designed to slow the spread of HIV-1.
Adult↗
Vitamin A deficiency and the acute phase response among HIV-1-infected and -uninfected women in Kenya.
Among HIV-1-infected individuals, vitamin A deficiency has been associated with faster disease progression and greater infectivity in observational studies, but randomized clinical trials have shown no effect of vitamin A supplementation. We conducted a cross-sectional study of 400 HIV-1-infected and 200 HIV-1-uninfected women in Mombasa, Kenya to examine the relations between vitamin A deficiency (serum retinol <30 microg/dL) and HIV-1 status, HIV-1 disease stage, and the acute phase response (serum C-reactive protein >or=10 mg/L and/or alpha1-acid glycoprotein >or=1.2 g/L). Among the HIV-1-infected women, the effect of vitamin A supplementation was examined in a randomized trial. Vitamin A deficiency was independently associated with HIV-1 infection (OR = 2.7, 95% CI: 1.9-4.0) and the acute phase response (OR = 2.8, 95% CI: 1.9-4.1). Among HIV-1-infected women, vitamin A deficiency and the acute phase response were associated with each other and were both independently associated with higher HIV-1 plasma viral load and lower CD4 count. HIV-1-infected women having an acute phase response had no increase in serum vitamin A levels after supplementation. Serum levels increased significantly among women without an acute phase response, although not to normal levels among women who were deficient at baseline. Among HIV-1-infected individuals, it is likely that low serum vitamin A concentrations reflect more active infection and the acute phase response. These results provide possible explanations for the disparity between observational studies and randomized trials of vitamin A for HIV-1 infection.
Adolescent↗
Sequence variability of the integrase protein from a diverse collection of HIV type 1 isolates representing several subtypes.
HIV-1 recombinants between viruses from different subtypes appear to be surprisingly common in several regions of the world. To detect such intersubtype recombinants that contain mosaic genomes, we have analyzed sequences from the integrase (IN)-coding region of the polymerase (pol) gene from 23 viruses of known envelope (env) subtype from South America and Africa. As defined by env sequences, these viral genomes included nine subtype A, four subtype B, three subtype C, and four subtype D viruses from group M, and three viruses from group O HIV-1. Mosaic genomes were common, with 7 mosaic genomes among the 20 group M isolates analyzed. Two of these isolates had mosaic IN-coding regions that were distinct, but that had recombination breakpoints at the same location, in the highly conserved polypurine track. Mosaic genomes were particularly common in the viruses from Kenya (five of nine), consistent with our previous prediction that there was a high frequency of intersubtype recombinants circulating in this country. The IN amino acid sequence was highly conserved among the several represented subtypes, including group O. Group M IN sequences shared 94% or greater amino acid sequence identity within a subtype and 91% or greater identity between subtypes. The most divergent M and O variant amino acid sequences differed by only 19%, and the known functional domains were conserved among all of the isolates. The high degree of genetic homogeneity among the virus isolates representing several subtypes indicates that a single drug targeted against IN might be effective for all HIV-1 infections.
Africa, Eastern↗
Virus load during primary Human Immunodeficiency Virus (HIV) type 1 infection is related to the severity of acute HIV illness in Kenyan women.
We evaluated the association between the severity of primary human immunodeficiency virus type 1 (HIV-1) illness and HIV-1 plasma virus load before seroconversion using stored plasma samples obtained from 74 prostitutes in Mombasa, Kenya. Fever, vomiting, headache, fatigue, arthralgia, myalgia, sore throat, skin rash, or being too sick to work were each associated with significantly higher virus loads before HIV-1 seroconversion, and each additional symptom or sign was associated with an increase in virus load of 0.4 log(10) copies/mL.
Female↗
HIV type 1 variants transmitted to women in Kenya require the CCR5 coreceptor for entry, regardless of the genetic complexity of the infecting virus.
Although nearly half of the HIV-1-infected adults in the world are women, little is known about the virologic determinants of transmission to women. Studies suggest that women are frequently infected with multiple HIV-1 genotypes, whereas men are infected with a single genotype. In the current study, we assessed whether the diverse HIV-1 genomes present at the time of infection in women encode viruses that have diverse coreceptor specificities. For this purpose, we defined the coreceptor requirements of viruses found in recently infected Kenyan women, three of whom had multiple viral genotypes and the remaining two of whom had a single genotype. Full-length envelope clones were amplified directly from blood and the dominant genotypes were identified. Envelope clones derived from all five women were able to pseudotype infectious particles competent to infect cells expressing CCR5, but not cells expressing only CXCR4. Thus, regardless of viral complexity at the time of infection, the viruses present at early stages of HIV-1 infection in women use CCR5, suggesting that cells expressing CCR5 are important targets for heterosexual HIV-1 transmission to women.
Base Sequence↗
Vitamin A supplementation and human immunodeficiency virus type 1 shedding in women: results of a randomized clinical trial.
Observational studies have associated vitamin A deficiency with vaginal shedding of human immunodeficiency virus (HIV) type 1-infected cells and mother-to-child HIV-1 transmission. To assess the effect of vitamin A supplementation on vaginal shedding of HIV-1, a randomized, double-blind, placebo-controlled trial of 6 weeks of daily oral vitamin A (10,000 IU of retinyl palmitate) was conducted among 400 HIV-1-infected women in Mombasa, Kenya. At follow-up, there was no statistically significant difference in the prevalence of HIV-1 DNA (18% vs. 21%, P=.4) or the quantity of HIV-1 RNA (3.12 vs. 3.00 log(10) copies/swab, P=1.0) in vaginal secretions of women receiving vitamin A, compared with women receiving placebo. No significant effect of supplementation on plasma HIV-1 load or CD4 or CD8 cell counts was observed, and no effect was seen among women who were vitamin A deficient at baseline. Vitamin A supplementation is unlikely to decrease the infectivity of women infected with HIV-1.
Acquired Immunodeficiency Syndrome↗