The early work on hormonal contraceptive use and HIV acquisition.
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Cohort Studies↗
Biomedical subjects
Julie Overbaugh
Publications and source records attributed to Julie Overbaugh.
Effect of contraceptive methods on natural history of HIV: studies from the Mombasa cohort.
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Cohort Studies↗
Selection for human immunodeficiency virus type 1 envelope glycosylation variants with shorter V1-V2 loop sequences occurs during transmission of certain genetic subtypes and may impact viral RNA levels.
Designing an effective human immunodeficiency virus type 1 (HIV-1) vaccine will rely on understanding which variants, from among the myriad of circulating HIV-1 strains, are most commonly transmitted and determining whether such variants have an Achilles heel. Here we show that heterosexually acquired subtype A HIV-1 envelopes have signature sequences that include shorter V1-V2 loop sequences and fewer predicted N-linked glycosylation sites relative to the overall population of circulating variants. In contrast, recently transmitted subtype B variants did not, and this was true for cases where the major risk factor was homosexual contact, as well as for cases where it was heterosexual contact. This suggests that selection during HIV-1 transmission may vary depending on the infecting subtype. There was evidence from 23 subtype A-infected women for whom there was longitudinal data that those who were infected with viruses with fewer potential N-linked glycosylation sites in V1-V2 had lower viral set point levels. Thus, our study also suggests that the extent of glycosylation in the infecting virus could impact disease progression.
Disease Progression↗
Longitudinal assessment of human immunodeficiency virus type 1 (HIV-1)-specific gamma interferon responses during the first year of life in HIV-1-infected infants.
Human immunodeficiency virus type 1 (HIV-1) infection results in different patterns of viral replication in pediatric compared to adult populations. The role of early HIV-1-specific responses in viral control has not been well defined, because most studies of HIV-1-infected infants have been retrospective or cross-sectional. We evaluated the association between HIV-1-specific gamma interferon (IFN-gamma) release from the cells of infants of 1 to 3 months of age and peak viral loads and mortality in the first year of life among 61 Kenyan HIV-1-infected infants. At 1 month, responses were detected in 7/12 (58%) and 6/21 (29%) of infants infected in utero and peripartum, respectively (P = 0.09), and in approximately 50% of infants thereafter. Peaks of HIV-specific spot-forming units (SFU) increased significantly with age in all infants, from 251/10(6) peripheral blood mononuclear cells (PBMC) at 1 month of age to 501/10(6) PBMC at 12 months of age (P = 0.03), although when limited to infants who survived to 1 year, the increase in peak HIV-specific SFU was no longer significant (P = 0.18). Over the first year of life, infants with IFN-gamma responses at 1 month had peak plasma viral loads, rates of decline of viral load, and mortality risk similar to those of infants who lacked responses at 1 month. The strength and breadth of IFN-gamma responses at 1 month were not significantly associated with viral containment or mortality. These results suggest that, in contrast to HIV-1-infected adults, in whom strong cytotoxic T lymphocyte responses in primary infection are associated with reductions in viremia, HIV-1-infected neonates generate HIV-1-specific CD8+-T-cell responses early in life that are not clearly associated with improved clinical outcomes.
Amino Acid Sequence↗
Evidence for frequent reinfection with human immunodeficiency virus type 1 of a different subtype.
A major premise underlying current human immunodeficiency virus type 1 (HIV-1) vaccine approaches is that preexisting HIV-1-specific immunity will block or reduce infection. However, the recent identification of several cases of HIV-1 reinfection suggests that the specific immune response generated for chronic HIV-1 infection may not be adequate to protect against infection by a second HIV-1 strain. It has been unclear, though, whether these individuals are representative of the global epidemic or are rare cases. Here we show that in a population of high-risk women, HIV-1 reinfection occurs almost as commonly as first infections. The study was designed to detect cases of reinfection by HIV-1 of a different subtype and thus captured cases where there was considerable diversity between the first and second strain. In each case, the second virus emerged approximately 1 year after the first infection, and in two cases, it emerged when viral levels were high, suggesting that a well-established HIV-1 infection may provide little benefit in terms of immunizing against reinfection, at least by more-divergent HIV-1 variants. Our findings indicate an urgent need for studies of larger cohorts to determine the incidence and timing of both intersubtype and intrasubtype reinfection.
Acquired Immunodeficiency Syndrome↗
Basic statistical considerations in virological experiments.
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Animals↗
Simian immunodeficiency virus variants that differ in pathogenicity differ in fitness under rapid cell turnover conditions.
Simian immunodeficiency virus (SIV) has been shown to progress through a number of changes that lead to the emergence of pathogenic viral variants in macaques initially infected with a mildly cytopathic variant, SIVMneCL8. One of these late-stage isolates, SIVMne170, replicates to high levels in vivo and causes a rapid disease course when reintroduced into naïve macaques, resulting in a viral set point up to 3,000-fold higher than the set point of the parental virus, SIVMneCL8. However, in cell culture both viruses replicate with similar kinetics. One major difference between in vivo and in vitro cultures is the life span of the infected cells. Here, we manipulated the life span of infected cells in vitro, and we show that the fitness of SIVMne170 in cultures with a limited cell life span dramatically increased compared to its fitness in cultures with a nonlimited life span of cells. The increase in fitness was at least partially due to the fact that the rapid turnover system eliminates the negative influence of the cytopathic effects associated with replication of SIVMne170. Because the relative fitness of SIVMneCL8 and SIVMne170 observed in the rapid turnover system more accurately reflects their fitness in vivo, the system represents an improved approach to comparing relative fitness of viruses.
Cell Line↗
Risk factors for human immunodeficiency virus type-1 acquisition in women in Africa.
Over 65% of individuals infected with human immunodeficiency virus type 1 (HIV-1) reside in sub-Saharan Africa, and thus efforts to change the course of the HIV-1 pandemic should focus on this geographic region. Here, we discuss factors, including sexually transmitted diseases and hormonal contraceptive use, that impact susceptibility to HIV-1 in women in sub-Saharan Africa. This population is of special interest, given that women in this region are more likely to be infected than men. In addition, they are a potential source of transmission to their infants. A better understanding of the factors that influence HIV-1 susceptibility is key to developing interventions to control the epidemic.
Acquired Immunodeficiency Syndrome↗
Contribution of HIV-1 infection to acquisition of sexually transmitted disease: a 10-year prospective study.
BACKGROUND: Sexually transmitted diseases (STDs) enhance human immunodeficiency virus (HIV)-1 susceptibility, but few studies have examined the reciprocal effect of HIV-1 on STD acquisition. METHODS: Data from a prospective cohort study conducted among female sex workers in Mombasa, Kenya between 1993 and 2003 were used to determine the effect of HIV-1 infection on STD susceptibility. The cohort included 1215 HIV-1-seronegative women who underwent monthly HIV-1 and STD screening, of whom 238 experienced seroconversion to HIV-1 during follow-up. Andersen-Gill proportional-hazards models were used to compare the incidence rates for genital-tract infections (syphilis, genital ulcer disease [GUD], Neisseria gonorrhoeae infection, Chlamydia trachomatis infection, Trichomonas vaginalis infection, vulvovaginal candidiasis, and bacterial vaginosis) in HIV-1-seropositive versus HIV-1-seronegative women, after controlling for sexual behavior and other potential confounding factors. RESULTS: HIV-1 infection was associated with a significantly higher incidence of GUD (hazard ratio [HR], 2.8; 95% confidence interval [CI], 2.0-3.9), gonorrhea (HR, 1.6; 95% CI, 1.1-2.2), and vulvovaginal candidiasis (HR, 1.5; 95% CI, 1.3-1.8). The risks of GUD and vulvovaginal candidiasis increased with progressive levels of immunosuppression. CONCLUSIONS: The increased incidence of genital-tract infections among HIV-1-seropositive women could promote the spread of both HIV-1 and other STDs, particularly in areas where these conditions are highly prevalent.
Adult↗
Micronutrient supplementation increases genital tract shedding of HIV-1 in women: results of a randomized trial.
To test the hypothesis that micronutrient supplementation decreases genital HIV-1 shedding, a double-blind, randomized, placebo-controlled trial of 6 weeks of multivitamin plus selenium supplementation vs. placebo was conducted among 400 HIV-1-seropositive, nonpregnant, antiretroviral-naive women in Mombasa, Kenya. Primary outcome measures included cervical and vaginal shedding of HIV-1-infected cells and RNA. Secondary outcomes included plasma viral load and CD4 count. Surprisingly, the odds of detection of vaginal HIV-1-infected cells were 2.5-fold higher (P = 0.001) and the quantity of HIV-1 RNA in vaginal secretions was 0.37 log10 copies/swab higher (P = 0.004) among women who received micronutrients in comparison to placebo, even after adjustment for potential confounders including baseline HIV-1 shedding and CD4 count. The increase in vaginal HIV-1 shedding was greatest among women who had normal baseline selenium levels. Micronutrient supplementation resulted in higher CD4 (+23 cells/microL, P = 0.03) and CD8 (+74 cells/microL, P = 0.005) counts compared with placebo but did not alter the plasma viral load. In this randomized trial, micronutrients resulted in higher levels of genital HIV-1 shedding compared with placebo. The potential benefit of micronutrient supplementation in HIV-1-seropositive women should be considered in relation to the potential for increased infectivity.
Adolescent↗
Hormonal contraception and risk of cervical infections among HIV-1-seropositive Kenyan women.
OBJECTIVE: To evaluate the relationship between hormonal contraceptive use and the acquisition of cervical sexually transmitted infections (STI) among HIV-1-infected women. DESIGN: A prospective cohort study of 242 commercial sex workers in Mombasa, Kenya, followed from the time of HIV-1 infection. METHODS: At monthly follow-up visits, sexual behavior and contraceptive use were recorded, and laboratory screening for STI was performed. Multivariate Andersen-Gill proportional hazards models were constructed to examine the association between the use of hormonal contraception and the occurrence of cervical STI. RESULTS: The median duration of follow-up after HIV-1 acquisition was 35 months, and 799 person-years of follow-up were accrued. After adjustment for demographic factors and sexual behavior, women using the injectable contraceptive depot medroxyprogesterone acetate were at increased risk of Chlamydia trachomatis infection [hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.0-9.4, P = 0.05] and cervicitis (HR 1.6, 95% CI 1.0-2.3, P = 0.03) compared with women using no contraception. The use of oral contraceptive pills was associated with an increased risk of cervicitis (HR 2.3, 95% CI 1.4-3.8, P = 0.001). Hormonal contraception was not associated with an increased risk of infection with Neisseria gonorrhoeae. CONCLUSION: The use of hormonal contraception by HIV-1-infected women was associated with an increased risk of cervicitis and cervical chlamydia infection. HIV-1-seropositive women using hormonal contraception should be counseled about the importance of consistent condom use to prevent both STI and HIV-1 transmission.
Adult↗
Association of levels of HIV-1-infected breast milk cells and risk of mother-to-child transmission.
Understanding how the level of human immunodeficiency virus type 1 (HIV-1)-infected breast milk cells (BMCs) affects HIV transmission via breast-feeding can shed light on the mechanism of infection and aid in establishing effective interventions. The proportion of infected cells to total cells was measured in serial breast milk samples collected from 291 HIV-1-infected women in Nairobi, Kenya, by use of real-time DNA polymerase chain reaction amplification of BMCs. The number of infected BMCs per million cells was associated with levels of cell-free viral RNA in breast milk (R=.144; P=.032), levels of cell-free virus in blood plasma (R=.365; P<.001), and the detection of proviral DNA in cervical and vaginal secretions (P<.001 and P = .030, respectively). The number of infected BMCs per million cells was lower in colostrum or early milk than in mature milk (P<.001). Previous studies demonstrated that the concentration of BMCs varies throughout lactation, and we used these data to transform infected BMCs per million cells to infected BMCs per milliliter. The estimated concentration of infected BMCs per milliliter was higher in colostrum or early milk than in mature milk (P<.001). Each log10 increase in infected BMCs per milliliter was associated with a 3.19-fold-increased risk of transmission (P=.002), after adjustment for cell-free virus in plasma (hazard ratio [HR], 2.09; P=.03) and breast milk (HR, 1.01; P=1.00). This suggests that infected BMCs may play a more important role in transmission of HIV via breast-feeding than does cell-free virus.
Blood↗
Cyclic shedding of HIV-1 RNA in cervical secretions during the menstrual cycle.
The association between hormone fluctuations during the menstrual cycle and human immunodeficiency virus type 1 (HIV-1) RNA shedding in cervical and vaginal secretions was examined daily for 17 HIV-1-seropositive women, for the duration of 1 cycle. Serum levels of RNA were evaluated 3 times/week. A marginally significant positive correlation between serum levels of progesterone and serum levels of HIV-1 RNA (P=.04) was observed. Cervical virus levels were significantly correlated with the number of days from the midcycle surge in luteinizing hormone (LH) (P=.008). The lowest levels of cervical HIV-1 RNA were present at the LH surge, and this nadir was followed by an increase in virus levels that reached a maximum before the start of menses. In contrast, there was no significant association between the number of days from the LH surge and the level of HIV-1 RNA in vaginal secretions (P=.4). These data support the hypothesis that the level of HIV-1 RNA in cervical secretions is influenced by the menstrual cycle, and they suggest that the risk of heterosexual transmission of HIV-1 may increase as menses is approached.
Cervix Uteri↗
Vitamin A supplementation and genital shedding of herpes simplex virus among HIV-1-infected women: a randomized clinical trial.
Cross-sectional analyses have associated vitamin A deficiency with genital shedding of herpes simplex virus (HSV) among human immunodeficiency virus type 1 (HIV-1)-infected women. A randomized clinical trial of vitamin A supplementation given daily for 6 weeks was conducted among 376 women in Mombasa, Kenya, who were coinfected with HSV-2 and HIV-1. At follow-up, there was no significant difference in the detection of genital HSV DNA between women receiving vitamin A supplementation and women receiving placebo (40% vs. 44%, respectively; P = .5) Among women shedding HSV, there was no significant difference in the mean HSV DNA quantity between the group that received vitamin A supplementation and the group that received placebo (4.51 vs. 4.67 log10 copies/swab; P = .6). HSV shedding was associated with significantly higher vaginal and cervical HIV-1 shedding, even after controlling for the plasma HIV-1 load and the CD4 count. Vitamin A supplementation is unlikely to decrease HSV shedding and infectivity.
Adult↗
Identification of modifiable factors that affect the genetic diversity of the transmitted HIV-1 population.
BACKGROUND: Our previous studies have shown that the majority of African women were infected with multiple HIV-1 genetic variants, while in the remaining women only a single viral genotype was detected early in infection. Infection with multiple viral variants was associated with higher plasma HIV-1 RNA levels and faster CD4 T-cell decline. METHOD: Socio-behavioral characteristics, use of hormonal contraceptives, and the presence of sexually transmitted diseases were prospectively assessed at approximately monthly intervals around the time of HIV-1 acquisition in female sex workers in Kenya. We assessed the relationship between these factors and HIV-1 genetic complexity early in infection. RESULTS: One hundred and fifty-six women were included in this analysis, of whom 89 had multiple viral genotypes and 67 had a single genotype at primary infection. Women with multiple variants were more likely to have a genital tract infection [odds ratio (OR), 4.7; 95% confidence interval (CI), 1.4-18.1] or to be using hormonal contraceptives (OR, 2.7; 95% CI, 1.3-5.6) at the time of their infection than those with a single variant. In multivariate analyses, these factors were independent predictors of early HIV-1 genetic complexity, and the presence of multiple viral variants early in infection remained significantly associated with a higher steady state plasma HIV-1 RNA level. CONCLUSION: The presence of genital tract infections and hormonal contraceptive use at the time of transmission were associated with the acquisition of multiple HIV-1 variants.
Adult↗
Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study.
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Adult↗
The effect of hormonal contraception on genital tract shedding of HIV-1.
OBJECTIVE: A previous cross-sectional study reported that hormonal contraception may be associated with increased infectivity in HIV-1 infected women. We conducted a prospective study to determine if cervical shedding of HIV-1 increased after initiating hormonal contraception. DESIGN: Shedding of HIV-1 DNA (a marker of HIV-1 infected cells) and HIV-1 RNA were measured before and after initiating hormonal contraception. METHODS: HIV-1 seropositive women were recruited from a Kenyan family planning clinic. At baseline, cervical secretions were collected for HIV-1 DNA and RNA assays in women initiating hormonal contraception; follow-up samples were collected a median of 64 days later. RESULTS: One-hundred and one women chose depot medroxyprogesterone (Depo), 53 chose low-dose oral contraceptives (OC), seven high-dose OC, and 52 progesterone-only OC. At follow-up, there was a significant increase in the prevalence of cervical HIV-1 DNA detection [from 42% to 52%, odds ratio (OR), 1.62; 95% confidence interval (CI), 1.03-2.63) for all hormonal contraception combined, and a trend for an increase for each individual type. Although the prevalence of cervical HIV-1 RNA increased slightly (from 82% to 86%; OR, 1.56; 95% CI, 0.83-3.03), the concentration of cervical HIV-1 RNA did not change significantly overall (from 2.81 to 2.84 log10 copies/swab; P = 0.77) or for individual contraception types. CONCLUSIONS: A modest but significant increase in shedding of HIV-1 DNA but not of HIV-1 RNA was detected after starting hormonal contraception. Our results may have important implications regarding the infectivity of women using hormonal contraception, and highlight the need for epidemiologic studies of transmission rates from women using and not using hormonal contraception.
Adolescent↗
Injectable contraceptive use and genital ulcer disease during the early phase of HIV-1 infection increase plasma virus load in women.
We examined the association between host factors present near the time of human immunodeficiency virus type 1 (HIV-1) acquisition and subsequent virus loads, in a prospective cohort study of women in Mombasa, Kenya. Women were prospectively followed monthly before HIV-1 infection. One hundred sixty-one commercial sex workers who became infected with HIV-1 were followed for a median of 34 months, and 991 plasma samples collected > or =4 months after infection were tested for HIV-1 RNA. The median virus set point at 4 months after infection was 4.46 log10 copies/mL, and the average virus load increase during subsequent follow-up was 0.0094 log10 copies/mL/month. In a multivariate analysis that controlled for sexual behavior, the use of the injectable contraceptive depot medroxyprogesterone acetate (DMPA) at the time of HIV-1 infection was associated with a higher virus set point, and the presence of genital ulcer disease (GUD) during the early phase of HIV-1 infection was associated with greater change in virus load during follow-up. These findings suggest that, in women, the use of DMPA and the presence of GUD during the early phase of HIV-1 infection may influence the natural course of infection.
Acquired Immunodeficiency Syndrome↗