Modeling the temporal dynamics of cervicovaginal microbiota identifies targets that may promote reproductive health (vol 9, 163, 2021)

Following the publication of the original article [1], the authors noticed a misspelling on the name of one of the co-authors. “Musie S. Ghebermichael” should read “Musie S. Ghebremichael” The original article has been updated

Antigen Presenting Cells Link the Female Genital Tract Microbiome to Mucosal Inflammation, With Hormonal Contraception as an Additional Modulator of Inflammatory Signatures

The microbiome of the female genital tract (FGT) is closely linked to reproductive health outcomes. Diverse, anaerobe-dominated communities with low Lactobacillus abundance are associated with a number of adverse reproductive outcomes, such as preterm birth, cervical dysplasia, and sexually transmitted infections (STIs), including HIV. Vaginal dysbiosis is associated with local mucosal inflammation, which likely serves as a biological mediator of poor reproductive outcomes. Yet the precise mechanisms of this FGT inflammation remain unclear. Studies in humans have been complicated by confounding demographic, behavioral, and clinical variables. Specifically, hormonal contraception is associated both with changes in the vaginal microbiome and with mucosal inflammation. In this study, we examined the transcriptional landscape of cervical cell populations in a cohort of South African women with differing vaginal microbial community types. We also investigate effects of reproductive hormones on the transcriptional profiles of cervical cells, focusing on the contraceptive depot medroxyprogesterone acetate (DMPA), the most common form of contraception in sub-Saharan Africa. We found that antigen presenting cells (APCs) are key mediators of microbiome associated FGT inflammation. We also found that DMPA is associated with significant transcriptional changes across multiple cell lineages, with some shared and some distinct pathways compared to the inflammatory signature seen with dysbiosis. These results highlight the importance of an integrated, systems-level approach to understanding host-microbe interactions, with an appreciation for important variables, such as reproductive hormones, in the complex system of the FGT mucosa

The incidence of HIV among women recruited during late pregnancy and followed up for six years after childbirth in Zimbabwe

<p>Abstract</p> <p>Background</p> <p>HIV incidence is a useful tool for improving the targeting of populations for interventions and assessing the effectiveness of prevention strategies. A study in Harare, Zimbabwe reported cumulative incidences of 3.4% (3.0-3.8) and 6.5% (5.7-7.4) among post-partum women followed for 12 and 24 months respectively between 1997 and 2001. According to a Government report on HIV the prevalence of HIV fell from about 30% in 1999 to 14% in 2008. The purpose of this study was to determine the incidence of HIV-1 among women enrolled during late pregnancy and followed for six years after childbirth and to identify risk factors associated with acquisition of HIV.</p> <p>Methods</p> <p>HIV-uninfected pregnant women around 36 weeks gestation were enrolled from primary health care clinics in peri-urban settlements around Harare and followed-up for up to six years after childbirth. At every visit a questionnaire was interview-administered to obtain socio-demographic data and sexual history since the previous visit. A genital examination was performed followed by the collection of biological samples.</p> <p>Results</p> <p>Of the 552 HIV-uninfected women 444 (80.4%) were seen at least twice during the six years follow-up and 39 acquired HIV, resulting in an incidence (95% CI) of 2.3/100 woman-years-at-risk (wyar) (1.1-4.1). The incidence over the first nine months post-partum was 5.7/100 wyar (3.3-8.1). A greater proportion of teenagers (15.3%) contributed to a high incidence rate of 2.9/100 (0.6-8.7) wyar. In multivariate analysis lower education of participant, RR 2.1 (1.1-4.3) remained significantly associated with HIV acquisition. Other risk factors associated with acquisition of HIV-1 in univariate analysis were young age at sexual debut, RR 2.3, (1.0-5.6) and having children with different fathers, RR 2.7(1.3-5.8). Women that knew that their partners had other sexual partners were about four times more likely to acquire HIV, RR 3.8 (1.3-11.2).</p> <p>Conclusion</p> <p>The incidence of HIV was high during the first nine months after childbirth. Time of seroconversion, age and educational level of seroconverter are important factors that must be considered when designing HIV intervention strategies.</p

Lack of Protection following Passive Transfer of Polyclonal Highly Functional Low-Dose Non-Neutralizing Antibodies

Recent immune correlates analysis from the RV144 vaccine trial has renewed interest in the role of non-neutralizing antibodies in mediating protection from infection. While neutralizing antibodies have proven difficult to induce through vaccination, extra-neutralizing antibodies, such as those that mediate antibody-dependent cellular cytotoxicity (ADCC), are associated with long-term control of infection. However, while several non-neutralizing monoclonal antibodies have been tested for their protective efficacy in vivo, no studies to date have tested the protective activity of naturally produced polyclonal antibodies from individuals harboring potent ADCC activity. Because ADCC-inducing antibodies are highly enriched in elite controllers (EC), we passively transferred highly functional non-neutralizing polyclonal antibodies, purified from an EC, to assess the potential impact of polyclonal non-neutralizing antibodies on a stringent SHIV-SF162P3 challenge in rhesus monkeys. Passive transfer of a low-dose of ADCC inducing antibodies did not protect from infection following SHIV-SF162P3 challenge. Passively administered antibody titers and gp120-specific, but not gp41-specific, ADCC and antibody induced phagocytosis (ADCP) were detected in the majority of the monkeys, but did not correlate with post infection viral control. Thus these data raise the possibility that gp120-specific ADCC activity alone may not be sufficient to control viremia post infection but that other specificities or Fc-effector profiles, alone or in combination, may have an impact on viral control and should be tested in future passive transfer experiments

R5-SHIV Induces Multiple Defects in T Cell Function during Early Infection of Rhesus Macaques Including Accumulation of T Reg Cells in Lymph Nodes

Background: HIV-1 is a pathogen that T cell responses fail to control. HIV-1gp120 is the surface viral envelope glycoprotein that interacts with CD4 T cells and mediates entry. HIV-1gp120 has been implicated in immune dysregulatory functions that may limit anti-HIV antigen-specific T cell responses. We hypothesized that in the context of early SHIV infection, immune dysregulation of antigen-specific T-effector cell and regulatory functions would be detectable and that these would be associated or correlated with measurable concentrations of HIV-1gp120 in lymphoid tissues. Methods: Rhesus macaques were intravaginally inoculated with a Clade C CCR5-tropic simian-human immunodeficiency virus, SHIV-1157ipd3N4. HIV-1gp120 levels, antigen-specificity, levels of apoptosis/anergy and frequency and function of Tregs were examined in lymph node and blood derived T cells at 5 and 12 weeks post inoculation. Results/Conclusions: We observed reduced responses to Gag in CD4 and gp120 in CD8 lymph node-derived T cells compared to the peripheral blood at 5 weeks post-inoculation. Reduced antigen-specific responses were associated with higher levels of PD-1 on lymph node-derived CD4 T cells as compared to peripheral blood and uninfected lymph node-derived CD4 T cells. Lymph nodes contained increased numbers of Tregs as compared to peripheral blood, which positively correlated with gp120 levels; T regulatory cell depletion restored CD8 T cell responses to Gag but not to gp120. HIV gp120 was also able to induce T regulatory cell chemotaxis in a dose-dependent, CCR5-mediated manner. These studies contribute to our broader understanding of the ways in which HIV-1 dysregulates T cell function and localization during early infection

Nonparametric estimation of bivariate mean residual life function

In survival analysis the additional lifetime that an object survives past a time t is called the residual life function of the object. Mathematically speaking if the lifetime of the object is described by a random variable T then the random variable R(t) = [T - t| T > t] is called the residual life random variable. The quantity e(t) = E( R(t)) = E[T - t|T > t] is called the mean residual lifetime (mrl) function or the life expectancy at age t. There are numerous situations where the bivariate mrl function is important. Times to death or times to initial contraction of a disease may be of interest for litter mate pairs of rats or for twin studies in humans. The time to a deterioration level or the time to reaction of a treatment may be of interest in pairs of lungs, kidneys, breasts, eyes or ears of humans. In reliability, the distribution of the lifelengths of a particular pair of components in a system may be of interest. Because of the dependence among the event times, we can not get reliable results by using the univariate mrl function on each event times in order to study the aging process. The bivariate mrl function is useful in analyzing the joint distribution of two event times where these times are dependent. In recent years, though considerable attention has been paid to the univariate mrl function, relatively little research has been devoted to the analysis of the bivariate mrl function. The specific contribution of this dissertation consists in proposing, and examining the properties of, nonparametric estimators of the bivariate mean residual life function when a certain order among such functions exists. That is, we consider the problem of nonparametric estimation of a bivariate mrl function when it is bounded from above by another known or unknown mrl function. The estimators under such an order constraint are shown to perform better than the empirical mrl function in terms of mean squared error. Moreover, they are shown to be projections, onto an appropriate space, of the empirical mean residual life function. Under suitable technical conditions, the asymptotic theory of these estimators is derived. Finally, the procedures are applied to a data set on bivariate survival. More specifically, we have used the Diabetic Retinopathy Study (DRS) data to illustrate our estimators. In this data set, the survival times of both left and right eyes are given for two groups of patients: juvenile and adult diabetics. Thus, it seems natural to assume that the mrl for the juvenile diabetics be longer than the mrl of the adult diabetics. Under this assumption, we calculated the estimators of the mrl function for each group. We have also calculated the empirical mrl functions of the two groups and compared them with the estimators of the mrl function obtained under the above assumption

Effect of premarital sex on sexually transmitted infections (STIs) and high risk behaviors in women

This research aimed to study the effect of premarital sex on sexually transmitted infections (STIs) and high risk behaviors among women in sub-Saharan Africa. It included 1,393 women randomly selected from the Moshi urban district of northern Tanzania. Participants&apos; demographic and socio-demographic characteristics, alcohol use, condom use, number of partners, symptoms of STIs and age at first sex and marriage were obtained. Moreover, blood and urine samples were tested for human immunodeficiency virus (HIV-1), herpes simplex virus (HSV-2), syphilis, chlamydia, gonorrhea, trichomonas and Mycoplasma genitalium infections. The average duration of premarital sex in the study participants was 1.66 years (standard deviation (SD) of 2.61 years). Women with longer duration of premarital sex had higher odds of HIV-1, HSV-2 and other STIs. Moreover, women with longer duration of premarital sex were more likely to report multiple sexual partners. These findings highlighted the importance of a lengthy period of premarital sex as a public health issue. STIs prevention programs in sub-Saharan Africa should address factors leading to a longer period of premarital sex in women

A Critical Reappraisal of Prolonged Neutropenia as a Risk Factor for Invasive Pulmonary Aspergillosis

Prolonged neutropenia is generally thought to be the major factor for invasive pulmonary aspergillosis (IPA). In the present study, we characterize the frequency, severity, and duration of neutropenia that immediately precedes IPA. Prolonged neutropenia was identified in only one third of all IPA cases and occurred exclusively in hematologic patients

Temporal effect of HLA-B*57 on viral control during primary HIV-1 infection Open Access

Background: HLA-B alleles are associated with viral control in chronic HIV-1 infection, however, their role in primary HIV-1 disease is unclear. This study sought to determine the role of HLA-B alleles in viral control during the acute phase of HIV-1 infection and establishment of the early viral load set point (VLSP). Findings: Individuals identified during primary HIV-1 infection were HLA class I typed and followed longitudinally. Associations between HLA-B alleles and HIV-1 viral replication during acute infection and VLSP were analyzed in untreated subjects. The results showed that neither HLA-B*57 nor HLA-B*27 were significantly associated with viral control during acute HIV-1 infection (Fiebig stage I-IV, n=171). HLA-B*57 was however significantly associated with a subsequent lower VLSP (p&lt;0.001, n=135) with nearly 1 log10 less median viral load. Analysis of a known polymorphism at position 97 of HLA-B showed significant associations with both lower initial viral load (p&lt;0.01) and lower VLSP (p&lt;0.05). However, this association was dependent on different amino acids at this position for each endpoint. Conclusions: TheeffectofHLA-B*57onviralcontrolismorepronounced during the later stages of primary HIV-1 infection, which suggests the underlying mechanism of control occurs at a critical period in the first several months after HIV-1 acquisition. The risk profile of polymorphisms at position 97 of HLA-B are more broadly associated with HIV-1 viral load during primary infection and may serve as a focal point in further studies of HLA-B function