The Colposcopic Atlas of Schistosomiasis in the Lower Female Genital Tract Based on Studies in Malawi,Zimbabwe, Madagascar and South Africa

Background

Schistosoma (S.) haematobium is a neglected tropical disease which may affect any part of the genital tract in women. Female genital schistosomiasis (FGS) may cause abnormal vaginal discharge, contact bleeding, genital tumours, ectopic pregnancies and increased susceptibility to HIV. Symptoms may mimic those typical of sexually transmitted infections (STIs) and women with genital schistosomiasis may be incorrectly diagnosed. An expert consensus meeting suggested that the following findings by visual inspection should serve as proxy indicators for the diagnosis of schistosomiasis of the lower genital tract in women from S. haematobium endemic areas: sandy patches appearing as (1) single or clustered grains or (2) sandy patches appearing as homogenous, yellow areas, or (3) rubbery papules. In this atlas we aim to provide an overview of the genital mucosal manifestations of schistosomiasis in women.

Methodology/Principal findings

Photocolposcopic images were captured from women, between 1994 and 2012 in four different study sites endemic for S. haematobium in Malawi, Zimbabwe, South Africa and Madagascar. Images and specimens were sampled from sexually active women between 15 and 49 years of age. Colposcopic images of other diseases are included for differential diagnostic purposes.

Significance

This is the first atlas to present the clinical manifestations of schistosomiasis in the lower female genital tract. It will be freely available for online use, downloadable as a presentation and for print. It could be used for training purposes, further research, and in clinical practice.     

Schistosoma haematobium Infection and CD4+ T-Cell Levels: A Cross-Sectional Study of Young South African Women

Schistosoma (S.) haematobium causes urogenital schistosomiasis and has been hypothesized to adversely impact HIV transmission and progression. On the other hand it has been hypothesized that HIV could influence the manifestations of schistosomiasis. In this cross-sectional study, we explored the association between urogenital S. haematobium infection and CD4 cell counts in 792 female high-school students from randomly selected schools in rural KwaZulu-Natal, South Africa. We also investigated the association between low CD4 cell counts in HIV positive women and the number of excreted schistosome eggs in urine. Sixteen percent were HIV positive and 31% had signs of urogenital schistosomiasis (as determined by genital sandy patches and / or abnormal blood vessels on ectocervix / vagina by colposcopy or presence of eggs in urine). After stratifying for HIV status, participants with and without urogenital schistosomiasis had similar CD4 cell counts. Furthermore, there was no significant difference in prevalence of urogenital schistosomiasis in HIV positive women with low and high CD4 cell counts. There was no significant difference in the number of eggs excreted in urine when comparing HIV positive and HIV negative women. Our findings indicate that urogenital schistosomiasis do not influence the number of circulating CD4 cells.     

S. haematobium as a Common Cause of Genital Morbidity in Girls: A Cross-sectional Study of Children in South Africa

Background

Schistosoma (S.) haematobium infection is a common cause of genital morbidity in adult women. Ova in the genital mucosal lining may cause lesions, bleeding, pain, discharge, and the damaged surfaces may pose a risk for HIV. In a heterogeneous schistosomiasis endemic area in South Africa, we sought to investigate if young girls had genital symptoms and if this was associated with urinary S. haematobium.

Methodology

In a cross-sectional study of 18 randomly chosen primary schools, we included 1057 schoolgirls between the age of 10 and 12 years. We interviewed assenting girls, whose parents had consented to their participation and examined three urines from each of them for schistosome ova.

Principal findings

One third of the girls reported to have a history of genital symptoms. Prior schistosomal infection was reported by 22% (226/1020), this was associated with current genital symptoms (p<0.001). In regression analysis the genital symptoms were significantly associated both with urinary schistosomiasis (p<0.001) and water contact (p<0.001).

Conclusions

Even before sexually active age, a relatively large proportion of the participating girls had similar genital symptoms to those reported for adult genital schistosomiasis previously. Anti-schistosomal treatment should be considered at a young age in order to prevent chronic genital damage and secondary infections such as HIV, sexually transmitted diseases and other super-infections.     

Examining the relationship between urogenital schistosomiasis and HIV infection

Background

Urogenital schistosomiasis, caused by infection with Schistosoma haematobium, is widespread and causes substantial morbidity on the African continent. The infection has been suggested as an unrecognized risk factor for incident HIV infection. Current guidelines recommend preventive chemotherapy, using praziquantel as a public health tool, to avert morbidity due to schistosomiasis. In individuals of reproductive age, urogenital schistosomiasis remains highly prevalent and, likely, underdiagnosed. This comprehensive literature review was undertaken to examine the evidence for a cause-effect relationship between urogenital schistosomiasis and HIV/AIDS. The review aims to support discussions of urogenital schistosomiasis as a neglected yet urgent public health challenge.

Methodology/Principal Findings

We conducted a systematic search of the literature including online databases, clinical guidelines, and current medical textbooks. We describe plausible local and systemic mechanisms by which Schistosoma haematobium infection could increase the risk of HIV acquisition in both women and men. We also detail the effects of S. haematobium infection on the progression and transmissibility of HIV in co-infected individuals. We briefly summarize available evidence on the immunomodulatory effects of chronic schistosomiasis and the implications this might have for populations at high risk of both schistosomiasis and HIV.

Conclusions/Significance

Studies support the hypothesis that urogenital schistosomiasis in women and men constitutes a significant risk factor for HIV acquisition due both to local genital tract and global immunological effects. In those who become HIV-infected, schistosomal co-infection may accelerate HIV disease progression and facilitate viral transmission to sexual partners. Establishing effective prevention strategies using praziquantel, including better definition of treatment age, duration, and frequency of treatment for urogenital schistosomiasis, is an important public health priority. Our findings call attention to this pressing yet neglected public health issue and the potential added benefit of scaling up coverage of schistosomal treatment for populations in whom HIV infection is prevalent.     

Absence of lower genital tract lesions among women of reproductive age infected with Schistosoma mansoni: A cross-sectional study using a colposcope in Western Kenya

BackgroundFemale genital schistosomiasis (FGS) constitutes four different lesions known to be caused by Schistosoma haematobium ova deposited in the genital tract. Schistosoma mansoni ova may also be found in the genital tract. However, it is not known if S. mansoni causes lower genital tract lesions characteristic of FGS.MethodologyThis study was conducted in 8 villages along the shores of Lake Victoria, western Kenya. Stool and urine samples, collected from women of reproductive age on three consecutive days, were analysed for S. mansoni and S. haematobium infection. S. mansoni positive and S. haematobium negative willing participants, aged 18–50 years were invited to answer a questionnaire (demographics, symptoms), undergo a gynaecological examination and cytology specimen collection by an FGS expert.Principal findingsGynaecologic investigations were conducted in 147 S. mansoni-positive women who had a mean infection intensity of 253.3 epg (95% CI: 194.8–311.9 epg). Nearly 90% of them used Lake Victoria as their main water source. None were found to have cervicovaginal grainy sandy patches or rubbery papules. Homogenous yellow patches were found in 12/147 (8.2%) women. Women with homogenous yellow patches were significantly older (47 years) than the rest (34 years, p = 0.001). No association was found between intensity of S. mansoni infection and homogenous yellow patches (p = 0.70) or abnormal blood vessels (p = 0.14). S. mansoni infection intensity was not associated with genital itch, bloody or malodorous vaginal discharge.ConclusionS. mansoni infection was neither associated with lower genital tract lesions nor symptoms typically found in women with FGS.     

Potential Cost-Effectiveness of Schistosomiasis Treatment for Reducing HIV Transmission in Africa – The Case of Zimbabwean Women

Background

Epidemiological data from Zimbabwe suggests that genital infection with Schistosoma haematobium may increase the risk of HIV infection in young women. Therefore, the treatment of Schistosoma haematobium with praziquantel could be a potential strategy for reducing HIV infection. Here we assess the potential cost-effectiveness of praziquantel as a novel intervention strategy against HIV infection.

Methods

We developed a mathematical model of female genital schistosomiasis (FGS) and HIV infections in Zimbabwe that we fitted to cross-sectional data of FGS and HIV prevalence of 1999. We validated our epidemic projections using antenatal clinic data on HIV prevalence. We simulated annual praziquantel administration to school-age children. We then used these model predictions to perform a cost-effectiveness analysis of annual administration of praziquantel as a potential measure to reduce the burden of HIV in sub-Saharan Africa.

Findings

We showed that for a variation of efficacy between 30–70% of mass praziquantel administration for reducing the enhanced risk of HIV transmission per sexual act due to FGS, annual administration of praziquantel to school-age children in Zimbabwe could result in net savings of US$16–101 million compared with no mass treatment of schistosomiasis over a ten-year period. For a variation in efficacy between 30–70% of mass praziquantel administration for reducing the acquisition of FGS, annual administration of praziquantel to school-age children could result in net savings of US$36−92 million over a ten-year period.

Conclusions

In addition to reducing schistosomiasis burden, mass praziquantel administration may be a highly cost-effective way of reducing HIV infections in sub-Saharan Africa. Program costs per case of HIV averted are similar to, and under some conditions much better than, other interventions that are currently implemented in Africa to reduce HIV transmission. As a cost-saving strategy, mass praziquantel administration should be prioritized over other less cost-effective public health interventions.     

Parameters of human immunodeficiency virus infection of human cervical tissue and inhibition by vaginal virucides

Heterosexual transmission of human immunodeficiency virus (HIV) is the most frequent mode of infection worldwide. However, the immediate events between exposure to infectious virus and establishment of infection are still poorly understood. This study investigates parameters of HIV infection of human female genital tissue in vitro using an explant culture model. In particular, we investigated the role of the epithelium and virucidal agents in protection against HIV infection. We have demonstrated that the major target cells of infection reside below the genital epithelium, and thus HIV must cross this barrier to establish infection. Immune activation enhanced HIV infection of such subepithelial cells. Furthermore, our data suggest that genital epithelial cells were not susceptible to HIV infection, appear to play no part in the transfer of infectious virus across the epithelium, and thus may provide a barrier to infection. In addition, experiments using a panel of virucidal agents demonstrated differential efficiency to block HIV infection of subepithelial cells from partial to complete inhibition. This is the first demonstration that virucidal agents designed for topical vaginal use block HIV infection of genital tissue. Such agents have major implications for world health, as they will provide women with a mechanism of personal and covert protection from HIV infection.     

Impact of mucosal inflammation on cervical human immunodeficiency virus (HIV-1)-specific CD8 T-cell responses in the female genital tract during chronic HIV infection

The female genital tract is the major route of heterosexual human immunodeficiency virus (HIV) acquisition and transmission. Here, we investigated whether HIV-specific CD8 T-cell-mediated immune responses could be detected in the genital mucosa of chronically HIV-infected women and whether these were associated with either local mucosal HIV shedding or local immune factors. We found that CD8⁺ T-cell gamma interferon responses to Gag were detectable at the cervix of HIV-infected women but that the magnitude of genital responses did not correlate with those similarly detected in blood. This indicates that ex vivo HIV responses in one compartment may not be predictive of those in the other. We found that increased genital tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) levels correlated significantly with levels of Gag-specific CD8⁺ T cells at the cervix. Women who were detectably shedding virus in the genital tract had significantly increased cervical levels of TNF-α, IL-1β, IL-6, and IL-8 compared to women who were not detectably shedding virus. We were, however, unable to detect any association between the magnitude of cervical HIV-specific responses and mucosal HIV shedding. Our results support the hypothesis that proinflammatory cytokines in the female genital tract may promote HIV replication and shedding. In addition, we further show that inflammatory cytokines are associated with increased levels of HIV-specific CD8 effector cells at the genital mucosa but that these were not able to control genital HIV shedding.     

Eosinophil Granule Proteins ECP and EPX as Markers for a Potential Early-Stage Inflammatory Lesion in Female Genital Schistosomiasis (FGS)

Background

Genital granulomas induced by Schistosoma haematobium eggs can manifest as different lesion types visible by colposcopy; rubbery papules (RP), homogenous sandy patches (HSP) and grainy sandy patches (GSP). Pronounced tissue eosinophilia is a candidate marker for active S. haematobium pathology, as viable schistosome egg granulomas often are eosinophil rich. Here it was investigated whether eosinophil granule proteins ECP (eosinophil cationic protein) and EPX (eosinophil protein-X) in urine and genital lavage can be used as markers for active FGS lesions.

Methods

Uro-genital samples from 118 Malagasy women were analysed for ECP and EPX by standard sandwich avidin/biotin amplified ELISA.

Principal findings

The women with RP lesions had significantly higher levels of ECP and EPX in both lavage and urine. Furthermore, women with RP lesions were significantly younger than those with GSP. This could indicate that RP lesions might be more recently established and thus represent an earlier inflammatory lesion stage.

Conclusion

ECP in genital lavage might be a future tool aiding the identification of FGS pathology at a stage where reversibility remains a possibility following praziquantel treatment.     

A New Mouse Model for Female Genital Schistosomiasis

Background

Over 112 million people worldwide are infected with Schistosoma haematobium, one of the most prevalent schistosome species affecting humans. Female genital schistosomiasis (FGS) occurs when S. haematobium eggs are deposited into the female reproductive tract by adult worms, which can lead to pelvic pain, vaginal bleeding, genital disfigurement and infertility. Recent evidence suggests co-infection with S. haematobium increases the risks of contracting sexually transmitted diseases such as HIV. The associated mechanisms remain unclear due to the lack of a tractable animal model. We sought to create a mouse model conducive to the study of immune modulation and genitourinary changes that occur with FGS.

Methods

To model FGS in mice, we injected S. haematobium eggs into the posterior vaginal walls of 30 female BALB/c mice. A control group of 20 female BALB/c mice were injected with uninfected LVG hamster tissue extract. Histology, flow cytometry and serum cytokine levels were assessed at 2, 4, 6, and 8 weeks post egg injection. Voiding studies were performed at 1 week post egg injection.

Results

Vaginal wall injection with S. haematobium eggs resulted in synchronous vaginal granuloma development within 2 weeks post-egg injection that persisted for at least 6 additional weeks. Flow cytometric analysis of vaginal granulomata revealed infiltration by CD4⁺ T cells with variable expression of the HIV co-receptors CXCR4 and CCR5. Granulomata also contained CD11b⁺F4/80⁺ cells (macrophages and eosinophils) as well as CXCR4⁺MerTK⁺ macrophages. Strikingly, vaginal wall-injected mice featured significant urinary frequency despite the posterior vagina being anatomically distant from the bladder. This may represent a previously unrecognized overactive bladder response to deposition of schistosome eggs in the vagina.

Conclusion

We have established a new mouse model that could potentially enable novel studies of genital schistosomiasis in females. Ongoing studies will further explore the mechanisms by which HIV target cells may be drawn into FGS-associated vaginal granulomata.     

Increased vascularity in cervicovaginal mucosa with Schistosoma haematobium infection

Background

Close to 800 million people in the world are at risk of schistosomiasis, 85 per cent of whom live in Africa. Recent studies have indicated that female genital schistosomiasis might increase the risk of human immunodeficiency virus (HIV) infection. The aim of this study is to quantify and analyse the characteristics of the vasculature surrounding Schistosoma haematobium ova in the female genital mucosa.

Methodology/Principal Findings

Cervicovaginal biopsies with S. haematobium ova (n = 20) and control biopsies (n = 69) were stained with immunohistochemical blood vessel markers CD31 and von Willebrand Factor (vWF), which stain endothelial cells in capillary buds and established blood vessels respectively. Haematoxylin and eosin (HE) were applied for histopathological assessment. The tissue surrounding S. haematobium ova had a higher density of established blood vessels stained by vWF compared to healthy controls (p = 0.017). Immunostain to CD31 identified significantly more granulation tissue surrounding viable compared to calcified ova (p = 0.032), and a tendency to neovascularisation in the tissue surrounding viable ova compared to healthy cervical mucosa (p = 0.052).

Conclusions/Significance

In this study female genital mucosa with S. haematobium ova was significantly more vascularised compared to healthy cervical tissue. Viable parasite ova were associated with granulation tissue rich in sprouting blood vessels. Although the findings of blood vessel proliferation in this study may be a step to better understand the implications of S. haematobium infection, further studies are needed to explore the biological, clinical and epidemiological features of female genital schistosomiasis and its possible influence on HIV susceptibility.     

gp340 expressed on human genital epithelia binds HIV-1 envelope protein and facilitates viral transmission

During sexual transmission of HIV in women, the first cells likely to be infected are submucosal CD4(+) T cells and dendritic cells of the lower genital tract. HIV is segregated from these target cells by an epithelial cell layer that can be bypassed even when healthy and intact. To understand how HIV penetrates this barrier, we identified a host protein, gp340, that is expressed on genital epithelium and binds the HIV envelope via a specific protein-protein interaction. This binding allows otherwise subinfectious amounts of HIV to efficiently infect target cells and allows this infection to occur over a longer period of time after binding. Our findings suggest a mechanism of viral entry during heterosexual transmission where HIV is bound to intact genital epithelia, which then promotes the initial events of infection. Understanding this step in the initiation of infection will allow for the development of tools and methods for blocking HIV transmission.     

The cotton rat provides a novel model to study genital herpes infection and to evaluate preventive strategies

Prevention of genital herpes and other sexually transmitted infections (STI) is a critical health priority because of the overwhelming impact on women and infants and the epidemiological association with human immunodeficiency virus (HIV)/AIDS. Small animal models are essential for evaluating strategies for prevention or treatment of STI. Neither the murine nor the guinea pig model of genital herpes fully recapitulates human disease. We demonstrate that herpes simplex virus type 2 (HSV-2) readily infects inbred cotton rats (Sigmodon hispidus). Consistent infection does not require pretreatment with medroxyprogesterone, and primary disease resembles that observed in humans. The animals develop genital lesions and fully recover. During primary infection, viral DNA is also detected in liver, lungs, brain, and kidneys. Clinical self-limited recurrences occur spontaneously but may also be induced by dexamethasone. Pretreatment of cotton rats with PRO 2000 gel, a candidate vaginal microbicide being evaluated in clinical trials to prevent HSV and HIV, protects cotton rats from HSV. Together, these studies suggest that the cotton rat may provide an excellent model to study genital herpes and to evaluate preventive strategies.     

Pyrosequencing of the genital microbiotas of HIV-seropositive and -seronegative women reveals Lactobacillus iners as the predominant Lactobacillus Species

The species of vaginal lactobacilli in HIV-seropositive and -seronegative women were determined by 16S gene pyrosequencing. Lactobacillus iners sequences were the predominant lactobacillus sequences in 66% of HIV(+) women and 90% of HIV(-) women. This has implications for resistance of HIV(+) and HIV(-) women to genital colonization by pathogenic organisms.     

Cervical lesion proportion measure using a digital gridded imaging technique to assess cervical pathology in women with genital schistosomiasis

Female genital schistosomiasis (FGS) is characterized by a pattern of lesions which manifest at the cervix and the vagina, such as homogeneous and grainy sandy patches, rubbery papules in addition to neovascularization. A tool for quantification of the lesions is needed to improve FGS research and control programs. Hitherto, no tools are available to quantify clinical pathology at the cervix in a standardized and reproducible manner. This study aimed to develop and validate a cervical lesion proportion (CLP) measure for quantification of cervical pathology in FGS. A digital imaging technique was applied in which a grid containing 424 identical squares was positioned on high resolution digital images from the cervix of 70 women with FGS. CLP was measured for each image by observers counting the total number of squares containing at least one type of FGS associated lesion. For assessment of inter- and intra-observer reliability, three different observers measured CLP independently. In addition, a rubbery papule count (RPC) was determined in a similar manner. The intraclass correlation coefficient was 0.94 (excellent) for the CLP inter-rater reliability and 0.90 (good) for intra-rater reliability and the coefficients for the RPC were 0.88 and 0.80 (good), respectively. The CLP facilitated a reliable and reproducible quantification of FGS associated lesions of the cervix. In the future, grading of cervical pathology by CLP may provide insight into the natural course of schistosome egg-induced pathology of the cervix and may have a role in assessing praziquantel treatment efficacy against FGS.Trial Registration: ClinicalTrials.gov, trial number {"type":"clinical-trial","attrs":{"text":"NCT04115072","term_id":"NCT04115072"}}NCT04115072; trial URL https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT04115072","term_id":"NCT04115072"}}NCT04115072?term=Female+genital+schistosomiasis+AND+Madagascar&draw=2&rank=1.     

Vaginal microbiome-hormonal contraceptive interactions associate with the mucosal proteome and HIV acquisition

Alterations to the mucosal environment of the female genital tract, such as genital inflammation, have been associated with increased HIV acquisition in women. As the microbiome and hormonal contraceptives can affect vaginal mucosal immunity, we hypothesized these components may interact in the context of HIV susceptibility. Using previously published microbiome data from 685 women in the CAPRISA-004 trial, we compared relative risk of HIV acquisition in this cohort who were using injectable depot medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), and combined oral contraceptives (COC). In women who were Lactobacillus-dominant, HIV acquisition was 3-fold higher in women using DMPA relative to women using NET-EN or COC (OR: 3.27; 95% CI: 1.24–11.24, P = 0.0305). This was not observed in non-Lactobacillus-dominant women (OR: 0.95, 95% CI: 0.44–2.15, P = 0.895) (interaction P = 0.0686). Higher serum MPA levels associated with increased molecular pathways of inflammation in the vaginal mucosal fluid of Lactobacillus-dominant women, but no differences were seen in non-Lactobacillus dominant women. This study provides data suggesting an interaction between the microbiome, hormonal contraceptives, and HIV susceptibility.     

Patterns of sexual behaviour and reported symptoms of STI/RTIs among young people in Croatia--implications for interventions' planning

This paper describes some of the results of the first national-level survey on sexual behaviour and the distribution of risks to sexually transmitted infections (STIs), including human immunodeficiency virus infection (HIV), among youth in Croatia, and the nature and the extent of their vulnerability to these adverse health outcomes. The study was a cross-sectional, probability-based household survey conducted in 2005, and included 1093 respondents aged 18-24. This paper aims to describe the findings related to the knowledge of HIV transmission, key behavioural outcomes relevant for potential transmission of HIV and STIs, and correlates of genital discharge in young men and young women. More than 80% of young people know that the correct use of condoms protects against HIV and that HIV can be transmitted by someone who looks healthy. Fifty-nine percent of young men and 52.4% of young women reported using condoms during the first sexual intercourse, and 59.3% of men and 46.1% of women used condoms during the last sexual intercourse with a casual partner. This points to the gap between knowledge of condom use and the actual use of condoms as a high proportion of risky sexual contact remain unprotected. Having sexual intercourse frequently or regularly while consuming alcohol was reported by 19.2% of men and 7.6% of women. Much lower proportion are using drugs frequently or regularly during sexual intercourse (3.7% of men and 2.1% of women). Among those sexually experienced, 11.8% of men and 44.1% of women reported ever having a genital discharge. Higher presence of genital discharge in women is suggestive of reproductive tract infections that are not necessarily sexually transmitted. In the multivariate analysis, the lack of knowledge of whether chlamydial infections is an STI and having more than five partners in life were correlates of genital discharge in men, while in women the correlates included having more than five partners in life and not using condoms during the first sexual intercourse. Higher burden of STI-related symptoms was found among men who have men as sexual partners, those who paid for sex, and those with concurrent partnerships. These findings point out to the immediate need to strengthen sexual health education among young people and to the necessity for further development of other broad-based interventions to prevent adverse sexual health outcomes among both men and women, as well as those targeted towards more vulnerable subgroups.     

Effect of Genital Herpes on Cervicovaginal HIV Shedding in Women Co-Infected with HIV AND HSV-2 in Tanzania

Objectives

To compare the presence and quantity of cervicovaginal HIV among HIV seropositive women with clinical herpes, subclinical HSV-2 infection and without HSV-2 infection respectively; to evaluate the association between cervicovaginal HIV and HSV shedding; and identify factors associated with quantity of cervicovaginal HIV.

Design

Four groups of HIV seropositive adult female barworkers were identified and examined at three-monthly intervals between October 2000 and March 2003 in Mbeya, Tanzania: (1) 57 women at 70 clinic visits with clinical genital herpes; (2) 39 of the same women at 46 clinic visits when asymptomatic; (3) 55 HSV-2 seropositive women at 60 clinic visits who were never observed with herpetic lesions; (4) 18 HSV-2 seronegative women at 45 clinic visits. Associations of genital HIV shedding with HIV plasma viral load (PVL), herpetic lesions, HSV shedding and other factors were examined.

Results

Prevalence of detectable genital HIV RNA varied from 73% in HSV-2 seronegative women to 94% in women with herpetic lesions (geometric means 1634 vs 3339 copies/ml, p = 0.03). In paired specimens from HSV-2 positive women, genital HIV viral shedding was similar during symptomatic and asymptomatic visits. On multivariate regression, genital HIV RNA (log₁₀ copies/mL) was closely associated with HIV PVL (β = 0.51 per log₁₀ copies/ml increase, 95%CI:0.41–0.60, p<0.001) and HSV shedding (β = 0.24 per log₁₀ copies/ml increase, 95% CI:0.16–0.32, p<0.001) but not the presence of herpetic lesions (β = −0.10, 95%CI:−0.28–0.08, p = 0.27).

Conclusions

HIV PVL and HSV shedding were more important determinants of genital HIV than the presence of herpetic lesions. These data support a role of HSV-2 infection in enhancing HIV transmissibility.     

CD4 T cell depletion at the cervix during HIV infection is associated with accumulation of terminally differentiated T cells

In blood, the accumulation of terminally differentiated (TD) T cells during HIV infection is associated with CD4 T cell loss and HIV disease progression. Here, we investigated the maintenance and functional characteristics of memory T cells at the cervix. We found that CD4 T cell depletion at the cervix mirrors CD4 depletion in blood. In all women, depletion of CD4 T cells at the cervix was associated with significant reductions in CD45RA- CCR7+ (central memory [CM]) T cells and the accumulation of CD45RA+ CCR7- (TD T cells). We determined whether inflammation in the genital tract was associated with the local differentiation of T cells at the cervix. In uninfected women, genital tract inflammation was associated with the accumulation of CD45RA- CCR7+ CM CD4 T cells and reduced frequencies of CD45RA+ CCR7- TD cells at the cervix. This finding may reflect the fact that, in the absence of HIV infection, TD T cells may be slowly lost in the presence of genital inflammation, while CD45RA- CCR7+ CM T cells are recruited to replenish the diminishing CD4 T cell pool. Following global stimulation with phorbol myristate acetate (PMA)-ionomycin, we noted a significant interleukin 2 (IL-2) deficit in both cervical and blood CD4 T cells from HIV-infected women compared to uninfected women, while gamma interferon (IFN-γ) production was similar, irrespective of HIV status. Few HIV-infected women had detectable IFN-γ and IL-2 HIV-specific T cell responses at the cervix, and these responses were significantly lower in magnitude than the corresponding responses in blood. These data suggest that CD4 depletion was associated with the accumulation of terminally differentiated T cell phenotypes at the cervical mucosa defective in their ability to produce IL-2. CD4 depletion and compromised immunity at the cervix may be accompanied by progressive decline of central memory-like T cells and development of T cells toward terminally differentiated phenotypes.     

Comparative study on spatial patterns of the Artemisia ordosica population in the Mu Us sandy land

Artemisia ordosica is an under-shrub species, which dominates the vegetation of the Mu Us sandy land in North China. The spatial patterns of the A. ordosica population in different sandy lands were compared with the methods of Spatial Auto-correlation Analysis, Semi-variance Analysis and Nine-Term Local Quadrat Variance (9TLQV). The results show that, by contrast with the A. ordosica population in fixed sandy land, the population in semi-fixed sandy land is of stronger auto-correlation and greater spatial heterogeneity, and meanwhile it presents more intense differentiation between patches and gaps. The spatial patterns of the A. ordosica population in semi-fixed sandy land are probably governed by drifting sand caused by strong winds. Drifting sand can easily put A. ordosica shrubs to death unless they live together in form of A. ordosica patches, where the distances between shrubs are short. In semi-fixed sandy land, patches are not only the form of the A. ordosica population to survive drifting sand, but also the foundation of the A. ordosica population to develop and broaden the area. The A. ordosica population is supposed to broaden the area through edge extending out from the patches scattering in semi-fixed sandy land. The spatial patterns of the A. ordosica population in fixed sandy land are possibly affected by intra-specific competition related to high plant coverage. This study is ecologically useful to improve the practice of vegetation restoration in sandy land. When transplanting A. ordosica shrubs to bare sandy land, one had better arrange them in form of patches separated by gaps, which can promote the survival of transplanted shrubs, and also help to take advantage of A. ordosica patches to revegetate bare gaps.