Plasma Lipidomic Profiling of Treated HIV-Positive Individuals and the Implications for Cardiovascular Risk Prediction

Background

The increased risk of coronary artery disease in human immunodeficiency virus (HIV) positive patients is collectively contributed to by the human immunodeficiency virus and antiretroviral-associated dyslipidaemia. In this study, we investigate the characterisation of the plasma lipid profiles of treated HIV patients and the relationship of 316 plasma lipid species across multiple lipid classes with the risk of future cardiovascular events in HIV- positive patients.

Methods

In a retrospective case-control study, we analysed plasma lipid profiles of 113 subjects. Cases (n = 23) were HIV-positive individuals with a stored blood sample available 12 months prior to their diagnosis of coronary artery disease (CAD). They were age and sex matched to HIV-positive individuals without a diagnosis of CAD (n = 45) and with healthy HIV-negative volunteers (n = 45).

Results

Association of plasma lipid species and classes with HIV infection and cardiovascular risk in HIV were determined. In multiple logistic regression, we identified 83 lipids species and 7 lipid classes significantly associated with HIV infection and a further identified 74 lipid species and 8 lipid classes significantly associated with future cardiovascular events in HIV-positive subjects. Risk prediction models incorporating lipid species attained an area under the receiver operator characteristic curve (AUC) of 0.78 (0.775, 0.785)) and outperformed all other tested markers and risk scores in the identification of HIV-positive subjects with increased risk of cardiovascular events.

Conclusions

Our results demonstrate that HIV-positive patients have significant differences in their plasma lipid profiles compared with healthy HIV-negative controls and that numerous lipid species were significantly associated with elevated cardiovascular risk. This suggests a potential novel application for plasma lipids in cardiovascular risk screening of HIV-positive patients.     

Invariant NKT Cell Response to Dengue Virus Infection in Human

Background

Dengue viral infection is a global health threat without vaccine or specific treatment. The clinical outcome varies from asymptomatic, mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF). While adaptive immune responses were found to be detrimental in the dengue pathogenesis, the roles of earlier innate events remain largely uninvestigated. Invariant natural killer T (iNKT) cells represent innate-like T cells that could dictate subsequent adaptive response but their role in human dengue virus infection is not known. We hypothesized that iNKT cells play a role in human dengue infection.

Methods

Blood samples from a well-characterized cohort of children with DF, DHF, in comparison to non-dengue febrile illness (OFI) and healthy controls at various time points were studied. iNKT cells activation were analyzed by the expression of CD69 by flow cytometry. Their cytokine production was then analyzed after α-GalCer stimulation. Further, the CD1d expression on monocytes, and CD69 expression on conventional T cells were measured.

Results

iNKT cells were activated during acute dengue infection. The level of iNKT cell activation associates with the disease severity. Furthermore, these iNKT cells had altered functional response to subsequent ex vivo stimulation with α-GalCer. Moreover, during acute dengue infection, monocytic CD1d expression was also upregulated and conventional T cells also became activated.

Conclusion

iNKT cells might play an early and critical role in the pathogenesis of severe dengue viral infection in human. Targeting iNKT cells and CD1d serve as a potential therapeutic strategy for severe dengue infection in the future.     

Disposal of iNKT cell deficiency and an increase in expression of SLAM signaling factors characterizes sarcoidosis remission: a 4-year longitudinal study

Background

Invariant NKT (iNKT) cells are regulatory lymphocytes that may be important in disorders with increased Th1 responses. We utilized a 4-year longitudinal observational study of iNKT cells and SLAM signaling pathway factors, which are important for iNKT development in patients with newly diagnosed sarcoidosis.

Methods

Detailed clinical, functional, and radiographic evaluation and determination of iNKT peripheral blood cell counts and expression of SLAM signaling factors was carried out at presentation and after 3 months, 1 year, and 4 years of disease follow-up in 29 patients with pulmonary sarcoidosis. At presentation, we also evaluated the frequencies of pulmonary BALF iNKT cells. We also included 37 control subjects.

Results

We demonstrated a marked deficiency of blood and lung iNKT cells and decreased expression of SLAM signaling factors in patients with newly diagnosed sarcoidosis. During 4 years of disease follow-up, there was a significant increase in blood iNKT cell numbers and in expression of SLAM signaling factors, mainly SLAMF1, SLAMF6, and FYN. This increase clearly correlated with improvement in patients’ clinical symptoms. At the 4-year endpoint, the disease had gone into remission in the great majority of patients and thus also iNKT cell deficiency. Moreover, at the 4-year endpoint iNKT level reached the iNKT level of the control subjects.

Conclusions

Our longitudinal study showed that a disposal of iNKT deficiency in parallel with an increase in expression of SLAM signaling factors characterizes the clinical remission of sarcoidosis.     

Australian Gay and Bisexual Men’s Attitudes to HIV Treatment as Prevention in Repeated,National Surveys, 2011-2013

Objective

Assess the acceptability of HIV treatment as prevention and early antiretroviral treatment among gay and bisexual men in Australia and any changes in attitudes over time.

Methods

National, online, cross-sectional surveys of gay and bisexual men were repeated in 2011 and 2013. Changes in attitudes to HIV treatment over time were assessed with multivariate analysis of variance. The characteristics of men who agreed that HIV treatment prevented transmission and thought that early treatment was necessary were identified with multivariate logistic regression.

Results

In total, 2599 HIV-negative, untested and HIV-positive men participated (n = 1283 in 2011 and n = 1316 in 2013). Attitudes changed little between 2011 and 2013; most participants remained sceptical about the preventative benefits of HIV treatment. In 2013, only 2.6% of men agreed that HIV treatment prevented transmission; agreement was associated with being HIV-positive, having an HIV-positive regular partner, and having received HIV post-exposure prophylaxis. In contrast, 71.8% agreed that early antiretroviral treatment is necessary; younger men were more likely and HIV-positive men and participants with HIV-positive partners were much less likely to agree with this.

Conclusions

Promoting the individual health benefits of HIV treatment rather than its preventative benefits remains more acceptable to Australian gay and bisexual men.     

iNKT Cells Control Mouse Spontaneous Carcinoma Independently of Tumor-Specific Cytotoxic T Cells

Background

CD1d-restricted invariant NKT (iNKT) cells are a subset of T lymphocytes endowed with innate effector functions that aid in the establishment of adaptive T and B cell immune responses. iNKT cells have been shown to play a spontaneous protective role against experimental tumors. Yet, the interplay between iNKT and tumor-specific T cells in cancer immune surveillance/editing has never been addressed. The transgenic adenocarcinoma of the mouse prostate (TRAMP) is a realistic model of spontaneous oncogenesis, in which the tumor-specific cytotoxic T cell (CTL) response undergoes full tolerance upon disease progression.

Principal Findings

We report here that lack of iNKT cells in TRAMP mice resulted in the appearance of more precocious and aggressive tumors that significantly reduced animal survival. TRAMP mice bearing or lacking iNKT cells responded similarly to a tumor-specific vaccination and developed tolerance to a tumor-associated antigen at comparable rate.

Conclusions

Hence, our data argue for a critical role of iNKT cells in the immune surveillance of carcinoma that is independent of tumor-specific CTL.     

Neurobehavioral effects in HIV-positive individuals receiving highly active antiretroviral therapy (HAART) in Gaborone, Botswana

Objective

To explore the prevalence and features of HIV-associated neurocognitive disorders (HANDS) in Botswana, a sub-Saharan country at the center of the HIV epidemic.

Design and Methods

A cross sectional study of 60 HIV-positive individuals, all receiving highly active antiretroviral therapy (HAART), and 80 demographically matched HIV-seronegative control subjects. We administered a comprehensive neuropsychological test battery and structured psychiatric interview. The lowest 10^th percentile of results achieved by control subjects was used to define the lower limit of normal performance on cognitive measures. Subjects who scored abnormal on three or more measures were classified as cognitively impaired. To determine the clinical significance of any cognitive impairment, we assessed medication adherence, employment, and independence in activities of daily living (ADL).

Results

HIV+ subjects were impaired for all cognitive-motor ability areas compared with matched, uninfected control subjects. Thirty seven percent of HIV+ patients met criteria for cognitive impairment.

Conclusion

These findings indicate that neurocognitive impairment is likely to be an important feature of HIV infection in resource-limited countries; underscoring the need to develop effective treatments for subjects with, or at risk of developing, cognitive impairment.     

Missed opportunities: poor linkage into ongoing care for HIV-positive pregnant women in Mwanza, Tanzania

Background

Global coverage of prevention of mother-to-child (PMTCT) services reached 53% in 2009. However the number of pregnant women who test positive for HIV in antenatal clinics and who link into long-term HIV care is not known in many resource-poor countries. We measured the proportion of HIV-positive pregnant women in Mwanza city, Tanzania, who completed the cascade of care from antenatal HIV diagnosis to assessment and engagement in care in adult HIV clinics.

Methods

Thirty antenatal and maternity ward health workers were interviewed about PMTCT activities. Nine antenatal HIV education sessions were observed. A prospective cohort of 403 HIV-positive women was enrolled by specially-trained clinicians and nurses on admission to delivery and followed for four months post-partum. Information was collected on referral and attendance at adult HIV clinics, eligibility for highly active antiretroviral therapy (HAART) and reasons for lack of attendance.

Results

Overall, 70% of PMTCT health workers referred HIV-positive pregnant women to the HIV clinic for assessment and care. Antenatal HIV education sessions did not cover on-going care for HIV-infected women. Of 310 cohort participants tested in pregnancy, 51% had received an HIV clinic referral pre-delivery. Only 32% of 244 women followed to four months post-partum had attended an HIV clinic and been assessed for HAART eligibility. Non-attendance for HIV care was independently associated with fewer antenatal visits, poor PMTCT prophylaxis compliance, non-disclosure of HIV status, and non-Sukuma ethnicity.

Conclusion

Most women identified as HIV-positive during pregnancy were not assessed for HAART eligibility during pregnancy or in the first four months post-partum. Initiating HAART at the antenatal clinic, improved counselling and linkages to care between PMTCT and adult HIV treatment services and reducing stigma surrounding disclosure of HIV results would benefit on-going care of HIV-positive pregnant women.     

Combination of Intratumoral Invariant Natural Killer T Cells and Interferon-Gamma Is Associated with Prognosis of Hepatocellular Carcinoma after Curative Resection

Purpose

To investigate the prognostic value of intratumoral invariant natural killer T (iNKT) cells and interferon-gamma (IFN-γ) in hepatocellular carcinoma (HCC) after curative resection.

Experimental Design

Expression of TRAV10, encoding the Vα24 domain of iNKT cells, and IFN-γ mRNA were assessed by quantitative real-time polymerase chain reaction in tumor from 224 HCC patients undergoing curative resection. The prognostic value of these two and other clinicopathologic factors was evaluated.

Results

Either intratumoral iNKT cells and IFN-γ alone or their combination was an independent prognostic factor for OS (P = 0.001) and RFS (P = 0.001) by multivariate Cox proportional hazards analysis. Patients with concurrent low levels of iNKT cells and IFN-γ had a hazard ratio (HR) of 2.784 for OS and 2.673 for RFS. The areas under the curve of iNKT cells, IFN-γand their combination were 0.618 vs 0.608 vs 0.654 for death and 0.591 vs 0.604 vs 0.633 for recurrence respectively by receiver operating characteristic curve analysis. The prognosis was the worst for HCC patients with concurrent low levels of iNKT cells and IFN-γ, which might be related with more advanced pTNM stage and more vascular invasion.

Conclusions

Combination of intratumoral iNKT cells and IFN-γ is a promising independent predictor for recurrence and survival in HCC, which has a better power to predict HCC patients’ outcome compared with intratumoral iNKT cells or IFN-γ alone.     

Developmental Dynamics of Post-Selection Thymic DN iNKT

Background

Invariant natural killer T (iNKT) cells develop in the thymus and branch off from the maturation pathway of conventional T cell at the DP stage. While different stages of iNKT cellular development have been defined, the actual time that iNKT cell precursors spend at each stage is still unknown.

Methodology/Principal Finding

Here we report on maturation dynamics of post-selection DN iNKT cells by injecting wild-type DP^dim thymocytes into the thymus of TCRα^−/− mice and using the Vα14-Jα18 rearrangements as a molecular marker to follow the maturation dynamics of these cells.

Conclusion/Significance

This study shows that the developmental dynamics of DN iNKT cells in DP^dim are very rapid and that it takes less than 1 day to down-regulate CD4 and CD8 and become DN. These DN cells are precursors of peripheral DN iNKT cells and appear in the spleen in 1–2 days. Thymic DN iNKT residents are predominantly derived from cells that quickly return from the periphery. The expansion of a very small subset of DN iNKT precursors could also play a small role in this process. These data are an example of measuring T cell maturation in the thymus and show that the maturation dynamics of selected DN iNKT cells fall within the same general time frame as conventional αβ T cells.     

Causes of Death on Antiretroviral Therapy: A Post-Mortem Study from South Africa

Background

Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients.

Methods

HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death.

Results

Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7–90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death.

Conclusions

Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.     

Provider-initiated HIV testing and counseling: increased uptake in two public community health centers in South Africa and implications for scale-up

Background

International guidance recommends the scale up of routinely recommended, offered, and delivered health care provider-initiated HIV testing and counseling (PITC) to increase the proportion of persons who know their HIV status. We compared HIV test uptake under PITC to provider-referral to voluntary counseling and testing (VCT referral) in two primary health centers in South Africa.

Methods

Prior to introducing PITC, clinical providers were instructed to refer systematically selected study participants to VCT. After PITC and HIV rapid test training, providers were asked to recommend, offer and provide HIV testing to study participants during the clinical consultation. Participants were interviewed before and after their consultation to assess their HIV testing experiences.

Results

HIV test uptake increased under PITC (OR 2.85, 95% CI 1.71, 4.76), and more patients felt providers answered their questions on HIV (104/141 [74%] versus 73/118 [62%] for VCT referral; p 0.04). After three months, only 4/106 (3.8%) HIV-positive patients had registered for onsite HIV treatment. Providers found PITC useful, but tested very few patients (range 0–15).

Conclusion

PITC increased the uptake of HIV testing compared with referral to onsite VCT, and patients reported a positive response to PITC. However, providing universal PITC will require strong leadership to train and motivate providers, and interventions to link HIV-positive persons to HIV treatment centers.     

Trouble with bleeding: risk factors for acute hepatitis C among HIV-positive gay men from Germany--a case-control study

Objectives

To identify risk factors for hepatitis C among HIV-positive men who have sex with men (MSM), focusing on potential sexual, nosocomial, and other non-sexual determinants.

Background

Outbreaks of hepatitis C virus (HCV) infections among HIV-positive MSM have been reported by clinicians in post-industrialized countries since 2000. The sexual acquisition of HCV by gay men who are HIV positive is not, however, fully understood.

Methods

Between 2006 and 2008, a case-control study was embedded into a behavioural survey of MSM in Germany. Cases were HIV-positive and acutely HCV-co-infected, with no history of injection drug use. HIV-positive MSM without known HCV infection, matched for age group, served as controls. The HCV-serostatus of controls was assessed by serological testing of dried blood specimens. Univariable and multivariable regression analyses were used to identify factors independently associated with HCV-co-infection.

Results

34 cases and 67 controls were included. Sex-associated rectal bleeding, receptive fisting and snorting cocaine/amphetamines, combined with group sex, were independently associated with case status. Among cases, surgical interventions overlapped with sex-associated rectal bleeding.

Conclusions

Sexual practices leading to rectal bleeding, and snorting drugs in settings of increased HCV-prevalence are risk factors for acute hepatitis C. We suggest that sharing snorting equipment as well as sharing sexual partners might be modes of sexual transmission. Condoms and gloves may not provide adequate protection if they are contaminated with blood. Public health interventions for HIV-positive gay men should address the role of blood in sexual risk behaviour. Further research is needed into the interplay of proctosurgery and sex-associated rectal bleeding.     

Willingness to Participate in HIV Therapeutic Vaccine Trials among HIV-Infected Patients on ART in China

Background

More and more HIV therapeutic vaccines will enter clinical trials; however, little is known about the willingness to participate (WTP) in HIV therapeutic vaccine trials among HIV-positive individuals.

Objective

To investigate the WTP in HIV therapeutic vaccine trials among Chinese HIV-infected patients.

Methods

We conducted a cross-sectional survey on HIV-positive inpatients and outpatients at Shanghai Public Health Center. A total of 447 participants were recruited into this study. Following an introduction with general information on HIV therapeutic vaccine and its potential effectiveness and side effects, each participant completed a questionnaire in a self-administered form. The questionnaires covered demographics, high-risk behaviors, clinical characteristics and willingness to participate in HIV therapeutic vaccine trial.

Results

The overall willingness to participate in HIV therapeutic vaccine trials was 91.5%. Interestingly, multivariate logistic regression analyses demonstrated that the willingness was higher for those sexually infected by HIV (odds ratio [OR]: 4.36; 95% confidence interval [CI]: 1.53–12.41), diagnosed as HIV-1 infection for greater than 5 years (OR: 7.12, 95% CI: 1.83–27.76), and with the presence of infectious complications (OR: 2.75; 95% CI: 1.02–7.45). The primary reason for participation was to delay or reduce antiretroviral treatment (ART) and to avoid ART side effects (76.6%), and then followed by delaying disease progression (74.9%), increasing immune response to suppress opportunistic infections (57.7%) and preventing the development of drug resistance (37.1%). Reasons for unwillingness to participate mainly included concern for safety (37.0%), lack of knowledge on therapeutic vaccine (33.3%), and satisfaction with ART effectiveness (22.2%).

Conclusions

The WTP in HIV therapeutic vaccine trials was high among HIV-infected Chinese patients. HIV⁺ subjects who acquired infection through sexual contact and who were diagnosed for more than 5 years may represent a good candidate population for enrollment in therapeutic vaccine trials.     

A Descriptive Analysis of HIV Prevalence,HIV Service Uptake,and HIV-Related Risk Behaviour among Patients Attending a Mental Health Clinic in Rural Malawi

Background

Human immunodeficiency virus (HIV) and mental illness are interlinked health problems; mental illness may pose a risk for contracting HIV and HIV-positive individuals are at higher risk of mental illness. However, in countries with high HIV prevalence, the main focus of HIV-related health programmes is usually on prevention and treatment of somatic complications of HIV, and mental illness is not given high priority. We examined HIV prevalence, uptake of HIV services, and HIV-related risk behaviour among people attending a mental health clinic in rural Malawi.

Methodology

Semi-structured interviews were performed with patients capable to consent (94%), and with those accompanied by a capable caregiver who consented. HIV counselling and testing was offered to participants.

Findings

Among 174 participants, we collected 162 HIV test results (91%). HIV prevalence was 14.8%. Women were three times as likely to be HIV-positive compared to men. Two-thirds of participants reported having been tested for HIV prior to this study. The uptake of HIV-services among HIV-positive patients was low: 35% did not use recommended prophylactic therapy and 44% of patients not receiving antiretroviral treatment (ART) had never been assessed for ART eligibility. The reported rate of sexual activity was 61%, and 9% of sexually active participants had multiple partners. Inconsistent condom use with stable (89%) and occasional (79%) sexual partners, and absence of knowledge of the HIV status of those partners (53%, 63%) indicate high levels of sexual risk behaviour.

Conclusions

HIV-prevalence among persons attending the clinic, particularly men, was lower than among the general population in a population survey. The rate of HIV testing was high, but there was low uptake of preventive measures and ART. This illustrates that HIV-positive individuals with mental illness or epilepsy constitute a vulnerable population. HIV programmes should include those with neuropsychiatric illness.     

The Impact of Antiretroviral Therapy on Mortality in HIV Positive People during Tuberculosis Treatment: A Systematic Review and Meta-Analysis

Objective

To quantify the impact of antiretroviral therapy (ART) on mortality in HIV-positive people during tuberculosis (TB) treatment.

Design

We conducted a systematic literature review and meta-analysis. Studies published from 1996 through February 15, 2013, were identified by searching electronic resources (Pubmed and Embase) and conference books, manual searches of references, and expert consultation. Pooled estimates for the outcome of interest were acquired using random effects meta-analysis.

Subjects

The study population included individuals receiving ART before or during TB treatment.

Main Outcome Measures

Main outcome measures were: (i) TB-case fatality ratio (CFR), defined as the proportion of individuals dying during TB treatment and, if mortality in HIV-positive people not on ART was also reported, (ii) the relative risk of death during TB treatment by ART status.

Results

Twenty-one studies were included in the systematic review. Random effects pooled meta-analysis estimated the CFR between 8% and 14% (pooled estimate 11%). Among HIV-positive TB cases, those receiving ART had a reduction in mortality during TB treatment of between 44% and 71% (RR = 0.42, 95%CI: 0.29–0.56).

Conclusion

Starting ART before or during TB therapy reduces the risk of death during TB treatment by around three-fifths in clinical settings. National programmes should continue to expand coverage of ART for HIV positive in order to control the dual epidemic.     

Cardiovascular and musculskeletal co-morbidities in patients with alpha 1 antitrypsin deficiency

Background

Determining the presence and extent of co-morbidities is fundamental in assessing patients with chronic respiratory disease, where increased cardiovascular risk, presence of osteoporosis and low muscle mass have been recognised in several disease states. We hypothesised that the systemic consequences are evident in a further group of subjects with COPD due to Alpha-1 Antitrypsin Deficiency (A1ATD), yet are currently under-recognised.

Methods

We studied 19 patients with PiZZ A1ATD COPD and 20 age, sex and smoking matched controls, all subjects free from known cardiovascular disease. They underwent spirometry, haemodynamic measurements including aortic pulse wave velocity (aPWV), an independent predictor or cardiovascular risk, dual energy X-ray absorptiometry to determine body composition and bone mineral density.

Results

The aPWV was greater in patients: 9.9(2.1) m/s than controls: 8.5(1.6) m/s, p = 0.03, despite similar mean arterial pressure (MAP). The strongest predictors of aPWV were age, FEV₁% predicted and MAP (all p < 0.01). Osteoporosis was present in 8/19 patients (2/20 controls) and was previously unsuspected in 7 patients. The fat free mass and bone mineral density were lower in patients than controls (p < 0.001).

Conclusions

Patients with A1ATD related COPD have increased aortic stiffness suggesting increased risk of cardiovascular disease and evidence of occult musculoskeletal changes, all likely to contribute hugely to overall morbidity and mortality.     

Changes in Seroadaptive Practices from before to after Diagnosis of Recent HIV Infection among Men Who Have Sex with Men

Objective

We assessed changes in sexual behavior among men who have sex with men (MSM), before and for several years after HIV diagnosis, accounting for adoption of a variety of seroadaptive practices.

Methods

We collected self-reported sexual behavior data every 3 months from HIV-positive MSM at various stages of HIV infection. To establish population level trends in sexual behavior, we used negative binomial regression to model the relationship between time since diagnosis and several sexual behavior variables: numbers of (a) total partners, (b) potentially discordant partners (PDP; i.e., HIV-negative or unknown-status partners), (c) PDPs with whom unprotected anal intercourse (UAI) occurred, and (d) PDPs with whom unprotected insertive anal intercourse (uIAI) occurred.

Results

A total of 237 HIV-positive MSM contributed 502 interviews. UAI with PDPs occurred with a mean of 4.2 partners in the 3 months before diagnosis. This declined to 0.9 partners/3 months at 12 months after diagnosis, and subsequently rose to 1.7 partners/3 months at 48 months, before falling again to 1.0 partners/3 months at 60 months. The number of PDPs with whom uIAI occurred dropped from 2.4 in the pre-diagnosis period to 0.3 partners/3 months (an 87.5% reduction) by 12 months after enrollment, and continued to decline over time.

Conclusion

Within months after being diagnosed with HIV, MSM adopted seroadaptive practices, especially seropositioning, where the HIV-positive partner was not in the insertive position during UAI, resulting in a sustained decline in the sexual activity associated with the highest risk of HIV transmission.     

IL-27-Induced Gene Expression Is Downregulated in HIV-Infected Subjects

Objective

To characterize the effect of HIV infection on IL-27-induced gene expression.

Design

During HIV infection, cytokine expression and function become deregulated. IL-27 is an important modulator of inflammatory responses. Interestingly, IL-27 can inhibit HIV replication in T cells and monocytes, implicating IL-27 as a potential adjunct to anti-viral treatment. Our previous work demonstrated that circulating HIV may suppress IL-27 expression, therefore, this study, in continuation of our previous work, aimed to understand how HIV affects expression levels of the IL-27 receptor and downstream functions of IL-27.

Methods

Peripheral blood mononuclear cells (PBMC) were isolated from whole blood of HIV negative and HIV positive (viremic) individuals to assess IL-27-induced gene expression by flow cytometry and ELISA. PBMC were also processed for monocyte enrichment to assess IL-27 receptor expression by flow cytometry and real-time PCR.

Results

Expression of the IL-27 receptor subunit, gp130, was upregulated in response to IL-27 in HIV negative individuals, however, in HIV positive individuals, this IL-27 response was diminished. Furthermore, we observed downregulation of IL-27-induced IL-6, TNF-α, and IL-10 expression in HIV positive subjects.

Conclusion

In HIV infection, IL-27-induced gene expression was impaired, indicating HIV-mediated dysregulation of IL-27 functions occurs during HIV infection. This study provides evidence for new viral pathogenic mechanisms contributing to the widespread impairment of immune responses observed in HIV pathogenesis.     

Heterogeneities in Leishmania infantum Infection: Using Skin Parasite Burdens to Identify Highly Infectious Dogs

Background

The relationships between heterogeneities in host infection and infectiousness (transmission to arthropod vectors) can provide important insights for disease management. Here, we quantify heterogeneities in Leishmania infantum parasite numbers in reservoir and non-reservoir host populations, and relate this to their infectiousness during natural infection. Tissue parasite number was evaluated as a potential surrogate marker of host transmission potential.

Methods

Parasite numbers were measured by qPCR in bone marrow and ear skin biopsies of 82 dogs and 34 crab-eating foxes collected during a longitudinal study in Amazon Brazil, for which previous data was available on infectiousness (by xenodiagnosis) and severity of infection.

Results

Parasite numbers were highly aggregated both between samples and between individuals. In dogs, total parasite abundance and relative numbers in ear skin compared to bone marrow increased with the duration and severity of infection. Infectiousness to the sandfly vector was associated with high parasite numbers; parasite number in skin was the best predictor of being infectious. Crab-eating foxes, which typically present asymptomatic infection and are non-infectious, had parasite numbers comparable to those of non-infectious dogs.

Conclusions

Skin parasite number provides an indirect marker of infectiousness, and could allow targeted control particularly of highly infectious dogs.     

Interferon Regulatory Factor 1 Polymorphisms Previously Associated with Reduced HIV Susceptibility Have No Effect on HIV Disease Progression

Introduction

Interferon regulatory factor 1 (IRF1) is induced by HIV early in the infection process and serves two functions: transactivation of the HIV-1 genome and thus replication, and eliciting antiviral innate immune responses. We previously described three IRF1 polymorphisms that correlate with reduced IRF1 expression and reduced HIV susceptibility.

Objective

To determine whether IRF1 polymorphisms previously associated with reduced HIV susceptibility play a role in HIV pathogenesis and disease progression in HIV-infected ART-naïve individuals.

Methods

IRF1 genotyping for polymorphisms (619, MS and 6516) was performed by PCR in 847 HIV positive participants from a sex worker cohort in Nairobi, Kenya. Rates of CD4+ T cell decline and viral loads (VL) were analyzed using linear mixed models.

Results

Three polymorphisms in the IRF1, located at 619, microsatellite region and 6516 of the gene, previously associated with decreased susceptibility to HIV infection show no effect on disease progression, either measured by HIV-1 RNA levels or the slopes of CD4 decline before treatment initiation.

Conclusion

Whereas these three polymorphisms in the IRF1 gene protect against HIV-1 acquisition, they appear to exert no discernable effects once infection is established.