Immunodeficiency Virus Disease Progression Research Articles

Sustained immune activation and impaired epithelial barrier integrity in the ectocervix of women with chronic HIV infection.

Chronic systemic immune activation significantly influences human immunodeficiency virus (HIV) disease progression. Despite evidence of a pro-inflammatory environment in the genital tract of HIV-infected women, comprehensive investigations into cervical tissue from this region remain limited. Similarly, the consequences of chronic HIV infection on the integrity of the female genital epithelium are poorly understood, despite its importance in HIV transmission and replication. Ectocervical biopsies were obtained from HIV-seropositive (n = 14) and HIV-seronegative (n = 47) female Kenyan sex workers. RNA sequencing and bioimage analysis of epithelial junction proteins (E-cadherin, desmoglein-1, claudin-1, and zonula occludens-1) were conducted, along with CD4 staining. RNA sequencing revealed upregulation of immunoregulatory genes in HIV-seropositive women, primarily associated with heightened T cell activity and interferon signaling, which further correlated with plasma viral load. Transcription factor analysis confirmed the upregulation of pro-inflammatory transcription factors, such as RELA, NFKB1, and IKZF3, which facilitates HIV persistence in T cells. Conversely, genes and pathways associated with epithelial barrier function and structure were downregulated in the context of HIV. Digital bioimage analysis corroborated these findings, revealing significant disruption of various epithelial junction proteins in ectocervical tissues of the HIV-seropositive women. Thus, chronic HIV infection associated with ectocervical inflammation, characterized by induced T cell responses and interferon signaling, coupled with epithelial disruption. These alterations may influence HIV transmission and heighten susceptibility to other sexually transmitted infections. These findings prompt exploration of therapeutic interventions to address HIV-related complications and mitigate the risk of sexually transmitted infection transmission.

Plasma galectin-9 levels correlate with blood monocyte turnover and predict simian/human immunodeficiency virus disease progression

Abstract Background Late-stage human immunodeficiency virus (HIV) infection is typically characterized by low CD4 + T-cell count. We previously showed that profound changes in the monocyte turnover (MTO) rate in rhesus macaques infected by the simian immunodeficiency virus (SIV) outperforms declining CD4 + T-cell counts in predicting rapid health decline associated with progression to terminal disease. High MTO is associated with increased tissue macrophage death. However, MTO analysis is complex and not directly applicable to humans. Methods We explored blood-available biomarkers associated with MTO using comprehensive immune cell profiling via flow cytometry, blood cell count and chemistry, and ELISA. Results Plasma galectin-9 was identified as the most highly correlated marker with MTO. This correlation remained statistically significant during acute, chronic, and late-stage infections caused by three different SIV strains tested. In addition, the galectin-9 level also predicted decline in animal health, requiring medical cull. The correlation between MTO and galectin-9 was maintained even in uninfected animals showing variable MTO. Conclusions These findings support the exploration of galectin-9 as a surrogate biomarker of MTO for non-invasive monitoring of disease progression (e.g. HIV) that may also be applicable in humans and as a potential indicator of tissue macrophages apoptosis.

Severe intestinal barrier damage in HIV-infected immunological non-responders

The intestinal epithelial barrier plays an important role during human immunodeficiency virus (HIV) disease progression. However, the extent to which the intestinal epithelial barrier is damaged in immunological non-responders (INRs) and immunological responders (IRs) is largely unknown. In this study, we investigated and compared the levels of intestinal gland damage and related molecules, including the tight junction protein claudin-1, apoptosis marker caspase-3, HIV DNA, CD4+ T cell count, and inflammation marker tumor necrosis factor-α (TNF-α) among the IRs (n = 10), INRs (n = 8), and healthy controls (HCs, n = 7). Intestinal damage was not completely restored in both INRs and IRs and was more serious in INRs than that in IRs. Moreover, intestinal damage was positively correlated with HIV DNA levels and negatively correlated with CD4+ T cell counts. These results provide insight into understanding the characteristics of intestinal epithelial barrier damage between IRs and INRs.

Do correlates of white matter features differ between older men and women living with human immunodeficiency virus?

Given estrogen's role in human immunodeficiency virus (HIV) disease progression and the higher rates of neurocognitive decline in affected women, the purpose of this study was to assess whether the relationship of white matter features and reproductive hormone levels differed between men versus women (sex as a moderator), controlling for selected cardiometabolic risk factors, HIV-related health indicators, and demographics in an aging population of persons living with HIV (PLWH). Older PLWH (50 y and older; 44 women and 35 men; mean ± SD age, 59.8 ± 0.6 y; 55.7% women; 72.2% non-Hispanic Black) participated in a cross-sectional study involving a fasting blood draw and a demographic survey (visit 1) and a magnetic resonance imaging scan (visit 2) to determine white matter volume and white matter hyperintensity (WMH) volume. Associations between reproductive hormones (follicle-stimulating hormone [FSH], estradiol, testosterone, dehydroepiandrosterone sulfate [DHEA-S]) and white matter features were assessed in linear regression models. Covariates were age, body mass index, hypertension, diabetes, dyslipidemia, current smoking status, CD4 count, and cranial size. For white matter volume, a sexually dimorphic interaction was seen for DHEA-S (B = 21.23; P = 0.012) and observed for FSH (B = -22.97, P = 0.08) with a trend for significance after controlling for risk factors. In women, higher white matter volume was associated with higher DHEA-S (B = 13.89, P = 0.017) and lower FSH (B = 23.58, P = 0.01). No hormone associations were shown in men for white matter volume. For WMH volume, no significant interaction effects between sex and reproductive hormones were identified. For WMH, sex did not predict associations with reproductive hormones after controlling for risk factors. Although sexually dimorphic interactions of reproductive hormones and total white matter volume were demonstrated, our study findings do not support a role for sex-based differences in reproductive hormones as predictive correlates of WMH in a small sample of older PLWH.

Surrogate Biomarkers of Disease Progression in Human Pegivirus Seropositive Human Immunodeficiency Virus-Infected Individuals.

Scientific observations indicate that an actively prevailing systemic condition could alleviate the pathology of another disease. Human pegivirus (HPgV), a highly ubiquitous flavivirus is believed to be associated with slow human immunodeficiency virus (HIV) disease progression, and has seldom been linked to hepatic pathology. In this study, we investigated whether HPgV seropositivity had any impact on surrogate markers of HIV disease progression in a cohort of HIV-infected HPgV seropositive (n = 28) and seronegative (n = 12) individuals who were prospectively evaluated for absolute CD4+ T cell counts, plasma viral load (PVL), liver enzymes, and plasma cytokine levels. The HIV PVL was relatively lower in HPgV seropositive than in HPgV seronegative HIV-infected subjects. Clinical markers of hepatic injury were significantly low among HPgV seropositive HIV-infected participants. HPgV seropositive individuals showed significantly higher levels of interleukin-7 (IL-7), and although not significant, the levels of IL-6 were lower among HPgV seropositive subjects. Spearman correlation analysis showed that the absolute CD4+T cell count was inversely correlated with HIV PVL. Exposure to HPgV appears to have a positive prognostic impact on the levels of surrogate biomarkers of HIV disease progression.

Altered HIV-1 Viral Copy Number and Gene Expression Profiles of Peripheral (CEM CCR5+) and Mucosal (A3R5.7) T Cell Lines Co-Infected with HSV-2 In Vitro.

Co-infecting pathogens have been speculated to influence Human Immunodeficiency Virus (HIV) disease progression. Herpes Simplex Virus Type-2 (HSV-2), another sexually transmitted pathogen, is commonly observed in individuals with HIV-1. Some clinical studies have observed an increase in HIV-1 viral copy number in HSV-2 co-infected individuals. In vitro studies have also demonstrated an increase in the expression of HIV-1 co-receptors on immune cells infected with HSV-2. Although both the viruses show distinctive persistent infection, the influence of HSV-2 on HIV-1 is poorly understood. Here we present a comparative analysis of primary CD4+ T-cells and four different T-cell lines (PM-1, CEM CCR5+, MOLT4 CCR5+, and A3R5.7) to assess the influence of HSV-2 co-infection on HIV-1 replication in vitro. Cell lines indicating significant changes in HIV-1 viral copy number [CEM CCR5+ (0.61 Log10), A3R5.7 (0.78 Log10)] were further evaluated for the infectivity of HIV-1 virions and the changes in gene expression profiles of HSV-2/HIV-1 co-infected and mono-infected cells, which were further confirmed by qPCR. Significant changes in NUP, MED, and VPS mRNA expression were observed in the gene expression profiles in co-infected CEM CCR5+ and A3R5.7 cells. In both cell lines, it was observed that the WNT signaling, PI3 kinase, apoptosis, and T-cell activation pathways were negatively affected in co-infected cells. The data suggest that HSV-2 infection of T-cells may influence the expression of genes that have been previously shown to affect HIV-1 replication in vitro. This idea needs to be explored further to identify anti-viral targets for HSV-2 and HIV-1.

Higher Risk of Mortality and Virologic Failure in HIV-Infected Patients With High Viral Load at Antiretroviral Therapy Initiation: An Observational Cohort Study in Chongqing, China.

BackgroundViral load (VL) is a strong predictor of human immunodeficiency virus (HIV) disease progression. The aim of this study was to evaluate the effect of high baseline VL on antiretroviral therapy (ART) outcomes among HIV-infected patients.MethodsThis retrospective study observed HIV-infected patients who had baseline VL test at ART initiation between 2015 and 2019 in Chongqing, China. Cox proportional hazards regression and logistic regression models were used to evaluate the effects of baseline VL on Acquired immunodeficiency syndrome (AIDS)-related mortality and virologic failure, respectively.ResultsThe cohort included 7,176 HIV-infected patients, of whom 38.7% had a baseline VL ≥ 100,000 copies/mL. Of the patients who died during follow-up, 58.9% had a baseline VL ≥ 100,000 copies/mL. Compared with a baseline VL < 10,000 copies/mL, ART initiation at VL ≥ 100,000 copies/mL was significantly associated with the AIDS-related death (adjusted hazard ratio, AHR = 1.4) and virologic failure (adjusted odds ratio, AOR = 2.4). Compared with patients with a baseline VL < 10,000 copies/mL, patients on the recommended first-line regimen with a VL ≥ 100,000 copies/mL at ART initiaition had higher mortality rate (5.1 vs. 1.7 per 100 person-years), but there was no significant difference in the mortality accoding to the initial VL level among patients on second-line ART (2.8 vs. 2.7 per 100 person-years). ART initiation ≤ 30 days after HIV diagnosis was associated with a lower risk of AIDS-related death (AHR = 0.6).ConclusionsART initiation with VL ≥ 100,000 copies/mL was associated with a significantly greater risk of mortality and virologic failure. Optimizing the ART regimen and initiating ART early may help to reduce mortality effectively among patients with a high baseline VL. VL testing for all HIV patients is recommended at HIV diagnosis or on ART initiation.

Mold, Mycotoxins and a Dysregulated Immune System: A Combination of Concern?

Fungi represent one of the most diverse and abundant eukaryotes on earth. The interplay between mold exposure and the host immune system is still not fully elucidated. Literature research focusing on up-to-date publications is providing a heterogenous picture of evidence and opinions regarding the role of mold and mycotoxins in the development of immune diseases. While the induction of allergic immune responses by molds is generally acknowledged, other direct health effects like the toxic mold syndrome are controversially discussed. However, recent observations indicate a particular importance of mold/mycotoxin exposure in individuals with pre-existing dysregulation of the immune system, due to exacerbation of underlying pathophysiology including allergic and non-allergic chronic inflammatory diseases, autoimmune disorders, and even human immunodeficiency virus (HIV) disease progression. In this review, we focus on the impact of mycotoxins regarding their impact on disease progression in pre-existing immune dysregulation. This is complemented by experimental in vivo and in vitro findings to present cellular and molecular modes of action. Furthermore, we discuss hypothetical mechanisms of action, where evidence is missing since much remains to be discovered.

975. Why Sex Make a Difference in HIV Clinical Course? Bioinformatics Analysis of Differential Expressed Gene in Females and Males with HIV Disease

BackgroundHuman immunodeficiency virus (HIV) disease progression are different among genders, in which women usually progress to acquired immunodeficiency syndrome (AIDS) faster than men. The mechanisms resulting in the gender biases of HIV progression are unclear. We conducted a bioinformatics analysis of differentially expressed genes (DEGs) in women and men with HIV disease to understand the sex-based differences in HIV pathogenesis.MethodsWe obtained microarray data from the Gene Expression Omnibus (GEO) database using our pre-defined search strategy and analyzed data using the GEO2R platform. The t-test was done to compare DEGs between females and males with HIV diseases. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was implemented to systematically extract biological features and processes of retrieving DEGs via gene ontology (GO) analysis. A Systemic search was performed to evaluate each DEG function and its possible association with HIV.ResultsOne gene expression profiling data were retrieved: GSE 140713, composed of 40 males and 10 females with HIV1 infected samples. A GEO2R analysis yielded 19 DEGs (Table 1). The GO analysis result was demonstrated in Tables 2 and 3. Following a systemic search, we found two DEGs, which have previous studies reported an association with HIV: DDX3X (20 studies) and PDS5 (1 study). We proposed DDX3X (t 5.3, p 0.0037) is responsible for gender inequalities of HIV progression because of: 1. DDX3X is needed in the HIV1 life cycle. 2. Several studies confirmed a positive correlation between DDX3X expression and HIV1 replication. 3. Our study found an up-regulated DDX3X expression in women corresponded to the fact that women progress to AIDS faster than men. 4. Our GO analysis showed female up-regulated genes were enriched in positive regulation of the gene expression pathway, which can be explained by DDX3X and its underlying mechanism.Table 1: DEGs in women and men with HIV1 disease Table 2: GO functional enrichment pathway analyses of overall retrieving DEGs Table 3: GO functional enrichment pathway analyses of down- and up-regulated clusters of DEGs ConclusionAberrant DDX3X expression may contribute to sex-based differences in HIV disease. Drugs modifying DDX3X gene expression will be beneficial in the treatment of HIV especially resolving the HIV drug resistance problem because current anti-HIV drugs target viral components posed the risk of viral mutation.Disclosures All Authors: No reported disclosures

The incidence of aggressive behavior in cats naturally infected with Feline Immunodeficiency Virus (FIV) and its interaction with FIV disease progression.

A study was undertaken to determine the possible interaction between aggressive behavior and Feline immunodeficiency virus (FIV) disease progression based on semi‑quantitative viral load levels and health status in naturally FIV‑infected cats. FIV status was determined in ninety‑six owned and stray cats, using nested polymerase chain reaction (PCR). Aggressive tendencies were assessed based on observation and the cats' demeanor as determined by the owners and shelter caretakers. Results showed that forty‑seven cats (49%) were PCR‑positive for FIV infection and all aggressive cats were FIV‑positive (100%). FIV infection was significantly linked to extreme aggressive tendencies and the extremely aggressive FIV‑infected cats were more likely to have an unhealthy status compared to the non‑aggressive individuals (p = 0.022). There was also a significant difference (p = 0.012) in the mean Cycle threshold (Ct) values between the aggressive and non‑aggressive FIV‑infected cats and also between the unhealthy FIV‑infected cats with extreme aggressive tendencies and the healthy FIV‑infected individuals without aggression (p = 0.001). Accordingly, results indicated that parameters associated with FIV disease progression are directly linked to aggression. The possible impact of FIV on the behavioral pattern of naturally infected cats should not be underestimated. However, there is an urgent need to conduct more experiments to support the assumptions about the possible exacerbation of aggression tendencies in naturally FIV‑infected cats following the direct effect of FIV through the course of the infection.

Modelling immune deterioration, immune recovery and state-specific duration of HIV-infected women with viral load adjustment: using parametric multistate model

BackgroundCD4 cell and viral load count are highly correlated surrogate markers of human immunodeficiency virus (HIV) disease progression. In modelling the progression of HIV, previous studies mostly dealt with either CD4 cell counts or viral load alone. In this work, both biomarkers are in included one model, in order to study possible factors that affect the intensities of immune deterioration, immune recovery and state-specific duration of HIV-infected women.MethodsThe data is from an ongoing prospective cohort study conducted among antiretroviral treatment (ART) naïve HIV-infected women in the province of KwaZulu-Natal, South Africa. Participants were enrolled in the acute HIV infection phase, then followed-up during chronic infection up to ART initiation. Full-parametric and semi-parametric Markov models were applied. Furthermore, the effect of the inclusion and exclusion viral load in the model was assessed.ResultsInclusion of a viral load component improves the efficiency of the model. The analysis results showed that patients who reported a stable sexual partner, having a higher educational level, higher physical health score and having a high mononuclear component score are more likely to spend more time in a good HIV state (particularly normal disease state). Patients with TB co-infection, with anemia, having a high liver abnormality score and patients who reported many sexual partners, had a significant increase in the intensities of immunological deterioration transitions. On the other hand, having high weight, higher education level, higher quality of life score, having high RBC parameters, high granulocyte component scores and high mononuclear component scores, significantly increased the intensities of immunological recovery transitions.ConclusionInclusion of both CD4 cell count based disease progression states and viral load, in the time-homogeneous Markov model, assisted in modeling the complete disease progression of HIV/AIDS. Higher quality of life (QoL) domain scores, good clinical characteristics, stable sexual partner and higher educational level were found to be predictive factors for transition and length of stay in sequential adversity of HIV/AIDS.

Beneficial Efficacy of Histone Deacetylase Inhibitor Butyrate and Histone Crotonylation to Human Immunodeficiency Virus-Infected Subjects

The mechanism of how gut microbiota is involved in the host inflammatory processes that influence human immunodeficiency virus (HIV) replication and disease progression in HIV is elucidated in present review.

A correlation analysis of HHV infection and its predictive factors in an HIV-seropositive population in Yunnan, China.

Human herpesviruses (HHVs) have a particularly high prevalence in certain high‐risk populations and cause increased morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). Screening and treating subclinical HHV infections reduce human immunodeficiency virus (HIV) infection incidence, disease progression, and transmission. However, there are few studies on HHVs, HIV coinfection rates, and their related risk factors. We aimed to clarify the prevalence of all eight HHVs in peripheral blood samples collected from HIV‐positive patients, and explore the association of HHV infection in HIV‐positive patients in an HIV‐seropositive population in Yunnan. We recruited 121 HIV‐positive patients with highly active antiretroviral therapy (HAART) and 45 healthy individuals. All the eight HHVs were detected using polymerase chain reaction and their epidemiological information and clinical data were collected and statistically analyzed. A high prevalence of HHVs (89.3%) was observed in individuals with HIV infections and with herpes simplex virus (HSV)‐2 (65.3%), and HSV‐1 (59.5%) being the most common. Coinfection with more than two different HHVs was more common in patients with HIV infections receiving HAART (72.7%) than in healthy controls. Older age, being married, higher HIV‐1 plasma viral loads, and use of antiviral protease inhibitors were independently correlated with an increased frequency of HHVs, but we found no association with CD4 count, WHO HIV clinical stage, and HIV infection duration. Our findings are of great significance for the prevention of HHV opportunistic infection in patients with AIDS and their clinical treatment.

Gender differences in innate responses and gene expression profiles in memory CD4 T cells are apparent very early during acute simian immunodeficiency virus infection.

Gender differences in Human immunodeficiency virus (HIV) disease progression and comorbidities have been extensively reported. Using the simian immunodeficiency virus (SIV) infected rhesus macaque model, we show that these differences are apparent very early during the course of infection. Though there were no major changes in the proportions of CD4 T cells or its subsets, central memory CD4 T cells from female macaques were found to differentially regulate a significantly larger number of genes at day 4 post-infection (PI) as compared to males. Pathway analysis revealed divergence of both canonical and biological pathways that persisted at day 10 PI. Changes in gene expression profiles were accompanied by a significant increase in plasma levels of pro-inflammatory mediators such as MCP-1/CCL2, I-TAC/CXCL11, and MIF. Though plasma levels of IFNα did not differ between male and female macaques, the expression levels of IFNα subtype-14, 16, IFNβ, and IFNω were significantly upregulated in the lymph nodes of female macaques at day 10 PI as compared to male macaques. Our results suggest that the pathogenic sequelae seen during chronic infection may be shaped by gender differences in immune responses induced very early during the course of HIV infection.

Major depression disorder trajectories and HIV disease progression: results from a 6-year outpatient clinic cohort.

Contradictory evidence exists on the role of Major depression disorder (MDD) as a predictor of human immunodeficiency virus (HIV) disease progression, particularly regarding the effect of MDD presence versus pattern of illness. The objective of this study was to examine whether MDD status and pattern of illness differentially predict HIV disease progression. Retrospective cohort data from a six-year follow-up of HIV patients at an outpatient clinic were analyzed. MDD trajectories were identified by latent class growth analysis and generalized linear mixed models were used to examine their relation to low CD4+ T-lymphocyte counts (<200 cells/μL) during follow-up. Among 1,494 HIV patients, four MDD trajectory groups were identified: Low-Chronic, Moderate-Ascending, High-Episodic, and High-Chronic. Trajectory group membership was predicted by male sex (P = .04), minority race (P < .01), older age (P < .01) and low baseline CD4 count (P = .04). The High-Chronic group had lower odds of having a low CD4 count than the Low-Chronic group (adjusted Odds Ratio [aOR]: 0.63; 95%CI: 0.49–0.81) while the Moderate-Ascending group had higher odds (aOR: 1.53; 95%CI: 1.08–2.19). The odds of having a low CD4 count were higher among male (aOR: 1.25; 95%CI: 1.03–1.52), minority races (American Indian [aOR: 1.85; 95%CI: 1.38–2.49] and African Americans [aOR: 1.58; 95%CI: 1.33–1.87]), Hispanic (aOR: 1.52; 95%CI: 1.06–2.18), and divorced/separated patients (aOR: 1.62; 95%CI: 1.16–2.28) but decreased over time (P < .01) across trajectory groups. In this study, because MDD trajectories and CD4 counts were determined based on secondary data abstracted from electronic medical records, the results should be interpreted cautiously due to the potential for selection and misclassification bias. Overall, study findings suggest the pattern of MDD illness among HIV patients can be classified into clinically meaningful trajectory groups that appear to be programmed by known risk factors, and are useful for predicting HIV disease progression. Targeted interventions among at-risk patients may be critical to altering MDD illness patterns and curtailing HIV disease progression.

Monkey Models and HIV Vaccine Research.

Since the discovery of acquired immunodeficiency syndrome (AIDS) in 1981, it has been extremely difficult to develop an effective vaccine or a therapeutic cure despite over 36years of global efforts. One of the major reasons is due to the lack of an immune-competent animal model that supports live human immunodeficiency virus (HIV) infection and disease progression such that vaccine-induced correlates of protection and efficacy can be determined clearlybefore human trials. Nevertheless, rhesus macaques infected with simian immunodeficiency virus (SIV) and chimeric simian human immunodeficiency virus (SHIV) have served as invaluable models not only for understanding AIDS pathogenesis but also for studying HIV vaccine and cure. In this chapter, therefore, we summarize major scientific evidence generated in these models since the beginning of the AIDS pandemic. Hopefully, the accumulated knowledge and lessons contributed by thousands of scientists will be useful in promoting the search of an ultimate solution to end HIV/AIDS.

Understanding the association between chromosomally integrated human herpesvirus 6 and HIV disease: a cross-sectional study.

We conducted a cross-sectional investigation to identify evidence of a potential modifying effect of chromosomally integrated human herpes virus 6 (ciHHV-6) on human immunodeficiency virus (HIV) disease progression and/or severity. ciHHV-6 was identified by detecting HHV-6 DNA in hair follicle specimens of 439 subjects. There was no statistically significant relationship between the presence of ciHHV-6 and HIV disease progression to acquired immunodeficiency syndrome. However, after adjusting for use of antiretroviral therapy, all subjects with ciHHV-6 had low severity HIV disease; these findings were not statistically significant. A multi-center study with a larger sample size will be needed to more precisely determine if there is an association between ciHHV-6 and low HIV disease severity.

Negative Checkpoint Regulatory Molecule 2B4 (CD244) Upregulation Is Associated with Invariant Natural Killer T Cell Alterations and Human Immunodeficiency Virus Disease Progression.

The CD1d-restricted invariant natural killer T (iNKT) cells are implicated in innate immune responses against human immunodeficiency virus (HIV). However, the determinants of cellular dysfunction across the iNKT cells subsets are seldom defined in HIV disease. Herein, we provide evidence for the involvement of the negative checkpoint regulator (NCR) 2B4 in iNKT cell alteration in a well-defined cohort of HIV-seropositive anti-retroviral therapy (ART) naïve, ART-treated, and elite controllers (ECs). We report on exaggerated 2B4 expression on iNKT cells of HIV-infected treatment-naïve individuals. In sharp contrast to CD4−iNKT cells, 2B4 expression was significantly higher on CD4+ iNKT cell subset. Notably, an increased level of 2B4 on iNKT cells was strongly correlated with parameters associated with HIV disease progression. Further, iNKT cells from ART-naïve individuals were defective in their ability to produce intracellular IFN-γ. Together, our results suggest that the levels of 2B4 expression and the downstream co-inhibitory signaling events may contribute to impaired iNKT cell responses.

Thymic Function Failure Is Associated With Human Immunodeficiency Virus Disease Progression.

Thymic function has been mainly analyzed with surrogate peripheral markers affected by peripheral T-cell expansion, making it difficult to assess the role of thymic failure in human immunodeficiency virus (HIV) disease progression. The assay of signal-joint/DβJβ T-cell rearrangement excision circles (sj/β-TREC ratio) overcomes this limitation but has only been assayed in small cohorts. Thus, the aim of this study was to determine the role of thymic function, measured by the sj/β-TREC ratio, on CD4 T-cell maintenance in prospective HIV cohorts that include patients with a wide age range and different immunological phenotypes. Seven hundred seventy-four patients including typical progressors, long-term nonprogressors (LTNPs), and vertically HIV-infected subjects were analyzed. Thymic function was quantified in peripheral blood samples using the sj/β-TREC ratio. Associations between thymic function and CD4 T-cell dynamics and combination antiretroviral therapy (cART) onset were analyzed using linear, logistic, and Cox proportional hazard models. Thymic function failure (sj/β-TREC ratio <10) was independently associated with HIV progression. In agreement, patients with distinctive high CD4 T-cell levels and low progression rates (vertically HIV-infected patients and LTNPs, including HIV controllers) had significantly higher thymic function levels whereas patients with thymic function failure had lower CD4 T-cell levels, lower nadir, and faster CD4 T-cell decay. This work establishes the relevance of thymic function, measured by sj/β-TREC ratio, in HIV disease progression by analyzing a large number of patients in 3 cohorts with different HIV disease progression phenotypes. These results support and help to understand the mechanisms underlying the rationale of early cART onset.

Endosomal toll-like receptor gene polymorphisms and susceptibility to HIV and HCV co-infection – Differential influence in individuals with distinct ethnic background

The genetic background of human populations can influence the susceptibility and outcome of infection diseases. Toll-like receptors (TLRs) have been previously associated with susceptibility to human immunodeficiency virus (HIV) infection, disease progression and hepatitis C, virus (HCV) co-infection in different populations, although mostly in Europeans. In this study, we investigated the genetic role of endosomal TLRs on susceptibility to HIV infection and HCV co-infection through the analysis of TLR7 rs179008, TLR8 rs3764880, TLR9 rs5743836 and TLR9 rs352140 polymorphisms in 789 Brazilian individuals (374 HIV+ and 415 HIV−), taking into account their ethnic background. Amongst the 357 HIV+ individuals with available data concerning HCV infection, 98 were positive. In European descendants, the TLR9 rs5743836 C carriers displayed a higher susceptibility to HIV infection [dominant, Odds Ratio (OR)=1.53; 95% CI: 1.05–2.23; P=0.027]. In African descendants, TLR9 rs5743836 CT genotype was associated with protection to HIV infection (codominant, OR=0.51; 95% CI: 0.30–0.87; P=0.013). Also, the TLR9 rs352140 AA variant genotype was associated with susceptibility to HIV+/HCV+ co-infection in African descendants (recessive, OR=2.92; 95% CI: 1.22–6.98, P=0.016). These results are discussed in the context of the different ethnic background of the studied individuals highlighting the influence of this genetic/ethnic background on the susceptibility to HIV infection and HIV/HCV co-infection in Brazilian individuals.