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The lethal combination involving TB and HIV, known as “syndemic” diseases, synergistically act upon one another to magnify the disease burden. Individuals on anti-retroviral therapy (ART) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). The underlying inflammatory complication includes the rapid restoration of immune responses following ART, eventually leading to exaggerated inflammatory responses to MTB antigens. TB-IRIS continues to be a cause of morbidity and mortality among HIV/TB coinfected patients initiating ART, and although a significant quantum of knowledge has been acquired on the pathogenesis of IRIS, the underlying pathomechanisms and identification of a sensitive and specific diagnostic marker still remain a grey area of investigation. Here, we reviewed the latest research developments into IRIS immunopathogenesis, and outlined the modalities to prevent and manage strategies for better clinical and diagnostic outcomes for IRIS.

In biofilm formation, pathogens within the bacterial community coordinate a cell-cell communication system called quorum sensing (QS). This is achieved through various signalling pathways that regulate bacterial virulence and host immune response. Here, we reviewed the host responses, key clinical implications, and novel therapeutic approaches against the biofilms of P. aeruginosa. Given the high degree of intrinsic antibiotic resistance and biofilm formation by the pathogen, the ensuing treatment complications could result in high morbidity and mortality rates worldwide. Notwithstanding the availability of intervention strategies, there remains a paucity of effective therapeutic options to control biofilmogenesis. This review discusses the basic understanding of QS-associated virulence factors and several key therapeutic interventions to foil the biofilm menace of P. aeruginosa.

In light of the COVID-19 pandemic, researchers across the world hastened to develop vaccines that would aid in bolstering herd immunity. Utilizing mRNA coding and viral vector technology, the currently approved vaccines were required to undergo extensive testing to confirm their safety for mass usage in the general population. However, clinical trials failed to test the safety and efficacy of the COVID-19 vaccines in groups with weakened immune systems, especially pregnant women. Lack of information on the effects of vaccinations in pregnancy and the safety of fetuses are among the topmost reasons preventing pregnant women from receiving immunization. Thus, the lack of data examining the effects of COVID-19 vaccinations on pregnant women must be addressed. This review focused on the safety and efficacy of the approved COVID-19 vaccinations in pregnancy and their impact on both maternal and fetal immune responses. For that, we took the approach of combined systematic review/meta-analysis and compiled the available data from the original literature from PubMed, Web of Science, EMBASE and Medline databases. All articles analyzed presented no adverse effects of vaccination in pregnancy, with varying conclusions on the degree of effectiveness. The majority of the findings described robust immune responses in vaccinated pregnant women, successful transplacental antibody transfer, and implications for neonatal immunity. Hence, findings from the cumulative data available can be helpful in achieving COVID-19 herd immunization, including pregnant women.

The interplay of immune mediators is paramount to optimal host anti-viral immune responses, especially against chronic hepatitis B virus (HBV) infection. Here, we investigated the dynamic changes in host immune responses in chronic HBV-infected individuals with and without liver cirrhosis by examining the signatures of apoptosis and plasma levels of pro-inflammatory cytokines, chemokines, and cytotoxic proteins. A total of 40 chronic HBV patients with and without liver cirrhosis were studied for plasma levels of immune mediators, and signatures of apoptosis in peripheral blood mononuclear cells (PBMCs). The intracellular concentrations of reactive oxygen species (ROS) in patients with chronic HBV with liver cirrhosis was relatively higher as compared to chronic HBV patients. The onset of apoptosis was sustained due to ongoing liver inflammation in concert with plasma TNF-α and IL-6 levels. Plasma VEGF was upregulated among chronic HBV patients with liver cirrhosis, whereas CCL2, CCL5 and granzyme B levels were down-regulated. High levels of ROS, IL-6 and TNF-α correlated with ongoing inflammation among chronic HBV patients with liver cirrhosis, which likely attributed to the expression of biosignatures of apoptosis and activation in immune cells.

Gut microbiome alterations may play a paramount role in determining the clinical outcome of clinical COVID-19 with underlying comorbid conditions like T2D, cardiovascular disorders, obesity, etc. Research is warranted to manipulate the profile of gut microbiota in COVID-19 by employing combinatorial approaches such as the use of prebiotics, probiotics and symbiotics. Prediction of gut microbiome alterations in SARS-CoV-2 infection may likely permit the development of effective therapeutic strategies. Novel and targeted interventions by manipulating gut microbiota indeed represent a promising therapeutic approach against COVID-19 immunopathogenesis and associated co-morbidities. The impact of SARS-CoV-2 on host innate immune responses associated with gut microbiome profiling is likely to contribute to the development of key strategies for application and has seldom been attempted, especially in the context of symptomatic as well as asymptomatic COVID-19 disease.

A vast proportion of coronavirus disease 2019 (COVID-19) individuals remain asymptomatic and can shed severe acute respiratory syndrome (SARS-CoV) type 2 virus to transmit the infection, which also explains the exponential increase in the number of COVID-19 cases globally. Furthermore, the rate of recovery from clinical COVID-19 in certain pockets of the globe is surprisingly high. Based on published reports and available literature, here, we speculated a few immunovirological mechanisms as to why a vast majority of individuals remain asymptomatic similar to exotic animal (bats and pangolins) reservoirs that remain refractile to disease development despite carrying a huge load of diverse insidious viral species, and whether such evolutionary advantage would unveil therapeutic strategies against COVID-19 infection in humans. Understanding the unique mechanisms that exotic animal species employ to achieve viral control, as well as inflammatory regulation, appears to hold key clues to the development of therapeutic versatility against COVID-19.

Background: Dengue fever (DF) is caused by an arthropod-borne dengue virus (DENV), has four serotypes and several genotypes. Although having clinical and epidemiological significance, the information on the circulating serotypes/genotypes is scarce in India. Materials and Methods: Blood specimens were collected from the patients suspected of DF and they are tested for DENV NS1 antigen and DENV IgM by ELISA. Antigen-positive samples were further serotyped by reverse transcriptase polymerase chain reaction. Representative samples from each serotype were sequenced to identify the genotypes. Results: All the four DENV serotypes were detected with the pre-dominance of DENV-1 (n = 49; 41.9%). Cases with multiple DENV serotype infections were also identified. Genotyping showed that DENV-1 belonging to genotype I, DENV-2 cosmopolitan (IV), DENV-3 genotype III and DENV-4 genotype I were active in the circulation during the outbreak in 2017. Conclusion: Our study documents the molecular characteristics of DENV circulating in our geographical locality. The detection of heterologous DENV serotypes highlights the importance of regular molecular monitoring for the early recognition of any switch in pre-dominant serotype.

Background We have previously shown an association of elevated co-inhibitory molecule 2B4 expression with iNKT cells alterations in HIV disease. Herein we show a comparative analysis of 2B4 expression on iNKT cells of HIV long-term non-progressors (LTNPs) and progressors. Methods Anti-retroviral therapy (ART) naive HIV-seropositive individuals (progressors, n=16) and long-term non-progressors (LTNPs, n=10) were recruited for this study. We employed multi-color flow cytometry on frozen peripheral blood mononuclear cells (PBMCs) to determine iNKT subset frequencies, the levels of co-inhibitory 2B4 expression, and intracellular IFN-γ production. CD1d tetramer was used to characterize iNKT cells. Results We report significantly lower level of 2B4 expression on bulk LTNPs iNKT cells as well as on their CD4 subsets compared to HIV progressors. Furthermore, the iNKT cells from LTNPs produced higher amount of IFN-γ than HIV progressors as detected by intracellular cytokine staining. Interestingly, the frequency of 2B4iNKT cells of progressors but not LTNPs significantly correlates with CD4 T cell count, HIV viral load and IFNγ production by iNKT cells. Conclusion Our results suggest that in addition to suppressed HIV replication, diminished 2B4 expression and associated co-inhibitory signaling, and substantial production of IFN-γ could contribute to preserved iNKT cell phenotype in LTNPs.

Objectives Eradication of Helicobacter pylori is influenced by susceptibility to antimicrobial agents, elevated bacterial load and degree of acid inhibition, which can be affected by genotypes of drug-metabolizing enzymes [cytochrome P450 (CYP) 2C19 polymorphism]. Theoretically, the choice and dose of proton pump inhibitor may also influence the suppression of H. pylori infection. The CYP2C19 genotype has recently been found to have an impact on peptic ulcer healing, H. pylori eradication and therapeutic efficacy of proton pump inhibitors. Methods Here, we investigated the impact of the CYP2C19 genotype polymorphism and the success of triple therapy (fluoroquinolones/metronidazole/clarithromycin) on antibiotic-resistant strains in eradicating H. pylori in human subjects with non-ulcer dyspepsia (NUD), in human subjects with peptic ulcer disease (PUD) and in asymptomatic human subjects (positive and negative for H. pylori infection). Results Based on the CYP2C19 genotypes, determined by Droplet Digital PCR (ddPCR) analysis, we found 11.2%, 62.5% and 26.3% corresponding to rapid metabolizers, intermediate metabolizers and poor metabolizers, respectively. However, we did not find any significant effect for homozygous ABCB1 or CYP2C19*2 and CYP2C19*3 alleles. We detected several participants heterozygous for both ABCB1 and CYP2C19*2, CYP2C19*3 and CYP2C19*17 loci. The participants heterozygous for both ABCB1 and CYP2C19*2 and *3 loci should be defined as intermediate and poor metabolizers according to the haplotype analysis in the NUD, PUD and asymptomatic subjects. Conclusions Consequently, fluoroquinolones/metronidazole/clarithromycin-based triple therapies can be used to eradicate H. pylori infection, if one does not know the CYP2C19 genotype of the patient.

Hepatitis B virus (HBV) infection is a major cause of chronic liver disease that may progress to liver cirrhosis and hepatocellular carcinoma. Host immune responses represent the key determinants of HBV clearance or persistence. Here, we investigated the role of the early activation marker, CD69 and effector cytokines, granzyme B (GrB) and IFN-γ in the exhaustion of innate-like TCR Vα7.2+CD4+T cells, in 15 individuals with chronic HBV (CHB) infection where six were HBV DNA+ and nine were HBV DNA–. The percentage of cytokine-producing T cells and MAIT cells were significantly perturbed in HBV patients relative to healthy controls (HCs). The intracellular expression of GrB and IFN-γ was significantly reduced in MAIT cells derived from HBV-infected patients as compared to HCs, and the levels correlated with the percentage and levels [mean fluorescence intensity (MFI)] of CD69 expression. The total expression of CD69 (iMFI) was lower in CHB patients as compared to HCs. The frequency of CD69+ cells correlated with the levels of cytokine expression (MFI), particularly in CHB patients as compared to HCs. In summary, the polyfunctionality of peripheral T cells was significantly reduced among CHB patients, especially in the TCR Vα7.2+CD4+T cells, and the levels of cytokine expression correlated with functional cytokine levels.

Background: Chronic HIV infection leads to marked depletion of CD4+ T cells in the gastrointestinal tract and increased microbial translocation measured by an increase in circulating lipopolysaccharide (LPS) levels. Here, we hypothesized that single-nucleotide polymorphisms (SNPs) in genes encoding the Toll-like receptor 4 (TLR4) and CD14, the principal receptors for LPS, were associated with CD4+ T-cell recovery postantiretroviral therapy (ART). Methods: Prospective study of predominantly white HIV-infected participants receiving suppressive ART for at least 12 months. We analysed the CD14 SNPs C-260T and the TLR4 SNPs A+896G, C+1196T. We also determined the levels of LPS and soluble CD14 in plasma samples collected pre-ART and post-ART initiation. CD4+ T-cell recovery was assessed by linear mixed models. Results: Following ART, individuals with a TT genotype compared with a CT or CC genotype for CD14 C-260T SNP showed higher levels of soluble CD14 (P = 0.008 and 0.003, respectively). The CC genotype for the CD14 C-260T SNP, compared with CT or TT, and the TLR4 SNP (AC/GT), compared with the homozygous genotype (AA/CC), were both independently associated with enhanced long-term CD4+ T-cell recovery (>3 months; P < 0.001). Conclusion: Polymorphisms in CD14 and TLR4 are independently associated with long-term CD4+ T-cell recovery in HIV-infected individuals post-ART.

Background Melioidosis is a neglected tropical disease endemic across South East Asia and Northern Australia. The etiological agent, Burkholderia pseudomallei (B.pseudomallei), is a Gram-negative, rod-shaped, motile bacterium residing in the soil and muddy water across endemic regions of the tropical world. The bacterium is known to cause persistent infections by remaining latent within host cells for prolonged duration. Reactivation of the recrudescent disease often occurs in elders whose immunity wanes. Moreover, recurrence rates in melioidosis patients can be up to ~13% despite appropriate antibiotic therapy, suggestive of bacterial persistence and inefficacy of antibiotic regimens. The mechanisms behind bacterial persistence in the host remain unclear, and hence understanding host immunity during persistent B. pseudomallei infections may help designing potential immunotherapy. Methodology/Principal findings A persistent infection was generated using a small-colony variant (SCV) and a wild-type (WT) B. pseudomallei in BALB/c mice via intranasal administration. Infected mice that survived for >60 days were sacrificed. Lungs, livers, spleens, and peripheral blood mononuclear cells were harvested for experimental investigations. Histopathological changes of organs were observed in the infected mice, suggestive of successful establishment of persistent infections. Moreover, natural killer (NK) cell frequency was increased in SCV- and WT-infected mice. We observed programmed death-1 (PD-1) upregulation on B cells of SCV- and WT-infected mice. Interestingly, PD-1 upregulation was only observed on NK cells and monocytes of SCV-infected mice. In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) downregulation was seen on NK cells of WT-infected mice, and on monocytes of SCV- and WT-infected mice. Conclusions/Significance The SCV and the WT of B. pseudomallei distinctly upregulated PD-1 expression on B cells, NK cells, and monocytes to dampen host immunity, which likely facilitates bacterial persistence. PD-1/PD-L1 pathway appears to play an important role in the persistence of B. pseudomallei in the host., Author summary B. pseudomallei is a bacterium that causes melioidosis, a disease endemic in Southeastern Asia and Northern Australia. It is estimated that melioidosis leads to 89,000 deaths worldwide each year. Nevertheless, melioidosis continues to remain a neglected tropical disease that is not even on the list of neglected tropical diseases of the World Health Organization. Furthermore, the disease has a high mortality and recurrence rate, which can be up to 40% and 13%, respectively. It has also been well documented that B. pseudomallei causes latent/persistent infections for a prolonged period without showing apparent symptoms in the infected individual. The mechanisms that are responsible for bacterial persistence in the host remain unclear. Our results demonstrated that B. pseudomallei were able to upregulate PD-1 expression on B cells, NK cells, and/or monocytes during persistent diseases, which likely diminish optimal host immunity. The weakened host immunity in turns facilitates persistence of the bacterium. Interestingly, the SCV had a higher PD-1 expression on distinct immune cells compared to the WT, which might explain its frequent association with persistent infections. Immunotherapies by targeting PD-1/PD-L1 pathway could serve as a better treatment than the conventional antibiotic regimens, which cause a high rate of recurrence in melioidosis patients.

Immune reconstitution inflammatory syndrome (IRIS) continues to be a complication in HIV/tuberculosis (TB) co-infected patients initiating highly active antiretroviral therapy (HAART). The aim of this study was to evaluate the risk factors associated with developing IRIS to identify a possible biomarker to predict or diagnose IRIS in patients initiating HAART. A total of 175 HIV/TB co-infected patients initiating HAART were followed up longitudinally during September 2010 to May 2013 attending a HIV care clinic in Chennai. Patients were followed up longitudinally after HAART initiation and baseline demographic, laboratory parameters and treatment characteristics between patients with IRIS events and those without IRIS events were compared. Chi-square or Fisher's exact test for categorical variables and a Wilcoxon rank-sum test for continuous variables were performed using SPSS, version 12.0 software. Patients with IRIS had a significantly lower median baseline CD4+ T-cell count (P = 0.0039). There were no differences in terms of sex, CD4 T-cell %, plasma viral load, time interval between initiating ATT and HAART between the IRIS and non-IRIS patients. Low CD4+ T-cell count (

Tuberculosis (TB) and human immunodeficiency virus (HIV) infection interfere and impact the pathogenesis phenomena of each other. Owing to atypical clinical presentations and diagnostic complications, HIV/TB co-infection continues to be a menace for healthcare providers. Although the increased access to highly active antiretroviral therapy (HAART) has led to a reduction in HIV-associated opportunistic infections and mortality, the concurrent management of HIV/TB co-infection remains a challenge owing to adverse effects, complex drug interactions, overlapping toxicities and tuberculosis -associated immune reconstitution inflammatory syndrome. Several hypotheses have been put forward for the exacerbation of tuberculosis by HIV and vice versa supported by immunological studies. Discussion on the mechanisms produced by infectious cofactors with impact on disease pathology could shed light on how to design potential interventions that could decelerate disease progression. With no vaccine for HIV and lack of an effective vaccine for tuberculosis, it is essential to design strategies against HIV-TB co-infection.

Background During infection, successful bacterial clearance is achieved via the host immune system acting in conjunction with appropriate antibiotic therapy. However, it still remains a tip of the iceberg as to where persistent pathogens namely, Burkholderia pseudomallei (B. pseudomallei) reside/hide to escape from host immune sensors and antimicrobial pressure. Methods We used transmission electron microscopy (TEM) to investigate post-mortem tissue sections of patients with clinical melioidosis to identify the localisation of a recently identified gut microbiome, B. pseudomallei within host cells. The intranuclear presence of B. pseudomallei was confirmed using transmission electron microscopy (TEM) of experimentally infected guinea pig spleen tissues and Live Z-stack, and ImageJ analysis of fluorescence microscopy analysis of in vitro infection of A549 human lung epithelial cells. Results TEM investigations revealed intranuclear localization of B. pseudomallei in cells of infected human lung and guinea pig spleen tissues. We also found that B. pseudomallei induced actin polymerization following infection of A549 human lung epithelial cells. Infected A549 lung epithelial cells using 3D-Laser scanning confocal microscopy (LSCM) and immunofluorescence microscopy confirmed the intranuclear localization of B. pseudomallei. Conclusion B. pseudomallei was found within the nuclear compartment of host cells. The nucleus may play a role as an occult or transient niche for persistence of intracellular pathogens, potentially leading to recurrrent episodes or recrudescence of infection., Author Summary Burkholderia pseudomallei (B. pseudomallei), the causative agent of melioidosis, is endemic across parts of South East Asia and Northern Australia. Of the key features of B. pseudomallei, is its ability to remain latent in the host causing recrudescent disease years after initial infection. However, it still remains unclear as to where B. pseudomallei resides to escape from host immune sensors and antimicrobial pressure. Here, we have found that B. pseudomallei was able to enter into the nuclear compartment of host cells. The nucleus may play a role as a temporary abode for persistence, leading to recurrrent episodes of infection.

Background Burkholderia pseudomallei (B. pseudomallei), the causative agent of melioidosis, is a deadly pathogen endemic across parts of tropical South East Asia and Northern Australia. B. pseudomallei can remain latent within the intracellular compartment of the host cell over prolonged periods of time, and cause persistent disease leading to treatment difficulties. Understanding the immunological mechanisms behind persistent infection can result in improved treatment strategies in clinical melioidosis. Methods Ten-day LD50 was determined for the small-colony variant (SCV) and its parental wild-type (WT) via intranasal route in experimental BALB/c mice. Persistent B. pseudomallei infection was generated by administrating sub-lethal dose of the two strains based on previously determined LD50. After two months, peripheral blood mononuclear cells (PBMCs) and plasma were obtained to investigate host immune responses against persistent B. pseudomallei infection. Lungs, livers, and spleens were harvested and bacterial loads in these organs were determined. Results Based on the ten-day LD50, the SCV was ~20-fold less virulent than the WT. The SCV caused higher bacterial loads in spleens compared to its WT counterparts with persistent B. pseudomallei infection. We found that the CD4+ T-cell frequencies were decreased, and the expressions of PD-1, but not CTLA-4 were significantly increased on the CD4+ and CD8+ T cells of these mice. Notably, persistent infection with the SCV led to significantly higher levels of PD-1 than the WT B. pseudomallei. Plasma IFN-γ, IL-6, and IL-17A levels were elevated only in SCV-infected mice. In addition, skewed plasma Th1 and Th17 responses were observed in SCV-infected mice relative to WT-infected and uninfected mice. Conclusion B. pseudomallei appears to upregulate the expression of PD-1 on T cells to evade host immune responses, which likely facilitates bacterial persistence in the host. SCVs cause distinct pathology and immune responses in the host as compared to WT B. pseudomallei., Author Summary Melioidosis is an endemic tropical disease in South East Asia and Northern Australia, which is caused by Burkholderia pseudomallei, an environmental bacterium found in the soils of paddy fields and muddy waters across these regions. The bacterium is known to reside within the host cell for prolonged periods of time and is capable of causing long-lasting disease. Recurrent disease is common even with appropriate antibiotic treatments. The mechanisms behind the persistence of B. pseudomallei in the host are still unclear. We investigated the host cell-mediated immune responses against persistent B. pseudomallei infection in BALB/c mice. We found a reduced CD4+ T-cell frequency in mice with persistent B. pseudomallei infection, suggestive of the key role of these cells in experimental melioidosis. Moreover, we also observed significant upregulation of PD-1 on both CD4+ and CD8+ T cells in mice with persistent B. pseudomallei infection, possibly indicating that the T cells were undergoing exhaustion. Based on our results, we postulated that B. pseudomallei is able to impair host immune responses, likely by facilitating the depletion of CD4+ T cells and upregulation of PD-1 on T cells, which potentially facilitates bacterial persistence in the host. Targeting T-cell responses could be an approach to develop vaccines or therapeutics against persistent B. pseudomallei infection.

Objectives. Cold agglutinin (CA) titers are one among the first pathological indicators for diagnosing Mycoplasma pneumoniae disease. We prospectively studied the prevalence of CAs in 300 HIV-positive and 75 HIV-negative individuals with respiratory disease in Chennai, India. Methods. The cold agglutination test was used and retrospectively compared with the results of a particle agglutination test. Results. While CAs were positive in 51 HIV cases, particle agglutination test detected anti-M pneumoniae antibodies from 43 cases with HIV disease (P = .001). The seroprevalence of CAs was 2.6% (n = 2) among HIV-negative participants. The mean CD4 count in CApositive and -negative HIV cases was 107.4 + 121.2 and 259.2 + 247.2 cells/µL (P = .001), respectively. Conclusion. Our report suggests a basis for the existence of CAs in HIV-positive cases. Definitive diagnosis may be done only when CA detection is used in conjunction with a specific test.

The GB virus (GBV)/hepatitis G virus is a member of the Flaviviridae family and belongs to the hepatitis group of viruses transmitted parenterally, common among intravenous drug users. The strong association between GBV and HIV infection suggests that the two viruses may share similar epidemiological and transmission features. GBV infection is widely believed to prolong HIV disease progression as well as decreasing the HIV viral load and increasing the CD4(+) T-cell level. GBV-driven anti-E2 antibodies have been shown to inhibit HIV replication in vitro. Preliminary studies also suggest that GBV infection of peripheral blood mononuclear cells leads to increased production of beta-chemokines, which may explain the in vitro inhibitory effects and warrants further studies. With sufficient knowledge of resistance patterns studied in tropical south India, researchers are now keen to study the competitive interactions between GBV-induced chemokines and HIV ligands to bind CCR5.

SummaryObjectiveThe role of oxidative stress in disease progression has been shown to be more complicated in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) compared to those who remain treatment-naïve. This study examined the changes in the antioxidant profile of HIV-infected subjects who remained HAART-naïve due to a high CD4 cell count and HIV-negative controls, over a 12-month follow-up period at YRG CARE, a tertiary HIV referral centre in southern India.MethodsWe prospectively studied 35 HIV-infected participants (18 on d4T+3TC+EFV (stavudine+lamivudine+efavirenz), eight on AZT+3TC+EFV (zidovudine+lamivudine+efavirenz), and nine who were antiretroviral therapy-naïve) and 20 HIV-negative controls. Antioxidant profile (total antioxidant status, glutathione reductase, glutathione peroxidase, uric acid, ceruloplasmin, zinc, and albumin), CD4 cell count, plasma viral load, dietary intake, and history of smoking and alcohol use were determined at baseline and at twelve months.ResultsAt 12 months, participants on HAART showed a significant increase in glutathione peroxidase (baseline: 1765 vs. 12 months: 2850U/l; p

Summary Objectives The prevalence of hepatitis B virus (HBV) is reportedly the main cause of hepatocellular carcinoma (HCC) in India, where hepatitis C virus (HCV)-associated HCC is believed to be relatively less prevalent. We verified the usefulness of alpha-fetoprotein (AFP) as a tumor marker and analyzed the influence of viral etiology on AFP levels in HCC. Methods Of a total of 1012 cases with liver disease, 202 were investigated for the presence of AFP (142 HCC cases, 30 cirrhosis cases, and 30 chronic liver disease (CLD) cases). In addition, serum samples from 30 healthy patients, 30 hepatitis B surface antigen (HBsAg) carriers, and 30 acute viral hepatitis cases were included as controls. AFP was quantitatively determined using a commercial ELISA (Quorum Diagnostics, Canada). Out of the 142 HCC cases screened for AFP, aflatoxin B1 (AFB1) detection was carried out in 38 HCC cases using an in-house immunoperoxidase test. Results In HBV and HCV co-infected HCC cases, the AFP positivity was 85.7%. In HBV alone-associated HCC, the positivity was 62.9%, and 54.5% of AFB1 positive HCC cases showed AFP positivity. In HBV and HCV negative HCC cases, the positivity was 20.5%, and in HCV-associated HCC it was 17.6%. The HBV/HCV co-infected group and HBV alone positive HCC cases had significantly elevated levels of AFP. When AFP positivity was analyzed based on the marker profile of HBV, 89.7% of AFP positive cases were HBV-DNA positive. Conclusions The overall positivity pattern of AFP in HCC does indicate that higher levels of AFP are observed with hepatitis virus positivity, especially with HBV. Further studies must be carried out to correlate the serum levels of AFP with the size, number, and degree of differentiation of HCC nodules.

Background Burkholderia pseudomallei, the causative agent of melioidosis poses a serious threat to humankind. B. pseudomallei secretes numerous virulence proteins that alter host cell functions to escape from intracellular immune sensors. However, the events underlying disease pathogenesis are poorly understood. Methods We determined the ability of B. pseudomallei to invade and survive intracellularly in A549 human lung epithelial cells, and also investigated the early transcriptional responses using an Illumina HumanHT-12 v4 microarray platform, after three hours of exposure to live B. pseudomallei (BCMS) and its secreted proteins (CCMS). Results We found that the ability of B. pseudomallei to invade and survive intracellularly correlated with increase of multiplicity of infection and duration of contact. Activation of host carbohydrate metabolism and apoptosis as well as suppression of amino acid metabolism and innate immune responses both by live bacteria and its secreted proteins were evident. These early events might be linked to initial activation of host genes directed towards bacterial dissemination from lungs to target organs (via proposed in vivo mechanisms) or to escape potential sensing by macrophages. Conclusion Understanding the early responses of A549 cells toward B. pseudomallei infection provide preliminary insights into the likely pathogenesis mechanisms underlying melioidosis, and could contribute to development of novel intervention strategies to combat B. pseudomallei infections., Author Summary Burkholderia pseudomallei, the causative agent of the fatal infectious disease melioidosis, is endemic across parts of South East Asia and Northern Australia. Melioidosis poses a serious worldwide emerging infectious disease problem and bioterrorism threat. Of the key features of B. pseudomallei, is its ability to remain latent in the host causing recrudescent disease years after initial infection. Relapses are also commonly reported despite appropriate and prolonged antibiotic therapy, suggesting the bacteria’s ability to escape the host’s front-line immune defenses and to manipulate the host’s responses to sustain survival in the host. However, the likely underlying mechanisms of bacterial persistence still remain unclear. Thus, here we proposed to study the host responses towards early interaction of the cell with live B. pseudomallei and its secretory proteins, in order to understand the potential roles of innate responses against the bacteria.

Virus-specific CD8(+) T cells play an important role in controlling viral infections including human immunodeficiency virus (HIV) infection. However, during chronic HIV infection, virus-specific CD8(+) T cells undergo functional exhaustion, lose effector functions and fail to control viral infection. HIV-specific CD8(+) T cells expressing high levels of co-inhibitory molecule programmed death-1 (PD-1) during the chronic infection and are characterized by lower proliferation, cytokine production, and cytotoxic abilities. Although, antiretroviral therapy has resulted in dramatic decline in HIV replication, there is no effective treatment currently available to eradicate viral reservoirs or restore virus-specific T or B-cell functions thatmay complement ART in order to eliminate the virus. In recent years, studies in mice and non-human primate models of HIV infection demonstrated the functional exhaustion of virus-specific T and B cells could be reversed by blockade of interaction between PD-1 and its cognate ligands (PD-L1 and PD-L2). In this review, we discuss recent advances in our understanding of PD-1 pathway in HIV/ SIV infection and discuss the beneficial effects of PD-1 blockade during chronic HIV/SIV infection and its potential role as immunotherapy for HIV/AIDS. Funding Agencies|NIH [R01 A107183, R01 A1074417, RC2CA149086]; University of Malaya Research Grant (UMRG) of the Health and Translational Medicine Research Cluster, University of Malaya, Kuala Lumpur [RP021A-13HTM]

Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a substantial problem in HIV/TB coinfected patients commencing antiretroviral therapy (ART). The immunopathogenesis of TB-IRIS includes increased production of proinflammatory chemokines and cytokines, including interleukin-18, which is a signature cytokine of the nucleotide-binding domain and leucine-rich repeat pyrin containing protein-3 inflammasome. We compared plasma levels of interleukin18 and other biomarkers of monocyte/macrophage activation in the prediction and characterization of TB-IRIS. Methods: Biomarkers were assayed pre-ART and during TB-IRIS, or equivalent timepoint, in a case‐control study of Malaysian HIV patients with paradoxical or unmasking TB-IRIS (n ¼15), TB no IRIS (n ¼14), and no TB or IRIS (n ¼15). Findings for interleukin18 were verified in another cohort of patients with paradoxical TB-IRIS (n ¼26) and their controls (n ¼22) from India. Results: Interleukin-18 was higher in TB-IRIS patients pre-ART and during the event in bothMalaysianpatients (P

Summary Background The true seroepidemiology of acute Mycoplasma pneumoniae infection in HIV infected individuals is ambiguous. Methods This study examined the serosurveillance of IgM antibodies to M. pneumoniae in HIV infected patients presenting with pulmonary symptoms at a tertiary AIDS care center in Chennai, Southern India, using cold-haemagglutination test and commercial enzyme linked immunosorbent assay in acute serum specimens. Results One hundred HIV infected patients had enrolled in the study; 21 (21%) were positive for M. pneumoniae IgM antibodies by ELISA and 34 (34%) showed evidence of cold hemagglutinins. Conclusion This serosurveillance study reports a 21% prevalence of M. pneumoniae IgM antibody among HIV infected patients with pulmonary symptoms by ELISA and non-specific diagnosis was confirmed in 34% of the cases screened. Determination of cold agglutination titer could be used as a substitute to other expensive procedures in limited resource settings and third-world nations to diagnose M. pneumoniae infections for prompt initiation of therapy, as CAT has been found to be 100% sensitive and 84% specific in the diagnosis of M. pneumoniae infection.

Background Hepatitis C virus (HCV) represents one of the persistent viral infections afflicting humankind, and a significant proportion of chronic HCV disease progresses over time through liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). One potential mechanism underlying the chronic disease is believed to be viral escape from immune surveillance via upregulation of inhibitory molecules on immune cells by HCV. We investigated the diverse expression of various inhibitory molecules in PBMCs of healthy non-HCV controls and chronically HCV infected patients. Methods The expression of inhibitory molecules on PBMCs was investigated in chronic HCV infected patients relative to healthy non-HCV controls using standard immunological and molecular methods. The serum levels of indoleamine 2, 3 deoxygenase (IDO) and cyclooxygenase-2 (COX-2) were also investigated. Results The gene expression profile of chronically HCV infected patients was significantly different from control individuals. Our results showed upregulation of TIM-3 (p≤0.01), PD-1 (p≤0.01), FOXP-3 (p≤0.01), BLIMP-1 (p≤0.01), CD160 (p≤0.01), CTLA-4 (p≤0.01), TRAIL (p≤0.01), BTLA (p≤0.01) and LAG-3 (p≤0.01) with fold change of 1.3, 0.4, 14.6, 0.87, 6.6, 0.4, 14.7, 10.9 and 2.5 respectively in chronically HCV infected patients. The plasma IDO and COX-2 levels were significantly higher (p=0.001) in chronically HCV infected subjects relative to healthy control. Conclusion

Over the past decade, an increasing number of opportunistic fungal infections have been reported in immunocompromised subjects. Microascus spp. and their anamorphs Scopulariopsis spp. have been recovered from a wide geographical range. We report a case of Scopulariopsis brumptii in a 27-year-old man with AIDS presenting with breathlessness, pericardial effusion and hydrothorax in Chennai, southern India, in February 2007. Because of respiratory arrest, the patient was intubated. However, the patient developed obstructive shock and died due to cardiac dysfunctions. This report underlines the need for a direct, intensive approach to investigations in immunocompromised patients, especially those with AIDS.

Cellular immune responses play a crucial role in the control of viral replication in HIV-infected individuals. However, the virus succeeds in exploiting the immune system to its advantage and therefore, the host ultimately fails to control the virus leading to development of terminal AIDS. The virus adopts numerous evasion mechanisms to hijack the host immune system. We and others recently described the expression of inhibitory molecules on T cells as a contributing factor for suboptimal T-cell responses in HIV infection both in vitro and in vivo. The expression of these molecules that negatively impacts the normal functions of the host immune armory and the underlying signaling pathways associated with their enhanced expression need to be discussed. Targets to restrain the expression of these molecular markers of immune inhibition is likely to contribute to development of therapeutic interventions that augment the functionality of host immune cells leading to improved immune control of HIV infection. In this review, we focus on the functions of inhibitory molecules that are expressed or secreted following HIV infection such as BTLA, CTLA-4, CD160, IDO, KLRG1, LAG-3, LILRB1, PD-1, TRAIL, TIM-3, and regulatory cytokines, and highlight their significance in immune inhibition. We also highlight the ensemble of transcriptional factors such as BATF, BLIMP-1/PRDM1, FoxP3, DTX1 and molecular pathways that facilitate the recruitment and differentiation of suppressor T cells in response to HIV infection. Funding Agencies|University of Malaya Research Grant (UMRG) of the Health and Translational Medicine Research Cluster, University of Malaya, Kuala Lumpur|RG448-12HTM|Swedish Research Council||Swedish Physicians against AIDS Research Foundation||Swedish International Development Cooperation Agency||SIDA SARC||VINNMER for Vinnova||Linkping University Hospital Research Fund||CALF||Swedish Society of Medicine||Ministry of Higher Education Malaysia, High Impact Research Grant|HIRGA E000001-20001||AI52731

GB virus C (GBV-C), a member of the Flaviviridae family of viruses, recently received considerable attention largely owing to its potential role in decelerating HIV-1 disease progression by interfering with HIV replication. With similar transmission features, GBV-C is parenterally transmitted, similar to the serum hepatitis viruses and HIV-1, and replicates in hemopoietic cells and T lymphocytes in particular, with no observable disease pathology. Progressive T-cell depletion and subsequent immune abrogation being the cardinal features of HIV-1 infection, accumulating evidence indicates that GBV-C effectively overturns HIV’s chances of exploiting the T-cell machinery and leads to enhanced survival rates of HIV-infected subjects. Much effort has been devoted to understanding the beneficial role of GBV-C in HIV disease. This review discusses recently proposed mechanisms underlying the pathophysiology of GBV-C coinfection in HIV disease.

Background: A great deal of effort has been devoted to understanding the role of AIDSassociated mycoplasmas in recent years. However, the role of Mycoplasma pneumoniae in HIV disease remains unclear. Methods: We studied 300 adult HIV infected persons (200 with community-acquired pneumonia (CAP) and 100 with no respiratory illness) and 75 HIV uninfected persons with CAP and analysed the prevalence of respiratory pathogens. Results: Prevalence of M. pneumoniae was 17% by induced sputum and 11.3% by throat swab culture in HIV positive subjects. Seroprevalence of anti-M. pneumoniae IgM was 11.7% by ELISA and 14.3% by gelatin microparticle agglutination test. Prevalence of M. pneumoniae among HIV negative cases was relatively low. Streptococcus pneumoniaewas predominant (28%) among subjects with lower respiratory disease, whereas Staphylococcus aureus (15%) was more common among cases with upper respiratory illness. Rales (P=0.001), pharyngeal erythema (P=0.02), cervical adenopathy (P=0.004) and crepitations (P=0.001) showed significance in relation to M. pneumoniae positivity. Statistical significance was observed with regard to total lymphocyte count (P=0.02) and erythrocyte sedimentation rate (P=0.04), and M. pneumoniae positivity. Conclusion: The prevalence of M. pneumoniae in HIV infected subjects was relatively higher than HIV uninfected subjects with respiratory disease.

Opportunistic infections (OIs) are the leading cause of mortality and morbidity among HIV-positive subjects. The breadth of reports of the rare occurrence of OIs in HIV/AIDS has been increasing over the years and more recent studies have outlined the changing trends in the emergence of newer pathogens. Recent reports of the association of certain protozoans that normally do not infect sites other than their normal sites of localization have generated huge interest among scientists. The complete depression of the immune system, followed by the onset of OIs, especially due to protozoans, i.e. toxoplasmosis, isosporiasis, leishmaniasis, cyclosporosis, microsporidiosis and cryptosporidiosis, is not uncommon in AIDS. The immunologic and pathologic basis behind the susceptibility of immunodepressed individuals to these ‘non-site-specific parasites’ is likely to have a huge impact on HIV disease progression. Certain possible shortcomings in the immunologic armory of immunodeficient subjects, their failure to contain the establishment of these ‘uncommon’ agents in the human host and their significance in HIV disease progression are discussed.

Background Inclusion of hepatitis B vaccine in the Universal Programme of Immunization of all Asian and African countries is hampered by the economic burden on the health budget because of the cost of hepatitis B vaccines. Here we evaluated the immunogenicity, safety, efficacy, and the persistence of antibody to hepatitis B surface antigen (anti-HBs) titers of a new and a low cost recombinant hepatitis B vaccine GeneVac B, with 2 different dosages in healthy adolescents in India. Methods GeneVac-B, a recombinant hepatitis B vaccine (Serum Institute of India, Pune, India), was administered in 10 or 20 microg dose intramuscularly to 2 groups of 100 healthy school-going adolescents at 0-, 1-, and 6-month intervals, who were followed up for 1 year. Group I received 20 mug doses whereas Group II received 10 mug doses. Blood samples were collected 1 month after each dose and 1 year after the third dose. The anti-HBs titers were assayed using commercially available kits to assess the immunogenicity of the 2 dosage schedules. Safety studies were also carried out. Results The geometric mean titer value of the anti-HBs titer 1 month after the third dose was 2629 (mlU/mL) in Group I and 1373 mlU/mL for Group II subjects. One year after the third dose, the persistence of anti-HBs in those who had received 20 mug was 2262 mlU/mL whereas it was 1039 mlU/mL in the group receiving 10 microg doses. All the subjects in both the groups were seroprotected at 1 year after vaccination. None of the vaccinees exhibited serious adverse reactions throughout the study period. Conclusions The study demonstrated the immunogenicity of the recombinant hepatitis B vaccine, and confirms that the 0.5 mL (10 microg) dose of GeneVac B can be administered with satisfactory safety and immunogenicity to adolescents up to 19 years of age, reducing the cost to less than U.S. $1.00 per dose making it acceptable for the Universal Programme of Immunization of developing and under developed countries.

A prevalence study on Campylobacter jejuni and other enteric bacterial pathogens was carried out in 200 HIV infected and 200 non-HIV infected subjects with diarrhoeal symptoms at an AIDS Hospital in southern India. Diarrhoeal specimens were inoculated onto standard culture media as well as onto Columbia and Campylobacter blood agar media for C. jejuni isolation. All the C. jejuni isolates were tested for antimicrobial susceptibility using Kirby-Bauer's method. A significant difference in recovery rates was observed between the 2 groups in relation to C. jejuni (por = 0.02; 95% CI 5.5 (1-10) and Shigella spp. (por = 0.02; 95% CI 6.5 (1-12). 21 isolates of Shigella spp., 16 C. jejuni, 5 Salmonella typhi, 3 Arcobacter spp., 3 Yersinia enterocolitica, and 2 Aeromonas hydrophila were recovered from the HIV infected cases. All the C. jejuni isolates were sensitive to ciprofloxacin whereas 1 strain was resistant to nalidixic acid. Interestingly, all the 29 Shigella spp. (21 from HIV and 8 from non-HIV cases) were resistant to erythromycin and most were resistant to many other antibiotics used. Our observations underline the need for epidemiological investigations to screen C. jejuni and Shigella spp. in HIV infected subjects with diarrhoea and analyse their antibiograms periodically to minimize disease burden in HIV/AIDS.

Summary Four hundred million people are carriers of hepatitis B virus (HBV) worldwide and ∼5% of these are reportedly positive for hepatitis delta virus (HDV). Several reports indicate a declining trend in the occurrence of HDV infection in the north of tropical India. To our knowledge, no study has been conducted to evaluate whether a similar epidemiological change is occurring in southern India. Therefore we evaluated the seroprevalence of HDV among 153 individuals with HBV-related liver diseases in Chennai, and assessed any change in epidemiological pattern by comparing the results with seroprevalence figures reported previously. Of the 153 patients screened, nine (5.9%) were reactive to anti-delta antibodies, six (3.9%) presented an evidence of past infection (IgG anti-delta positive) and three (2.0%) showed anti-HDV IgM, suggestive of recent HDV infection. Alanine transaminase elevation was not significant in HDV-associated infection compared with HBV alone-infected acute viral hepatitis (AVH) ( P = 0.82) and chronic liver disease ( P = 0.77) patients. The anti-HDV positivity in AVH was considerably low (6.6%), compared with previous Indian reports varying from 10.7% to >30%. HDV infection was relatively low and seems to play a minor determining factor of liver diseases in the tropical south Indian population.

Materials and methods The present study has been carried out on 60 HIV infected patients presenting with underlying pulmonary complaints and whose clinical presentation was consistent with disease caused by Mycoplasma pneumoniae, after obtaining informed consent subsequent to approval by the Institutional Review Board (IRB) on human ethics in Chennai where the recovery rates of Mycoplasma pneumoniae from induced sputum and throat swab specimens of HIV infected patients were compared and the haematological and immunological findings were analysed. Patients screened were from the age groups ranging from 15 to 60 years, whose respiratory specimens were cultured on PPLO glucose agar and broth, the later with 1% methylene blue. Presumptive identification of Mycoplasma pneumoniae was carried out using guidelines proposed by the Subcommittee on the Taxonomy of Mollicutes, 1979. The respiratory specimens from the HIV-infected subjects were later analysed for their recovery rates, incidence of other bacterial, fungal pathogens, AFB, Pneumocystis carinii and their correlation features with CD4+ and CD8+ lymphocytes were also analysed and compared.

Objectives Dengue represents one of the most serious life-threatening vector-borne infectious diseases that afflicts approximately 50 million people across the globe annually. Whilst symptomatic infections are frequently reported, asymptomatic dengue remains largely unnoticed. Therefore, we sought to investigate the immune correlates conferring protection to individuals that remain clinically asymptomatic. Methods We determined the levels of neutralizing antibodies (nAbs) and gene expression profiles of host immune factors in individuals with asymptomatic infections, and whose cognate household members showed symptoms consistent to clinical dengue infection. Results We observed broad down-regulation of host defense response (innate, adaptive and matrix metalloprotease) genes in asymptomatic individuals as against symptomatic patients, with selective up-regulation of distinct genes that have been associated with protection. Selected down-regulated genes include: TNF α (TNF), IL8, C1S, factor B (CFB), IL2, IL3, IL4, IL5, IL8, IL9, IL10 and IL13, CD80, CD28, and IL18, MMP8, MMP10, MMP12, MMP15, MMP16, and MMP24. Selected up-regulated genes include: RANTES (CCL5), MIP-1α (CCL3L1/CCL3L3), MIP-1β (CCL4L1), TGFβ (TGFB), and TIMP1. Conclusion Our findings highlight the potential association of certain host genes conferring protection against clinical dengue. These data are valuable to better explore the mysteries behind the hitherto poorly understood immunopathogenesis of subclinical dengue infection.

This letter to the editor describes a study which investigated the profile of tuberculosis (TB) and the nature of drug resistance pattern among 176 HIV-positive subjects suspected of TB based on the clinical grounds attending a tertiary AIDS care center in Chennai South India. It states that anti-TB drug susceptibility testing should be performed for all patients who are culture positive for M. tuberculosis and concludes that there is a need for strengthening collaboration between TB and AIDS control programs to counteract the impact of HIV on TB.

We investigated 245 diarrheal stool specimens from HIV-positive subjects between January 2003 and December 2006 to determine the etiological role of coproparasites. Parasitic etiology was observed in 91 (37.1%) cases. Isospora belli (26.1%) was the most common parasite followed by Entameba histolytica/dispar (3.3%), Cryptosporidium spp. (2.9%), Giardia intestinalis (1.6%), and Strongyloides stercoralis (1.2%). Interesting trends of significant increase in the number of cases of I. belli and decline in Cryptosporidium spp. were observed during the study period.