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Chikungunya virus (CHIKV) infection is endemic in many different countries. CHIKV outbreaks are emerging in new areas and re-emerging in previously exposed geographical regions, thus making it a significant public health concern. CHIKV infections are often clinically inapparent, especially in children, which poses a challenge to testing and evaluating any vaccine. During CHIKV infection, CHIKV-specific antibodies are produced, and some of these antibodies can neutralize viruses released from infected cells before they can enter uninfected cells. In this study, we evaluated IgG binding and neutralizing antibody responses in paired serum samples from CHIKV-infected children and those with other febrile illness, using a recombinant truncated E2 protein and whole CHIKV particles as test antigens. Antibody detection using the truncated E2 protein showed a significant overlap between CHIKV-infected subjects and those with other febrile illnesses. This overlap was greater when binding antibody titers were determined using fixed CHIKV particles as the test antigen. Acute- and convalescent-phase sera collected from children after CHIKV infection showed significant differences in their neutralizing capacity. The neutralizing and binding antibody response showed a significant positive correlation. We detected IgG antibodies in most cases during the acute phase of infection. This was observed at two different geographical locations, one of which is not considered highly endemic. Conventional wisdom would suggest this to be a marker of re-infection (secondary infection). However, dissenting opinions have been voiced in other viral diseases (such as Ebola) where studies have detected IgG in acute illness. In the absence of any significant body of work documenting secondary CHIKV infections, we believe further work is needed to understand the early IgG response that we observed. [ABSTRACT FROM AUTHOR]

India is one of the most affected countries by COVID-19 pandemic; but little is understood regarding immune responses to SARS-CoV-2 in this region. Herein we examined SARS-CoV-2 neutralizing antibodies, IgG, IgM, IgA and memory B cells in COVID-19 recovered individual from India. While a vast majority of COVID-19 recovered individuals showed SARS-CoV-2 RBD-specific IgG, IgA and IgM antibodies (38/42, 90.47%; 21/42, 50%; 33/42, 78.57% respectively), only half of them had appreciable neutralizing antibody titers. RBD-specific IgG, but not IgA or IgM titers, correlated with neutralizing antibody titers and RBD-specific memory B cell frequencies. These findings have timely significance for identifying potential donors for plasma therapy using RBD-specific IgG assays as surrogate measurement for neutralizing antibodies in India. Further, this study provides useful information needed for designing large-scale studies towards understanding of inter-individual variation in immune memory to SARS CoV-2 natural infection for future vaccine evaluation and implementation efforts. • This study characterized neutralizing/ binding antibodies and memory B cells in COVID-19 recovered individuals from India. • We show that half of the COVID-19 recovered individuals generated readily detectable SARS COV-2 neutralizing antibodies. • SARS COV-2 RBD specific IgG titers provide a surrogate measure for neutralizing titers and memory B cell frequencies. • These findings aid selection of suitable donors for plasma therapy against COVID-19. • Our findings have implications to understand generation and maintenance of SARS Cov-2 protective immunity and vaccines. [ABSTRACT FROM AUTHOR]

• More than eighty percent adults immune to at least one dengue serotype. • More than half of them are immune to all four dengue serotypes. • Substantial interindividual variation observed in MBC, neutralizing/binding antibodies levels. • Presence of the neutralizing antibodies correlate with presence of binding antibodies, but not vice versa. • Levels of neutralizing and binding antibodies are not in perfect correlation. The Indian population is facing highest dengue burden worldwide supporting an urgent need for vaccines. For vaccine introduction, evaluation and interpretation it is important to gain a critical understanding of immune memory induced by natural exposure. However, immune memory to dengue remains poorly characterized in this region. We enumerated levels of dengue specific memory B cells (MBC), neutralizing (NT) and binding antibodies in healthy adults (n = 70) from New Delhi. NT-antibodies, binding antibodies and MBC were detectable in 86%, 86.56% and 81.63% of the subjects respectively. Among the neutralizing positive subjects, 58%, 27%, 5% and 10% neutralized all four, any three, any two and any one dengue serotypes respectively. The presence of the neutralizing antibodies was associated with the presence of the MBC and binding antibodies. However, a massive interindividual variation was observed in the levels of the neutralizing antibodies (range, <1:50–1:30,264), binding antibodies (range, 1:3,000–1:134,000,) as well as the MBC (range = 0.006%–5.05%). These results indicate that a vast majority of the adults are immune to multiple dengue serotypes and show massive interindividual variation in neutralizing/binding antibodies and MBCs – emphasizing the importance of monitoring multiple parameters of immune memory in order to properly plan, evaluate and interpret dengue vaccines. [ABSTRACT FROM AUTHOR]

Background. Chikungunya fever (CHIK) is a major public health concern in India. Characterized by acute fever with joint pain and swelling, most patients recover from this self-limiting illness in 7-10 days, with cessation of joint pain post-acute episode. However, in some patients, joint pain persists, lasting for months or even years. The precise correlates to the chronic phase of this debilitating illness and/or this remarkable heterogeneity in disease manifestation are poorly understood. Methods. We evaluated 572 chikungunya patients from India who were recruited on the basis of positive real-time polymerase chain reaction and/or CHIK virus immunoglobulin (IgM) after receiving consent. Arthralgic conditions were monitored using visual analog score (VAS) 12 weeks after onset of fever in 130 patients. Initial viral load, IgG, and initial neutralization response were assayed and correlated with clinical and VAS information in 40 patients. Results. Our extensive screening revealed that patients with higher initial viral loads during the acute phase of illness had poor prognosis at the post-acute phase with more restricted joint movement and higher VAS. Additionally, patients who showed early seroconversion to neutralizing IgG responses had better prognosis, as many of these patients did not manifest restricted joint movements at the post-acute phase. Conclusions. Our study sheds light on chikungunya disease with respect to disease progression and assesses clinical, virological, and serological parameters of chikungunya disease severity. Importantly, it reveals that initial high viral load and neutralizing IgG response may function in a seemingly contrasting manner to negatively or positively dictate disease outcome. [ABSTRACT FROM AUTHOR]

Background & objectives: Mycobacterium tuberculosis infection has been shown to result in increased HIV replication and disease progression in HIV-infected individuals through increased immune activation. The objective of this study was to correlate plasma levels of immune activation markers with the presence of tuberculosis (TB) in HIV-infected and uninfected individuals, and to study the changes following anti-tuberculosis treatment. Methods: Plasma markers of immune activation - neopterin, beta-2-microglobulin (β2M) and soluble tumour necrosis factor alpha receptor type I (sTNFα-RI) were measured by ELISA in 42 HIV positive TB patients (HIV+TB+) undergoing a six-month course of TB chemotherapy. Thirty seven HIV+ persons without active TB, 38 TB patients without HIV infection, and 62 healthy volunteers served as controls. Results: Plasma levels of all three markers were elevated in HIV+ individuals, more so in those with active TB. When HIV+ individuals were further categorized based on CD4+ T cell counts, HIV+TB+ patients with CD4+ T cells counts ≤ 200 cells/µl were found to have the highest levels at baseline with a steep fall in neopterin and sTNFα-RI during treatment, but in most instances the levels did not drop to normal. βM levels remained persistently high despite completing TB treatment. Interpretation & conclusions: The findings of the study suggest that both HIV and TB act synergistically to activate the host immune system. Although ATT was effective in clearing M. tuberculosis infection, a high proportion of HIV+ TB patients continued to have levels well above the normal range, indicating that underlying immune activation persists despite TB treatment. None of the markers were specific enough to be used to assess cure of TB. [ABSTRACT FROM AUTHOR]

Dengue and Chikungunya are two major arboviral infections transmitted worldwide by the mosquitoes, Aedes aegypti and Ae. albopictus. India suffers enormously with both Dengue and Chikungunya as they pose a great public health challenge. The present study aims to evaluate the prevalence of Dengue Virus (DENV), Chikungunya Virus (CHIKV) and DENV/CHIKV coinfection (by Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR)/Enzyme Linked Immunosorbent Assay (ELISA), their clinical features, DENV serotypes and CHIKV specific Immunoglobulin G (IgG) within a 7 years gap in the Delhi population. The study sample included clinically suspected febrile patients (=7 days) sera collected during 2017-2018 (n=87) and during 2008-2010 (n=623) from Delhi. Captured ELISA was performed for CHIKV IgG screening and nested PCR was done for DENV serotyping. The percentage prevalence for DENV was significantly higher than CHIKV with 41.38% (n=87) and 16.1% (n=87), respectively; interestingly, DENV/CHIKV co-infection was detected in 10.34% (n=9/87) cases during 2017-2018. Similarly, a high DENV prevalence was observed during 2008-2010 with the prevalence rate of 38.3% (69/180), 34.65% (35/101) and 47.07% (161/342), respectively. DENV 1 and DENV 3 were dominant serotype during 2008-2010 and 2017-2018 respectively. We have noticed a high prevalence (36.67%, 22/60) of the CHIKV IgG antibody in the 2017-2018 samples. Joint pain was more preferential to CHIKV mono-infection and DENV/CHIKV co-infection compared to DENV mono-infection. The present study highlights the need for active surveillance simultaneously for both DENV and CHIKV and to evaluate the role of CHIKV/DENV co-infections in disease severity in the endemic regions. [ABSTRACT FROM AUTHOR]

CD8 T cells are important tools for protection against intracellularly replicating pathogens such as viruses. Previous studies showed that a discrete population of HLADR and CD38-expressing CD8 T cells expands massively during the acute febrile phase of human dengue virus infection--but very few of these cells secrete IFNγ upon in vitro stimulation with dengue peptides. To gain a better understanding of what other cytokines/chemokines do these massively expanding HLADR+CD38+ CD8 T cells express, we performed RNA seq of sorted HLADR+CD38+ CD8 T cell subsets after peptide stimulation. A majority of these peptide-stimulated HLADR+CD38+ CD8 T cells were CD69- IFNγ-, nearly a third were CD69+ IFNγ-, whereas very few (<10%) were CD69+ IFNγ+. The CD69- IFNγ- subset was enriched for the expression of key genes implicated in the negative regulation of T cell receptor (TCR) signaling and T-cell exhaustion, attraction of B cells and other lymphocytes, and cytokines related to Tc17/T-reg lineages or those that are implicated in immunosuppression/immunomodulatory and anti-inflammatory activities and angiogenesis. The CD69+ IFNγ- subset showed enriched transcription of key genes implicated in cytotoxic effector functions as well as costimulatory and signaling adaptors implicated in fine balancing of T cell receptor signaling. The CD69+ IFNγ+ subset largely shared the transcriptional profile with the CD69+ IFNγsubset--but with relatively more pronounced expression along with additional genes such as chemokines XCL1/XCL2. Our findings showing distinct functional subsets among these massively expanding CD8 T cells in dengue CD8 T cells warrant further studies to carefully examine the precise role of these T cell subsets in protection against dengue. [ABSTRACT FROM AUTHOR]

Summary: Dengue is a major global disease requiring improved treatment and prevention strategies. The recently licensed Sanofi Pasteur Dengvaxia vaccine does not protect children under the age of nine, and additional vaccine strategies are thus needed to halt this expanding global epidemic. Here, we employed a molecular engineering approach and plant expression to produce a humanized and highly immunogenic poly‐immunoglobulin G scaffold (PIGS) fused to the consensus dengue envelope protein III domain (cEDIII). The immunogenicity of this IgG Fc receptor‐targeted vaccine candidate was demonstrated in transgenic mice expressing human FcγRI/CD64, by induction of neutralizing antibodies and evidence of cell‐mediated immunity. Furthermore, these molecules were able to prime immune cells from human adenoid/tonsillar tissue ex vivo as evidenced by antigen‐specific CD4+ and CD8+ T‐cell proliferation, IFN‐γ and antibody production. The purified polymeric fraction of dengue PIGS (D‐PIGS) induced stronger immune activation than the monomeric form, suggesting a more efficient interaction with the low‐affinity Fcγ receptors on antigen‐presenting cells. These results show that the plant‐expressed D‐PIGS have the potential for translation towards a safe and easily scalable single antigen‐based tetravalent dengue vaccine. [ABSTRACT FROM AUTHOR]

Disease caused by Chikungunya virus (CHIKV) is clinically characterized by sudden-onset of fever and severe arthralgia, which may persist for weeks, months, or years after acute phase of the infection. CHIKV is spreading globally; in India it first appeared in the 1960s followed by a quiescent period and then a full-blown remergence in 2006 and sporadic persistence since then. Despite a large number of commercially available diagnostic kits for CHIKV, clinical preparedness and diagnostics suffer from sub-optimal assays. An international diagnostic laboratory survey suggested that there is a critical need for improved CHIKV diagnostics especially in the early acute phase of illness. With the recent studies indicating that a vast majority of human humoral response in CHIKV infection is directed against E2 protein, this supports strong interest to develop CHIKV E2 based serological tests. However, methods to produce large amounts of CHIKV protein are limited. Here we report cloning, expression and purification methods for obtaining a truncated 37 kDa Chikungunya E2 protein at a high yield of 65–70 mg/l. We found that this purified protein can be reliably used in ELISA and western blot to detect CHIKV specific antibodies in sera from patients who were PCR or IgM positive. Thus, using this protocol, laboratories can make large quantities of purified protein that can be potentially used in CHIKV serological analysis. [ABSTRACT FROM AUTHOR]

Plasmablasts represent a specialized class of antibody-secreting effector B cells that transiently appear in blood circulation following infection or vaccination. The expansion of these cells generally tends to be massive in patients with systemic infections such as dengue or Ebola that cause hemorrhagic fever. To gain a detailed understanding of human plasmablast responses beyond antibody expression, here, we performed immunophenotyping and RNA sequencing (RNA-seq) analysis of the plasmablasts from dengue febrile children in India. We found that plasmablasts expressed several adhesion molecules and chemokines or chemokine receptors that are involved in endothelial interactions or homing to inflamed tissues, including skin, mucosa, and intestine, and upregulated the expression of several cytokine genes that are involved in leukocyte extravasation and angiogenesis. These plasmablasts also upregulated the expression of receptors for several B-cell prosurvival cytokines that are known to be induced robustly in systemic viral infections such as dengue, some of which generally tend to be relatively higher in patients manifesting hemorrhage and/or shock than in patients with mild febrile infection. These findings improve our understanding of human plasmablast responses during the acute febrile phase of systemic dengue infection. IMPORTANCE Dengue is globally spreading, with over 100 million clinical cases annually, with symptoms ranging from mild self-limiting febrile illness to more severe and sometimes life-threatening dengue hemorrhagic fever or shock, especially among children. The pathophysiology of dengue is complex and remains poorly understood despite many advances indicating a key role for antibody-dependent enhancement of infection. While serum antibodies have been extensively studied, the characteristics of the early cellular factories responsible for antibody production, i.e., plasmablasts, are only beginning to emerge. This study provides a comprehensive understanding of the transcriptional profiles of human plasmablasts from dengue patients. [ABSTRACT FROM AUTHOR]

• Co-circulation of all four DENV serotypes seen in 2012–2015 dengue outbreaks in southern India. • Genotype GI of DENV-1 replaced GIII in 2014–15, possibly accounting for DENV-1 predominance. • Novel findings include identification of DENV-2 'GIVc' (new lineage), and two clades of DENV-4 GIC. • These genotypic variations may have contributed towards recent dengue outbreaks in southern India. To genotypically characterize dengue virus (DENV) isolates among dengue-infected children from 2012–13/2014–15 outbreaks in southern India. Children hospitalized with suspected dengue were tested for dengue RT-PCR targeting Capsid-preMembrane (C-prM) and Envelope (Env) regions. Following virologic confirmation (n = 612), a representative selection of DENV isolates (n = 99) were sequenced for C-prM , aligned using ClustalW and subjected to phylogenetic analysis by maximum-likelihood method in MEGA6. In 2012–13 (n = 113), DENV-3 (44, 38.9%) and DENV-2 (43, 38.1%) predominated; DENV-1 (22, 19.5%) and DENV-4 (1, 0.9%) were less common. The pattern changed in 2014–15 (n = 499), when DENV-1 (329, 65.7%) predominated, followed by DENV-2 (97, 21.2%), DENV-3 (36, 6.7%) and DENV-4 (10, 2.0%). Multiple-serotype co-infections occurred in 2.7% and 5.4% in 2012–13 and 2014–15, respectively. Genotype III (GIII) of DENV-1 predominated (85.7%) in 2012–13, ceding to GI predominance (80.8%) in 2014–15. Among DENV-2, 71.9% (23/32) showed distinct clustering suggesting a new lineage, 'GIVc'. All tested DENV-4 were GIC, whose clustering pattern showed the emergence of two distinct clades. New genotypic/lineage variations in DENV-1 and DENV-2 may have influenced the magnitude and severity of dengue epidemics in southern India during this period. These findings emphasize the role of active surveillance of DENV serotypes/genotypes in aiding outbreak control and vaccine studies. [ABSTRACT FROM AUTHOR]

Dengue surveillance relies on reverse transcription-polymerase chain reaction (RT-PCR), for confirmation of dengue virus (DENV) serotypes. We compared efficacies of published and modified primer sets targeting envelope ( Env ) and capsid-premembrane ( C-prM ) genes for detection of circulating DENV serotypes in southern India. Acute samples from children with clinically-diagnosed dengue were used for RT-PCR testing. All samples were also subjected to dengue serology (NS1 antigen and anti-dengue-IgM/IgG rapid immunochromatographic assay). Nested RT-PCR was performed on viral RNA using three methods targeting 654 bp C-prM, 511 bp C-prM and 641 bp Env regions, respectively. RT-PCR-positive samples were validated by population sequencing. Among 171 children with suspected dengue, 121 were dengue serology-positive and 50 were dengue serology-negative. Among 121 serology-positives, RT-PCR detected 91 (75.2%) by CprM654, 72 (59.5%) by CprM511, and 74 (61.1%) by Env641 . Among 50 serology-negatives, 10 (20.0%) were detected by CprM654 , 12 (24.0%) by CprM511 , and 11 (22.0%) by Env641 . Overall detection rate using three methods sequentially was 82.6% (100/121) among serology-positive and 40.0% (20/50) among serology-negative samples; 6.6% (8/120) had co-infection with multiple DENV serotypes. We conclude that detection of acute dengue was enhanced by a modified RT-PCR method targeting the 654 bp C-prM region, and further improved by using all three methods sequentially. [ABSTRACT FROM AUTHOR]

The catastrophic rise in dengue infections in India and globally has created a need for an accurate, validated low-cost rapid diagnostic test (RDT) for dengue. We prospectively evaluated the diagnostic performance of NS1/IgM RDT (dengue day 1) using 211 samples from a pediatric dengue cohort representing all 4 serotypes in southern India. The dengue-positive panel consisted of 179 dengue real-time polymerase chain reaction (RT-PCR) positive samples from symptomatic children. The dengue-negative panel consisted of 32 samples from dengue-negative febrile children and asymptomatic individuals that were negative for dengue RT-PCR/NS1 enzyme-linked immunosorbent assay/IgM/IgG. NS1/IgM RDT sensitivity was 89.4% and specificity was 93.8%. The NS1/IgM RDT showed high sensitivity throughout the acute phase of illness, in primary and secondary infections, in different severity groups, and detected all 4 dengue serotypes, including coinfections. This NS1/IgM RDT is a useful point-of-care assay for rapid and reliable diagnosis of acute dengue and an excellent surveillance tool in our battle against dengue. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest that India has the largest number of dengue virus infection cases worldwide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue, because they have been implicated in both protection and immunopathology. Here, we provide a detailed analysis of HLA-DR+ CD38+ and HLA-DR- CD38+ effector CD8 T cell subsets in dengue patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation, tissue homing, and cytotoxic effector functions, with the HLADR + CD38+ subset being the most striking in these effector qualities. The breadth of the dengue-specific CD8 T cell response was diverse, with NS3-specific cells being the most dominant. Interestingly, only a small fraction of these activated effector CD8 T cells produced gamma interferon (IFN-γ) when stimulated with dengue virus peptide pools. Transcriptomics revealed downregulation of key molecules involved in T cell receptor (TCR) signaling. Consistent with this, the majority of these CD8 T cells remained IFN-γ unresponsive even after TCR-dependent polyclonal stimulation (anti-CD3 plus anti-CD28) but produced IFN-γ by TCR-independent polyclonal stimulation (phorbol 12-myristate 13-acetate [PMA] plus ionomycin). Thus, the vast majority of these proliferating, highly differentiated effector CD8 T cells probably acquire TCR refractoriness at the time the patient is experiencing febrile illness that leads to IFN-γ unresponsiveness. Our studies open novel avenues for understanding the mechanisms that fine-tune the balance between CD8 T cell-mediated protective versus pathological effects in dengue. [ABSTRACT FROM AUTHOR]

• We report that co-infections of DENV-CHIKV occurred at a frequency of 6.7% in the transmission cycle. • While DENV-3 is now frequently detected in the Indian subcontinent, we do not see a serotype bias in the patients that are co-infected with ESCA strain of CHIKV. • The effector B cell response (plasmablasts) observed are specific to both infecting viruses indicating no overt bias. With explosive epidemics of chikungunya in India since 2004, chikungunya virus (CHIKV) now co-circulates in geographical areas where Dengue virus (DENV) is already endemic and thus provides opportunity for the same mosquito to be infected with both viruses. Although there are excellent studies that have addressed the clinical of mono and co-infection, we have little to no knowledge on the current viral sequences that pre-dominate co-infections, and the B cell response elicited. In this study, we analyzed febrile patients that were confirmed to have DENV-CHIKV co-infections and asked the following questions: 1) what is the frequency of co-infections found in a single cycle of transmission; 2) what are the viral sequences associated with them; 3) what does the antibody secreting cell / plasmablast response look like in patients that are co-infected with both viruses. We report those co-infections occur at a frequency of 6.7% in the transmission cycle, and while DENV-3 is now frequently detected, we do not see a serotype bias in the patients that are co-infected with ESCA strain of CHIKV. Moreover, the effector B cell response (plasmablasts) observed are specific to both infecting viruses indicating no overt bias. Further studies to associate whether any of these properties have a bearing on clinical disease manifestation will be both timely and important. [ABSTRACT FROM AUTHOR]

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an aberrant inflammatory response occurring in a subset of TB-HIV co-infected patients initiating anti-retroviral therapy (ART). Here, we examined monocyte activation by prospectively quantitating pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients from a South Indian cohort at baseline and following ART initiation at the time of IRIS, or at equivalent time points in non-IRIS controls. Pro-inflammatory biomarkers of innate and myeloid cell activation were increased in plasma of IRIS patients pre-ART and at the time of IRIS; this association was confirmed in a second cohort in South Africa. Increased expression of these markers correlated with elevated antigen load as measured by higher sputum culture grade and shorter duration of anti-TB therapy. Phenotypic analysis revealed the frequency of CD14++CD16− monocytes was an independent predictor of TB-IRIS, and was closely associated with plasma levels of CRP, TNF, IL-6 and tissue factor during IRIS. In addition, production of inflammatory cytokines by monocytes was higher in IRIS patients compared to controls pre-ART. These data point to a major role of mycobacterial antigen load and myeloid cell hyperactivation in the pathogenesis of TB-IRIS, and implicate monocytes and monocyte-derived cytokines as potential targets for TB-IRIS prevention or treatment. [ABSTRACT FROM AUTHOR]

Abstract: Tat, an important regulatory protein of HIV-1, has been implicated in HIV-related pathogenesis. Immune responses to Tat, although underrepresented, confer protection against disease progression, in natural infection and experimental immunization, making Tat an attractive vaccine candidate. Information on immune responses to Tat from India which has the second largest HIV incidence has been lacking. Here we report a cross-sectional study evaluating the humoral response to Tat from a large number of samples from two southern states of India. 14% of the seropositive (63/447) and 4.6% of seronegative samples (7/150) harbored Tat-reactive antibodies. A significant number of the seropositive samples contained high levels of anti-Tat antibodies (31/447) which demonstrated class-switch to IgG1 and bound to Tat with high avidity. Cross-reactivity analysis showed that these antibodies interacted with Tat from different clades with variable degree withthe highest interaction with subtype-AE and the least with subtype-B Tat. Importantly, a B-cell epitope in the cysteine-rich domain was found to be the most immunodominant one and antibodies interacting with this epitope blocked extracellular Tat efficiently. To the best of our knowledge this is the first report on immune responses to Tat from Indian populations and the data presented here could significantly contribute to HIV Tat vaccine design. [Copyright &y& Elsevier]

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. [ABSTRACT FROM AUTHOR]

Immune reconstitution inflammatory syndrome (IRIS) occurs in up to 40% of individuals co-infected with pulmonary tuberculosis (PTB) and HIV, primarily upon antiretroviral therapy (ART) initiation. Phenotypic changes in T-cells during TB-IRIS and their relationship with systemic inflammation are not fully understood. In this prospective cohort study, we followed 48 HIV-positive patients with PTB from South India before and after ART initiation, examining T-lymphocyte subsets and inflammatory biomarkers in peripheral blood. Quantification of naïve (CD27+CD45RO−) as well as effector memory CD4+ T cells (CD27−CD45RO+) at weeks 2-6 after ART initiation could distinguish TB-IRIS from non-IRIS individuals. Additional analyses revealed that ART reconstituted different quantities of CD4+ T lymphocyte subsets with preferential expansion of CXCR3+ CCR6− cells in TB-IRIS patients. Moreover, there was an expansion and functional restoration of central memory (CD27+CD45RO+) CXCR3+CCR6− CD4+ lymphocytes and corresponding cytokines, with reduction in CXCR3−CCR6+ cells after ART initiation only in those who developed TB-IRIS. Together, these observations trace a detailed picture of CD4+ T cell subsets tightly associated with IRIS, which may serve as targets for prophylactic and/or therapeutic interventions in the future. [ABSTRACT FROM AUTHOR]