Evaluation of antiviral T cell responses and TSCM cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India.

T cells play an important role in controlling viral replication during HIV infection. An effective vaccine should, therefore, lead to the induction of a strong and early viral-specific CD8+ T cell response. While polyfunctional T cell responses are thought to be important contributors to the antiviral response, there is evidence to show that polyfunctional HIV- specific CD8+ T cells are just a small fraction of the total HIV-specific CD8+ T cells and may be absent in many individuals who control HIV replication, suggesting that other HIV-1 specific CD8+ effector T cell subsets may be key players in HIV control. Stem cell-like memory T cells (TSCM) are a subset of T cells with a long half-life and self-renewal capacity. They serve as key reservoirs for HIV and contribute a significant barrier to HIV eradication. The present study evaluated vaccine-induced antiviral responses and TSCM cells in volunteers vaccinated with a subtype C prophylactic HIV-1 vaccine candidate administered in a prime-boost regimen. We found that ADVAX DNA prime followed by MVA boost induced significantly more peripheral CD8+ TSCM cells and higher levels of CD8+ T cell-mediated inhibition of replication of different HIV-1 clades as compared to MVA alone and placebo. These findings are novel and provide encouraging evidence to demonstrate the induction of TSCM and cytotoxic immune responses by a subtype C HIV-1 prophylactic vaccine administered using a prime-boost strategy.

Author Correction: Differential expression of CXCR3 and CCR6 on CD4+ T-lymphocytes with distinct memory phenotypes characterizes tuberculosis-associated immune reconstitution inflammatory syndrome.

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.

Differential expression of CXCR3 and CCR6 on CD4+ T-lymphocytes with distinct memory phenotypes characterizes tuberculosis-associated immune reconstitution inflammatory syndrome.

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.

HIV-infected patients retreated for tuberculosis with intermittent Category II regimen--treatment outcome at 24-month follow-up.

BACKGROUND: The management of tuberculosis re-treatment in HIV-infected individuals is complex. The clinical and radiological manifestations in this group and response to Category II treatment is not well described. METHODS: We performed a prospective cohort study of HIV-infected patients retreated for TB due to failure, relapse or default after treatment, at Tuberculosis Research Centre, Chennai, between February 2001 to September 2005. The Category II regimen followed in the TB programme in India (RNTCP) was administered (2 months of Streptomycin (S), Ethambutol (E), INH (H), Rifampicin (R), Pyrazinamide (Z)/1 month of EHRZ/5 months of HRE all given thrice weekly). Antiretroviral treatment was not routinely available at that time. RESULTS: Of the 42 patients enrolled, 35 (83%) were males. The mean age was 33.2 (SD-6.3) years. Cough was the commonest (67%) presenting symptom and opacities were the commonest (48%) radiographic occurrence. 31 patients were culture-positive at baseline, drug susceptibility results showed that 21 (68%) were fully susceptible to all first line drugs, four patients (13%) had MDR TB and four had resistance to INH alone. Among the 31 culture-positive patients, 15 patients (48.4%) completed treatment and were declared cured, of whom two subsequently relapsed. All four MDR patients died. Six patients who received ART, survived. CONCLUSION: Only 50% of HIV-infected, ART-naive patients who were retreated for tuberculosis using an intermittent Category II regimen had a favourable response to treatment. Early detection of MDRTB and concurrent antiretroviral therapy could contribute to improved outcomes.

Acquired alpha 1-antitrypsin deficiency in tropical pulmonary eosinophilia.

BACKGROUND & OBJECTIVES: Observation of an increased frequency of an intermediate deficiency of serum alpha1-antitrypsin (α1-AT) in patients with Tropical Pulmonary Eosinophilia (TPE) was earlier reported. Though the possibility of existence of an acquired deficiency was suggested, without phenotyping a hereditary α1-AT deficiency in TPE could not totally be ruled out. In this study, we have done Pi (Protease inhibitor) phenotyping to investigate the possibility of association of any heterozygous (or homozygous) α1-AT deficiency in patients with TPE. METHODS: Serum a1antitrypsin (α1-AT) was measured in 103 patients (Group A) with TPE, 99 patients with pulmonary eosinophilia who had associated intestinal worm infestation (Group B) and 43 healthy volunteers who served as controls. In 19 α1-AT deficient patients (9 of Group A and 10 of Group B), α1-AT level was measured before and after treatment. In 58 patients with TPE and in 5 controls, phenotyping was done. RESULTS: Fifteen patients of Group A and 16 from Group B showed intermediate α1-AT deficiency (150 mg % or less. None of the control subjects had α1-AT deficiency (<200 mg%). After treatment with DEC and/or deworming, in 19 patients there was a significant (P < 0.001) rise in α1-AT levels. Results of phenotyping showed that all had M1 or M 2 allele and none had S or Z variant (either homozygous or heterozygous) thus ruling out any underlying genetic cause for the observed α1-AT deficiency. INTERPRETATION & CONCLUSIONS: The observed α1-AT deficiency may be due to the chronic inflammation in TPE and associated oxidative stress. However, in such α1-AT deficient patients with TPE and those with worm infested pulmonary eosinophilia, faecal α1-AT concentration and faecal α1-AT clearance should be routinely estimated to rule out the possibility of any intestinal protein loss.

Serum C3d levels in tropical pulmonary eosinophilia.

BACKGROUND & OBJECTIVES: Results of earlier studies to evaluate the possible role of complement system in tropical pulmonary eosinophilia (TPE) using classical methods like serum haemolyte component CH50, C3 and C4 levels were inconclusive. In this study we determined levels of serum C3d which is a catabolic fragment of C3, to find out any direct evidence of activation of the complement system in TPE. METHODS: The study population consisted of 3 groups. Group A consisted of 37 patients with well characterized TPE. In group B, 26 patients with pulmonary eosinophilia had similar respiratory and haemotological features as in Group A but had associated worm infestation in stool. The control group consisted of 39 healthy volunteers. Serum C3d levels were determined by sandwich ELISA technique. RESULTS: The serum C3d levels in TPE patients were not significantly different from those of the patients of group B or the normal controls. INTERPRETATION & CONCLUSIONS: Absence of significant change in serum C3d goes against the possibility of complement activation in TPE. Results of our study suggest that complement system is unlikely to play a pivotal role in pathogenesis of TPE.

Pharmacokinetics of lamivudine & stavudine in generic fixed-dose combinations in HIV-1 infected adults in India.

BACKGROUND & OBJECTIVES: Antiretroviral drug concentrations are important determinants of clinical response to a drug accounting for both toxicity and efficacy. Several factors such as age, ethnicity, body weight and patients' immune status may influence antiretroviral drug concentrations. The aim of the study was to determine the influence of immunological status, sex and body mass index on the steady state pharmacokinetics of lamivudine (3TC) and stavudine (d4T) in HIV-infected adults, who were undergoing treatment with generic fixed dose combinations (FDC) of these drugs in India. METHODS: Twenty seven HIV-1 infected patients receiving antiretroviral treatment (ART) for at least two weeks at the Government ART clinic at Tambaram, Chennai, took part in the study. Serial blood samples were collected predosing and at different time points after drug administration. Plasma 3TC and d4T levels were estimated by HPLC. RESULTS: The patients' immune status, sex or body mass index had no impact on the pharmacokinetics of 3TC. In the case of d4T, peak concentration was significantly lower in patients with CD4 cell counts < 200 cells/microl than those with > or = 200 cells/ microl (P < 0.05), but were within the therapeutic range. The mean CD4 cell counts increased from 101 cells/microl at initiation of ART to 366 cells/microl at 12 months of treatment. INTERPRETATION & CONCLUSIONS: Blood levels of 3TC and d4T drugs that are part of generic FDCs commonly used by HIV-infected individuals in India were within the therapeutic range and not influenced by nutritional or immune status. There was a significant improvement in CD4 cell counts over 12 months of treatment. Indian generic FDCs manufactured and used widely in the developing world provide effective concentrations of antiretroviral drugs.

Incomplete immunological recovery following anti-tuberculosis treatment in HIV-infected individuals with active tuberculosis.

BACKGROUND & OBJECTIVE: 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 (beta2M) and soluble tumour necrosis factor alpha receptor type I (sTNFalpha-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

Steady-State Pharmacokinetics of Nevirapine in HIV-1 Infected Adults in India.

BACKGROUND AND OBJECTIVES: A variety of demographic factors, sex, and degree of immunosuppression can influence antiretroviral drug concentrations. The authors studied the influence of immune status, sex, and body mass index (BMI) on the steady-state pharmacokinetics of nevirapine delivered as a fixed-dose combination in HIV-1-infected patients in India. METHODS: Twenty-six HIV-1-infected adult patients undergoing treatment with nevirapine-based highly active antiretroviral therapy regimens participated in the study. Pharmacokinetic variables were compared between patients divided based on CD4 cell counts, sex, and BMI. RESULTS: Patients with higher BMI had lower peak and trough concentration and exposure of nevirapine than those with lower BMI; none of the differences in the pharmacokinetic variables of nevirapine between the various patient groups was statistically significant. CONCLUSIONS: Patients' immune status, sex, or BMI had no impact on the pharmacokinetics of nevirapine. Plasma nevirapine concentrations were maintained within the therapeutic range of the drug in the majority of the patients.

Short communication: Influence of active tuberculosis on chemokine and chemokine receptor expression in HIV-infected persons.

Tuberculosis (TB) is the major opportunistic infection of HIV-1-infected patients in developing countries. Concurrent infection with TB results in immune cells having enhanced susceptibility to HIV-1 infection, which facilitates entry and replication of the virus. Cumulative data from earlier studies indicate that TB provides a milieu of continuous cellular activation and irregularities in cytokine and chemokine circuits that favor viral replication and disease progression. To better understand the interaction of the host with HIV-1 during active tuberculosis, we investigated in vivo expression of the HIV-1 coreceptors, CCR5 and CXCR4, and circulating levels of the inhibitory beta-chemokines, macrophage inflammatory protein-1-alpha (MIP-1alpha), macrophage inflammatory protein-1-beta (MIP-1beta), and regulated upon activation T cell expressed and secreted (RANTES), in HIV-positive individuals with and without active pulmonary tuberculosis. We found a significant decrease from normal in the fraction of CD4+ T cells expressing CCR5 and CXCR4 in individuals infected with HIV. However, CCR5 and CXCR4 expression did not differ significantly between HIV patients with and without tuberculosis. Higher amounts of MIP-1alpha, MIP-1beta, and RANTES were detected in plasma of HIV-1-positive individuals, particularly those with dual infection, although the increase was not found to be statistically significant.