Human leukocyte antigens class I and class II alleles associated with vertical human immunodeficiency virus transmission - an exploratory study from Mumbai, India.

Background Human leukocyte antigens (HLA) an important host genetic factor is responsible for influencing human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) transmission and disease progression. Contributions of HLA I and II alleles have not been reported in the Indian population with respect to vertical HIV transmission. Aim In the current study we determined the frequencies of HLA class I and class II alleles in a cohort of children exposed to HIV through their mothers. Method In this exploratory study children perinatally exposed to HIV-1 who fit the study criteria and had completed 18 month follow-up were typed for HLA class I and class II alleles using polymerase chain reaction combined with sequence-specific oligonucleotides probes (PCR-SSOP) and sequence-specific primer (SSP) method. HLA typing was done in 30 positive and 60 HIV negative children along with confounding factors such as treatment regimens, viral load and CD4 count of the mother, feeding option, etc. SPSS software was used for statistical analysis and online docking tools for in-silico analysis. Results HLA-B*40 (p = 0.018) was significantly higher in negative children and was associated with protection, whereas HLA-A*01 (p = 0.05), HLA-B*37 (p = 0.032) and HLA-DRB1*09 (p = 0.017) were associated with transmission. Known protective allele HLA-B*27 was only present in negative children. Many specific haplotypes were exclusively present in the negative children or the positive ones. In-silico analysis was performed to predict the ability of HLA-B*40 to bind to antigenic peptides obtained from HIV-1 sequences in our study group. Limitations Small sample size is a concerning limitation of the study. Nonetheless this is a comprehensive study on HLA alleles in HIV exposed Indian children Conclusion Our study highlights the contribution of HLA class I and II alleles in the Indian children and further adds to understanding the immunogenetic mechanisms. These can be developed as markers for prediction of infection transmission. The observations also contribute to the database of genetic makeup of our population and can help in designing vaccine strategies.

The expression of FOXP3 in lesions of several forms of leprosy in patients co-infected with HIV.

BACKGROUND: Brazil remains endemic for infection by the human immunodeficiency virus (HIV) and leprosy, having a major impact on public health and the life quality of affected patients. Although the relevance of this co-infection is recognized, several aspects, such as the immune response, are not yet fully understood. The objective of this study was to investigate the expression of FOXP3+ Treg cells in leprosy skin lesions and to correlate their clinical forms, laboratory characteristics (CD4, CD8, and CV), and the immune reconstitution syndrome in HIV-leprosy co-infection. METHODOLOGY/PRINCIPAL FINDINGS: An observational, cross-sectional, and analytical study was carried out comparing four groups of patients: those with concomitant diagnosis of leprosy and HIV infection without a leprosy reaction, those with leprosy and HIV co-infection patients with a reverse reaction (RR), those with leprosy without HIV and without reaction, and those with leprosywithout HIV and with RR. The patients were diagnosed at a dermatology outpatient clinic located in Belém, Pará, Brazil, from 2003 to 2017. In the sample studied, there was a positive correlation between FOXP3+ cell density and viral load, negative correlation with blood CD4+ (not statistically significant), significant positive correlation in CD8 count in patients with leprosy reaction, and positive relationship in patients with IRIS. The density of cells expressing FOXP3 was higher in the BL/LL forms in patients without HIV, although the difference was not statistically significant. However, the cell mean was higher in the TT/BT forms in patients co-infected with leprosy and HIV, showing contradictory results. CONCLUSIONS/SIGNIFICANCE: These findings support that higher activity of the HIV may stimulate or result in a higher expression of FOXP3-Tregs and that they may be involved in active immunosuppression observed at the infection site at the tissue level. This supports the need to expand studies on FOXP3+ Treg cells in co-infected patients.

Macrophage Polarization in Leprosy-HIV Co-infected Patients.

In HIV-infected individuals, a paradoxical clinical deterioration may occur in preexisting leprosy when highly active antiretroviral therapy (HAART)-associated reversal reaction (RR) develops. Leprosy-HIV co-infected patients during HAART may present a more severe form of the disease (RR/HIV), but the immune mechanisms related to the pathogenesis of leprosy-HIV co-infection remain unknown. Although the adaptive immune responses have been extensively studied in leprosy-HIV co-infected individuals, recent studies have described that innate immune cells may drive the overall immune responses to mycobacterial antigens. Monocytes are critical to the innate immune system and play an important role in several inflammatory conditions associated with chronic infections. In leprosy, different tissue macrophage phenotypes have been associated with the different clinical forms of the disease, but it is not clear how HIV infection modulates the phenotype of innate immune cells (monocytes or macrophages) during leprosy. In the present study, we investigated the phenotype of monocytes and macrophages in leprosy-HIV co-infected individuals, with or without RR. We did not observe differences between the monocyte profiles in the studied groups; however, analysis of gene expression within the skin lesion cells revealed that the RR/HIV group presents a higher expression of macrophage scavenger receptor 1 (MRS1), CD209 molecule (CD209), vascular endothelial growth factor (VEGF), arginase 2 (ARG2), and peroxisome proliferator-activated receptor gamma (PPARG) when compared with the RR group. Our data suggest that different phenotypes of tissue macrophages found in the skin from RR and RR/HIV patients could differentially contribute to the progression of leprosy.

PGL-1 and LID-1 antibody levels in HIV-infected and HIV-uninfected individuals in a Hansen's disease (leprosy) endemic area of Brazil.

Serological tests for subclinical Mycobacterium leprae infection based on antibodies to phenolic glycolipid-1 (PGL-1) and leprosy IDRI diagnostic-1 (LID-1) have not been compared in HIV-infected and uninfected individuals. PGL-1 seropositivity by ELISA was 6.0 % (21/350) in HIV-infected compared with 29.1 % (102/350) in HIV-uninfected individuals (p < 0.001); LID-1 seropositivity was 45.4 % (159/350) in HIV-infected compared with 50.3 % (153/304) in HIV-uninfected individuals (p = 0.21). In HIV-infected individuals, LID-1 but not PGL-1 antibody levels were inversely associated with CD4+ cell count (p = 0.02). These differential associations of HIV infection and CD4 count with PGL-1 and LID-1 have implications for M leprae immunodiagnostic tools and require replication.

Distribution of killer immunoglobulin-like receptor genes in HIV infected long-term non-progressors from Mumbai, India.

BACKGROUND: Few reports suggest the association of killer immunoglobulin-like receptors of natural killer cells with human immunodeficiency virus infection. India with world's third largest population of human immunodeficiency virus / acquired immunodeficiency syndrome, offers scope to study such association. OBJECTIVE: Current study (2010-2015) was designed to evaluate if killer immunoglobulin-like receptors gene polymorphisms are associated with HIV infection outcomes specifically, with long term non progressors. METHODS: Killer immunoglobulin-like receptors genotyping was done using polymerase chain reaction - sequence-specific primer method. Viral load was measured by Cobas Taqman HIV-1 test. Estimation of CD4 counts was done using BD FACS CD4 count reagent. RESULTS: The activating gene frequencies identified were 3DS1 (53.8%), 2DS3 (69.2%), 2DS4 (76.9%), 2DS5 (69.2%), 2DS1 (76.9%) and 2DS2 (92.3%). The inhibitory gene frequencies were 2DL2 (92.3%), 2DL5 (76.9%), 2DL3 (69.5%), 3DL1 (84.6%), 3DL2 (92.3%) and 2DL1 (100%). The results highlight high frequency of 3DS1/3DL1 heterozygote and killer immunoglobulin-like receptor 2DS1, among these long term non progressors indicating their possible association with slow progression. Genotype analysis shows total 13 genotypes, of which 8 genotypes were identified for the first time from India. Two genotypes were unique/novel, which were unreported. All genotypes observed in this study were considered to be Bx genotype (100 %). LIMITATIONS: A small sample size (n=13, due to a rare cohort) and the absence of control group were the limitations of this study. CONCLUSIONS: The present study highlights the distribution of killer immunoglobulin-like receptor genes in a very rare group of human immunodeficiency virus -1 infected individuals - long term non progressors. All the long term non progressors tested show the presence of Bx haplotype and each long term non progressors has a different killer immunoglobulin-like receptor genotype.

New Players in the Same Old Game: Disturbance of Group 2 Innate Lymphoid Cells in HIV-1 and Mycobacterium leprae Co-infected Patients.

Leprosy control is achieved through a fine-tuning of TH1 and TH2 immune response pattern balance. Given the increasing epidemiological overlay of HIV and M. leprae infections, immune response in co-infected patients consists in an important contemporary issue. Here we describe for the first time the innate lymphoid cells compartment in peripheral blood of leprosy and HIV/M. leprae co-infected patients, and show that co-infection increases group 2 innate lymphoid whilst decreasing group 1 innate lymphoid cells frequencies and function.

Viral Co-infection and Leprosy Outcomes: A Cohort Study.

BACKGROUND: The role of the host immunity in determining leprosy clinical forms and complications is well recognized, implying that changes in the immune status may interfere with several aspects of the disease. Therefore, we hypothesized that the presence of viral co-infections and associated immunological changes will have a clinical impact on leprosy outcomes. The aim of our study was to determine the clinical impact of human immunodeficiency virus (HIV), human T cell lymphotrophic virus type 1 (HTLV-1), hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infection on the development of reactions, neuritis, neuropathy and relapses. METHODOLOGY/PRINCIPAL FINDINGS: Cohort study in 245 leprosy subjects from Bahia, Brazil. Patients were followed from the time of diagnosis until at least the end of multidrug therapy. Viral co-infection was detected in 36 out of the 245 patients (14.7%). Specific co-infection rates were 10.6% for HBV, 2.9% for HIV, 2.5% for HTLV-1 and 0.8% for HCV. All four groups of co-infected patients had higher rates of neuritis and nerve function impairment compared to non co-infected leprosy subjects. The relapse rate was also higher in the co-infected group (8.3%) versus patients without co-infection (1.9%); relative risk 4.37, 95% confidence interval 1.02-18.74. CONCLUSIONS/SIGNIFICANCE: Leprosy patients should be screened for HBV, HCV, HIV and HTLV-1 co-infections. Besides contributing to better health care, this measure will facilitate the early detection of severe complications through targeting of higher risk patients.

No association of cryptococcal antigenemia with poor outcomes among antiretroviral therapy-experienced HIV-infected patients in Addis Ababa, Ethiopia.

INTRODUCTION: There are limited data on clinical outcomes of ART-experienced patients with cryptococcal antigenemia. We assessed clinical outcomes of a predominantly asymptomatic, ART-experienced cohort of HIV+ patients previously found to have a high (8.4%) prevalence of cryptococcal antigenemia. METHODS: The study took place at All Africa Leprosy, Tuberculosis and Rehabilitative Training Centre and Black Lion Hospital HIV Clinics in Addis Ababa, Ethiopia. A retrospective study design was used to perform 12-month follow-up of 367 mostly asymptomatic HIV-infected patients (CD4<200 cells/µl) with high levels of antiretroviral therapy use (74%) who were previously screened for cryptococcal antigenemia. Medical chart abstraction was performed approximately one year after initial screening to obtain data on clinic visit history, ART use, CD4 count, opportunistic infections, and patient outcome. We evaluated the association of cryptococcal antigenemia and a composite poor outcome of death and loss to follow-up using logistic regression. RESULTS: Overall, 323 (88%) patients were alive, 8 (2%) dead, and 36 (10%) lost to follow-up. Among the 31 patients with a positive cryptococcal antigen test (titers ≥1∶8) at baseline, 28 were alive (all titers ≤1∶512), 1 dead and 2 lost to follow-up (titers ≥1∶1024). In multivariate analysis, cryptococcal antigenemia was not predictive of a poor outcome (aOR = 1.3, 95% CI 0.3-4.8). A baseline CD4 count <100 cells/µl was associated with an increased risk of a poor outcome (aOR 3.0, 95% CI 1.4-6.7) while an increasing CD4 count (aOR 0.1, 95% CI 0.1-0.3) and receiving antiretroviral therapy at last follow-up visit (aOR 0.1, 95% CI 0.02-0.2) were associated with a reduced risk of a poor outcome. CONCLUSIONS: Unlike prior ART-naïve cohorts, we found that among persons receiving ART and with CD4 counts <200 cells/µl, asymptomatic cryptococcal antigenemia was not predictive of a poor outcome.

Murabutide revisited: a review of its pleiotropic biological effects.

Despite the great efforts put into their development, the list of clinically approved immunological adjuvants is still very short. Evolution of the knowledge of the immune system has enabled for rational design of novel adjuvants and has led to the conclusion that more than one type of adjuvant will be required. Derivatives of muramyl dipeptide (MDP), the minimal immunomodulatory structure of bacterial cell wall peptidoglycan, have gained considerable attention in the past decades, because of their potent adjuvant effects. Murabutide is a safe derivative of MDP, which interacts with cells of the immune system, both innate and adaptive, and exerts its effect through activation of Nod2. The transcriptional response of murabutide-stimulated macrophages revealed enhanced expression of genes coding for various proteins such as immune mediators and their receptors, transcription factors and kinases, ion channels/transporters and proteins involved in cell metabolic activity, thus reflecting a broad spectrum of biological effects. In addition to its well recognized adjuvant effect, murabutide has also been shown to enhance the host's resistance against microbial infections, nonspecific resistance against tumors and the induction of cytokines and chemokines implicated in enhancing the immune response and hematopoesis. This article provides an insight into the mechanism of action of murabutide and its interactions with the cells of the immune system in vitro and in vivo. On account of its numerous biological effects, murabutide has been the subject of several clinical studies. Many of these have confirmed its potential to synergize with cytokines of therapeutic interest in potentiating the tumoricidal activity of macrophages or targeting chronic viral diseases, as well as reducing the cytokine dosage needed to achieve a therapeutic effect. This review covers the findings of all relevant studies and focuses on the role of murabutide and its potential in the treatment of several microbial diseases.

Lower numbers of natural killer T cells in HIV-1 and Mycobacterium leprae co-infected patients.

Natural killer T (NKT) cells are a heterogeneous population of lymphocytes that recognize antigens presented by CD1d and have attracted attention because of their potential role linking innate and adaptive immune responses. Peripheral NKT cells display a memory-activated phenotype and can rapidly secrete large amounts of pro-inflammatory cytokines upon antigenic activation. In this study, we evaluated NKT cells in the context of patients co-infected with HIV-1 and Mycobacterium leprae. The volunteers were enrolled into four groups: 22 healthy controls, 23 HIV-1-infected patients, 20 patients with leprosy and 17 patients with leprosy and HIV-1-infection. Flow cytometry and ELISPOT assays were performed on peripheral blood mononuclear cells. We demonstrated that patients co-infected with HIV-1 and M. leprae have significantly lower NKT cell frequencies [median 0.022%, interquartile range (IQR): 0.007-0.051] in the peripheral blood when compared with healthy subjects (median 0.077%, IQR: 0.032-0.405, P < 0.01) or HIV-1 mono-infected patients (median 0.072%, IQR: 0.030-0.160, P < 0.05). Also, more NKT cells from co-infected patients secreted interferon-γ after stimulation with DimerX, when compared with leprosy mono-infected patients (P = 0.05). These results suggest that NKT cells are decreased in frequency in HIV-1 and M. leprae co-infected patients compared with HIV-1 mono-infected patients alone, but are at a more activated state. Innate immunity in human subjects is strongly influenced by their spectrum of chronic infections, and in HIV-1-infected subjects, a concurrent mycobacterial infection probably hyper-activates and lowers circulating NKT cell numbers.

Type 2 lepra reaction with HIV1 co-infection: a case report with interesting management implications.

A patient co-infected with leprosy and Human Immunodeficiency Virus (HIV)-type 1 who developed type 2 lepra reaction in the absence of antiretroviral therapy is presented. The reaction responded only after initiating anti retroviral therapy (ART) despite normal CD4+ counts. The present report suggests that type 2 reactions in leprosy and HIV co-infected patients may not always be the typical manifestation of immune reconstitution inflammatory syndrome (IRIS) and stresses the importance of considering concomitant HIV infection in refractory lepra reactions. Extensive research is required into the manifestations of HIV in leprosy patients.

Post-kala-azar dermal leishmaniasis (PKDL), HIV and pulmonary tuberculosis.

Post-kala-azar dermal leishmaniasis is usually a sequel to visceral leishmaniasis. A 25-year-old woman presented with hypopigmented maculopapular lesions all over the body for the past 4 years without any previous history of visceral leishmaniasis. She was on treatment for leprosy and pulmonary tuberculosis for the past 2 months, but did not show any improvement. Investigations confirmed that she had post-kala-azar dermal leishmaniasis associated with pulmonary tuberculosis and HIV-1 infection. She was started on treatment for the triad of diseases, and showed improvement.

Atypical presentation of leprosy in HIV.

Atypical presentations can be expected when leprosy, a mycobacterial disease is associated with HIV. We report a case of a 28 year old male driver with a high risk behavior, who came for evaluation of hypoaesthetic, scaly erythematous plaques over face, trunk, upper extremity; verrucous lesions over elbows and necrotic lesions over the neck and lower extremities since 6 months. No other systemic complaints were present. Nerve examination showed grossly thickened left greater auricular nerve and cord like thickening of bilateral ulnar and lateral popliteal nerves. His investigations revealed anemia, a reactive ELISA for HIV-1 and CD4 of 400 cell/cmm. Ultrasonography of the thickened nerves revealed an abscess in the left ulnar nerve whereas the left greater auricular nerve showed neuritis. Histopathology from an erythematous plaque was suggestive of borderline tuberculoid leprosy in reaction. Final diagnosis was borderline tuberculoid leprosy in type 1 reaction with atypical and varied morphology in an immunocompromised male with neuritis of the left greater auricular nerve, a silent left ulnar nerve abscess with early left ulnar nerve palsy. Our case highlights the atypical morphology of leprosy lesions and the unexpected protective cellular response as suggested by formation of nerve abscess in a HIV positive patient.

Kaposi's sarcoma: a presenting manifestation of HIV infection in an Indian.

Kaposi's sarcoma (KS) is a multifocal neoplastic proliferation of endothelial cells predominantly involving skin and other organs. HIV-associated Kaposi's sarcoma has been rarely reported from India. A 38-year-old male presented with persistent swelling on the left lower limb for one year along with multiple erythematous to dusky papules and plaques of one and half months duration and swelling and black discoloration of right lower limb for one month. Cutaneous examination revealed numerous skin colored and erythematous papules and plaques distributed on the left lower limb on the anteromedial aspect and verrucous plaque on the left sole. Multiple erythematous, grouped papules were present over the soft palate. Skin biopsy showed numerous slit like spaces dissecting into the collagen of the upper and mid-dermis along with 'promontory sign' suggestive of Kaposi's sarcoma. Patient was found to be HIV-positive by ELISA test.