Anaemia in acute HIV-1 subtype C infection

Background

The high prevalence of anaemia and the increased morbidity and mortality associated with anaemia during AIDS has been well described yet there has been little information about anaemia and changes in haemoglobin levels during acute and early HIV-1 infection.

Methods

HIV-negative women (n = 245) were enrolled into an observational cohort as part of the Centre for the AIDS Programme of Research in South Africa (CAPRISA) Acute Infection Study. Acute infection was diagnosed following a positive HIV RNA PCR in the absence of antibodies, or detection of HIV-1 antibodies within 3 months of a previously negative antibody test. Haemotologic parameters were assessed before infection and at regular intervals in the first twelve months of HIV infection.

Results

Fifty-seven participants with acute HIV infection were identified at a median of 14.5 days post-infection (range 10–81) and were enrolled in the CAPRISA Acute Infection cohort at a median of 41 days post-infection (range 15–104). Mean haemoglobin prior to HIV-1 infection was 12.7 g/dL, with a mean decline of 0.46 g/dL following infection. The prevalence of anaemia increased from 25.0% prior to HIV-1 infection to 52.6% at 3 months post-infection, 61.1% at 6 months post-infection, and 51.4% at 12 months post-infection.

Conclusions

Haematologic derangements and anaemia with a trend towards iron deficiency are common with acute HIV-1 subtype C infection in this small cohort. The negative impact of anaemia concurrent with established HIV infection upon morbidity and mortality has been well documented but the prognostic potential and long-term effects of anaemia during acute HIV-1 infection remain unknown.     

IL-17 and Th17 cells in human inflammatory diseases

IL-17 was discovered in 1995/96 as a T cell derived cytokine with effects on inflammation and neutrophil activation. In 2006, the precise cell source of IL-17 was identified in the mouse, and these cells were named Th17 cells. They play a role in various human diseases associated with inflammation and destruction such as rheumatoid arthritis, psoriasis, Crohn's disease, multiple sclerosis, where IL-17 can be seen as a therapeutic target.     

Th17细胞在衣原体感染中的作用研究

衣原体是一类专性细胞内寄生的原核细胞型微生物,是感染人和动物常见的病原体之一,能够引起人和动物的多种疾病。近年来的研究表明,Th17细胞可能通过多种途径,在衣原体的免疫机制中发挥重要作用。虽然Th17细胞的生物学特征及其在炎症和自身免疫疾病的功能研究很多,但Th17细胞在衣原体感染中的作用机制尚不完全清楚,本文仅就对Th17细胞在衣原体感染中的诱导、发生、发育、分化等机制和免疫调节效应的研究进展予以简要综述。     

Human Th17 cells in infection and autoimmunity

IL-17-producing T cells (Th17) have been identified in mice as a distinct lineage of CD4⁺ T helper cells. Since their discovery, efforts have been made in characterizing human Th17 cells and the factors involved in their differentiation and in understanding the role these cells play in protective immunity and autoimmune diseases.     

Immune regulation of bone loss by Th17 cells

A significant macrophage and T-cell infiltrate commonly occurs in inflammatory joint conditions such as rheumatoid arthritis that have significant bone destruction. Cytokines produced by activated macrophages and T cells are implicated in arthritis pathogenesis and are involved in osteoclast-mediated bone resorption. The scope of the present review is to analyze current knowledge and to provide a better understanding of how macrophage-derived factors promote the differentiation of a novel T-helper subset (Th17) that promotes osteoclast formation and activation.     

Changed activation of HIV-1 LTR in monocytoid cells by mycobacteria with temporal progression of infection

Coincubation of monocytoid cell line U937 cells cotransfected with HIV-1 LTR CAT plasmid and Tat expression plasmid, with Mycobacterium smegmatis, M. avium, M. bovis BCG and M. tuberculosis enhanced chloramphenicol acetyltransferase (CAT) production, indicating that these mycobacteria could activate the LTR in this cell line. The amount of CAT in the cells coincubated with M. smegmatis was higher than that infected with the other mycobacteria after 12, 24 and 48 hour time periods. However, the amount of CAT production in the cells cocultured with M. tuberculosis was higher than those coincubated with the other mycobacteria at 72 hours. These findings indicated that avirulent mycobacteria such as M. smegmatis may activate HIV replication at an early time and its effects are gradually decreased, while the effect of virulent M. tuberculosis increased gradually, and lasted for a long time resulting in an acceleration of HIV disease in patients.     

Origin and dynamics of HIV-1 subtype C infection in India

Objective

To investigate the geographical origin and evolution dynamics of HIV-1 subtype C infection in India.

Design

Ninety HIV-1 subtype C env gp120 subtype C sequences from India were compared with 312 env gp120 reference subtype C sequences from 27 different countries obtained from Los Alamos HIV database. All the HIV-1 subtype C env gp120 sequences from India were used for the geographical origin analysis and 61 subtype C env gp120 sequences with known sampling year (from 1991 to 2008) were employed to determine the origin of HIV infection in India.

Methods

Phylogenetic analysis of HIV-1 env sequences was used to investigate the geographical origin and tMRCA of Indian HIV-1 subtype C. Evolutionary parameters including origin date and demographic growth patterns of Indian subtype C were estimated using a Bayesian coalescent-based approach under relaxed molecular clock models.

Findings

The majority of the analyzed Indian and South African HIV-1 subtype C sequences formed a single monophyletic cluster. The most recent common ancestor date was calculated to be 1975.56 (95% HPD, 1968.78–1981.52). Reconstruction of the effective population size revealed three phases of epidemic growth: an initial slow growth, followed by exponential growth, and then a plateau phase approaching present time. Stabilization of the epidemic growth phase correlated with the foundation of National AIDS Control Organization in India.

Interpretation

Indian subtype C originated from a single South African lineage in the middle of 1970s. The current study emphasizes not only the utility of HIV-1 sequence data for epidemiological studies but more notably highlights the effectiveness of community or government intervention strategies in controlling the trend of the epidemic.     

NKT cells in HIV-1 infection

Natural killer T （NKT） cells are a unique T cell population that have important immunoregulatory functions and have been shown to be involved in host immunity against a range of microorganisms. It also emerges that they might play a role in HIV-1 infection, and therefore be selectively depleted during the early stages of infection. Recent studies are reviewed regarding the dynamics of NKT depletion during HIV-1 infection and their recovery under highly active antiretroviral treatment （HAART）. Possible mechanisms for these changes are proposed based on the recent developments in HIV pathogenesis. Further discussions are focused on HIV＇s disruption of NKT activation by downregulating CDld expression on antigen presentation cells （APC）. HIV-1 protein Nefis found to play the major role by interrupting the intracellular trafficking of nascent and recycling CDld molecules.     

Virus phenotype switching and disease progression in HIV-1 infection

One of the phenotypic distinctions between different strains of human immunodeficiency virus type 1 (HIV-1) has to do with the ability to cause target cells to form large multinucleate bodies known as syncytia. There are two phenotypes according to this characterization: syncytium-inducing (SI) and non-syncytium-inducing (NSI). NSI strains are usually present throughout infection, while SI strains are typically seen at the beginning of the infection and near the onset of AIDS. The late emergence of SI strains is referred to as phenotype switching. In this paper we analyse the factors that lead to phenotype switching and contribute to the dynamics of disease progression. We show that a strong immune system selects for NSI strains while a weak immune system favours SI strains. The model explicitly accounts for the fact that CD4+ cells are both targets of HIV infection and crucial for activating immune responses against HIV In such a model, SI strains can emerge after a long and variable period of NSI dominated infection. Furthermore, versions of the model which do not explicitly account for HIV-specific, activated CD4+ cells do not exhibit phenotype switching, emphasizing the critical importance of this pool of cells.     

Influence of Gag-protease-mediated replication capacity on disease progression in individuals recently infected with HIV-1 subtype C

HLA class I-mediated selection of immune escape mutations in functionally important Gag epitopes may partly explain slower disease progression in HIV-1-infected individuals with protective HLA alleles. To investigate the impact of Gag function on disease progression, the replication capacities of viruses encoding Gag-protease from 60 individuals in early HIV-1 subtype C infection were assayed in an HIV-1-inducible green fluorescent protein reporter cell line and were correlated with subsequent disease progression. Replication capacities did not correlate with viral load set points (P = 0.37) but were significantly lower in individuals with below-median viral load set points (P = 0.03), and there was a trend of correlation between lower replication capacities and lower rates of CD4 decline (P = 0.09). Overall, the proportion of host HLA-specific Gag polymorphisms in or adjacent to epitopes was negatively associated with replication capacities (P = 0.04), but host HLA-B-specific polymorphisms were associated with higher viral load set points (P = 0.01). Further, polymorphisms associated with host-specific protective HLA alleles were linked with higher viral load set points (P = 0.03). These data suggest that transmission or early HLA-driven selection of Gag polymorphisms results in reduced early cytotoxic T-lymphocyte (CTL) responses and higher viral load set points. In support of the former, 46% of individuals with nonprotective alleles harbored a Gag polymorphism exclusively associated with a protective HLA allele, indicating a high rate of their transmission in sub-Saharan Africa. Overall, HIV disease progression is likely to be affected by the ability to mount effective Gag CTL responses as well as the replication capacity of the transmitted virus.     

Th1 and th2 responses, HIV-1 coreceptors, and HIV-1 infection.

The Th1/Th2 model provides an interesting paradigm for understanding several pathophysiological processes and possibly for developing new immunotherapeutical strategies. In HIV-1 infection the interaction between the type of HIV-1 strain and the pathway of the ongoing T-cell effector response, despite its complexity, may represent one of the crucial mechanisms in determining the outcome of virus infection. While the possibility of an HIV-1-driven Th1 to Th2 switch of the immune response is still debated, evidence is accumulating to suggest that cytokines produced during an immune response can contribute to promote a selective pressure toward the evolution of HIV-1 viral strains with different tropism. This article summarizes the results of our recent studies in which the expression of CCR5 and CXCR4 HIV-1 co-receptors, as well as the activity of R5- or X4- tropic strains of HIV-1 in different in vitro models of Th1/Th2 polarization was analyzed.     

Th1 and Th17 cells regulate innate immune responses and bacterial clearance during central nervous system infection

Brain abscesses arise following parenchymal infection with pyogenic bacteria and are typified by inflammation and edema, which frequently results in a multitude of long-term health problems. The impact of adaptive immunity in shaping continued innate responses during late-stage brain abscess formation is not known but is important, because robust innate immunity is required for effective bacterial clearance. To address this issue, brain abscesses were induced in TCR αβ knockout (KO) mice, because CD4(+) and NKT cells represented the most numerous T cell infiltrates. TCR αβ KO mice exhibited impaired bacterial clearance during later stages of infection, which was associated with alterations in neutrophil and macrophage recruitment, as well as perturbations in cytokine/chemokine expression. Adoptive transfer of either Th1 or Th17 cells into TCR αβ KO mice restored bacterial burdens and innate immune cell infiltrates to levels detected in wild-type animals. Interestingly, adoptively transferred Th17 cells demonstrated plasticity within the CNS compartment and induced distinct cytokine secretion profiles in abscess-associated microglia and macrophages compared with Th1 transfer. Collectively, these studies identified an amplification loop for Th1 and Th17 cells in shaping established innate responses during CNS infection to maximize bacterial clearance and differentially regulate microglial and macrophage secretory profiles.     

Direct correlation between Th1 and Th17 responses in immunity to Brucella infection

Th1 cells play a central role in immunity to brucellosis, while the exact role of Th17 cells has remained unknown. This study aimed to evaluate the peripheral distributions of Th1 and Th17 cells and serum levels of IFN-γ, IL-17A and IL-22 cytokines in brucellosis patients. One hundred patients (36 acute, 41 under-treatment and 23 relapsed) and 30 age- and sex-matched healthy controls were included. The frequencies of Th1 and Th17 cells were determined by flow cytometric analysis. Serum levels of IFN-γ, IL-17A and IL-22 were measured by multi-analyte flow assay. Increased frequencies of Th1 and Th17 cells were observed in acute and relapsed brucellosis versus under-treatment patients and healthy controls (P < 0.05). The mean serum levels of IFN-γ were significantly elevated in acute and relapsed groups compared to under-treatment patients (P = 0.002 and P = 0.01 respectively). Acute patients showed higher levels of IL-22 than under-treatment (P = 0.008). Direct correlations were found between increased frequencies of Th1 and Th17 cells in acute and relapsed patients (P = 0.007 and P = 0.001 respectively) and between IL-17A and IL-22 in both groups of patients. Our findings indicate a cooperative role for Th1 and Th17 cells in immunity to brucellosis which is more evident during acute and relapse phases of brucellosis.     

Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus

Introduction  

Interleukin (IL)-17 is a proinflammatory cytokine that is produced largely by a unique CD4⁺ T-helper (Th) subset called Th17 cells. The development of Th17 cells is suppressed by interferon (IFN)-γ produced by Th1 cells, suggesting cross-regulation between Th17 and Th1 cells. Thus, this study analyzed the balance of CD4⁺ Th17 and Th1 cell responses in peripheral blood from patients with systemic lupus erythematosus (SLE) and healthy subjects.