Immune reconstitution inflammatory syndrome in association with HIV/AIDS and tuberculosis: Views over hidden possibilities

Gut immune components are severely compromised among persons with AIDS, which allows increased translocation of bacterial lipopolysaccharides (LPS) into the systemic circulation. These microbial LPS are reportedly increased in chronically HIV-infected individuals and findings have correlated convincingly with measures of immune activation. Immune reconstitution inflammatory syndrome (IRIS) is an adverse consequence of the restoration of pathogen-specific immune responses in a subset of HIV-infected subjects with underlying latent infections during the initial months of highly active antiretroviral treatment (HAART). Whether IRIS is the result of a response to a high antigen burden, an excessive response by the recovering immune system, exacerbated production of pro-inflammatory cytokines or a lack of immune regulation due to inability to produce regulatory cytokines remains to be determined. We theorize that those who develop IRIS have a high burden of proinflammatory cytokines produced also in response to systemic bacterial LPS that nonspecifically act on latent mycobacterial antigens. We also hypothesize that subjects that do not develop IRIS could have developed either tolerance (anergy) to persistent LPS/tubercle antigens or could have normal FOXP3+ gene and that those with defective FOXP3+ gene or those with enormous plasma LPS could be vulnerable to IRIS. The measure of microbial LPS, anti-LPS antibodies and nonspecific plasma cytokines in subjects on HAART shall predict the role of these components in IRIS

Does CD4+CD25+foxp3+ cell (Treg) and IL-10 profile determine susceptibility to immune reconstitution inflammatory syndrome (IRIS) in HIV disease?

HIV-specific T-lymphocyte responses that underlie IRIS are incomplete and largely remain hypothetical. Of the several mechanisms presented by the host to control host immunological damage, Treg cells are believed to play a critical role. Using the available experimental evidence, it is proposed that enormous synthesis of conventional FoxP3- Th cells (responsive) often renders subjects inherently vulnerable to IRIS, whereas that of natural FoxP3+ Treg cell synthesis predominate among subjects that may not progress to IRIS. We also propose that IRIS non-developers generate precursor T-cells with a high avidity to generate CD4+CD25+FoxP3+ Tregs whereas IRIS developers generate T-cells of intermediate avidity yielding Th0 cells and effector T-cells to mediate the generation of proinflammatory cytokines in response to cell-signaling factors (IL-2, IL-6 etc.). Researchers have shown that IL-10 Tregs (along with TGF-β, a known anti-inflammatory cytokine) limit immune responses against microbial antigens in addition to effectively controlling HIV replication, the prime objective of HAART. Although certain technical limitations are described herein, we advocate measures to test the role of Tregs in IRIS

Cross Type Neutralizing Antibodies Detected in a Unique HIV-2 Infected Individual From India

Background: Infection with HIV-2, a retrovirus that is closely related to HIV-1, is characterized by slower disease progression and transmission, longer latency period and low or undetectable viremia. Host immunity, including production of potent neutralizing antibodies, may be one of the possible contributors to the distinction between the two infections. In an attempt to understand whether HIV-2 infection results in production of neutralizing antibodies and to characterize the nature of the neutralization response we screened plasma of 37 HIV-2 infected individuals for the presence of broadly neutralizing antibodies.Materials and Methods: Thirty seven asymptomatic, ART-naïve, HIV-2 infected individuals were recruited for the study. Plasma obtained from these individuals were screened for the presence of broadly cross reactive neutralizing antibodies (BCNabs) using the standard neutralization screening protocol with a panel of HIV-1 and HIV-2 pseudoviruses. Plasma exhibiting broad neutralization activity were assessed for their potency employing a titration assay. Further, an attempt was made to characterize the neutralization specificity of the plasma exhibiting broad and potent neutralization activity.Result: While majority of the samples tested were capable of neutralizing HIV-2 pseudoviruses with high to moderate potency, one unique sample demonstrated broad cross clade and cross type neutralization with ability to strongly neutralize the vast majority of both HIV-1 and HIV-2 viruses tested (19/20). Preliminary analyses indicate the possible presence of antibodies with multiple glycan epitope binding specificities.Conclusion: The study identified a unique HIV-2 sample with exceptional ability to neutralize HIV-2 viruses and cross-neutralize HIV-1 viruses with great breadth and potency. This sample holds promise for isolation of novel monoclonal antibodies that may exploited as potential therapeutic tools for HIV infection

Validation of a dye stain assay for vaginally inserted hydroxyethylcellulose-filled microbicide applicators

Background: The reliability and validity of self-reports of vaginal microbicide use are questionable given the explicit understanding that participants are expected to comply with study protocols. Our objective was to optimize the use of Population Council\u27s previously validated dye stain assay (DSA) and related procedures, and to establish predictive values for the DSAs ability to identify vaginally inserted single-use, low-density polyethylene microbicide applicators filled with hydroxyethylcellulose gel. Methods: Applicators, inserted by 252 female sex workers enrolled in a microbicide feasibility study in Southern India, served as positive controls for optimization and validation experiments. Before validation, optimal dye concentration and staining time were ascertained. Three validation experiments were conducted to determine sensitivity, specificity, and negative and positive predictive values. Results: The dye concentration of 0.05% (wt/vol) FD&C Blue No. 1 Granular Food Dye (Prime Ingredients, Inc, Saddlebrook, NJ) and staining time of 5 seconds were determined to be optimal and were used for the 3 validation experiments. There were a total of 1848 possible applicator readings across validation experiments; 1703 (92.2%) applicator readings were correct. On average, the DSA performed with 90.6% sensitivity, 93.9% specificity, and had a negative predictive value of 93.8% and a positive predictive value of 91.0%. No statistically significant differences between experiments were noted. Conclusions: The DSA was optimized and successfully validated for use with single use, low-density polyethylene applicators filled with hydroxyethylcellulose gel. We recommend including the DSA in future microbicide trials involving vaginal gels so as to identify participants who have low adherence to dosing regimens. In doing so, we can develop strategies to improve adherence as well as investigate the association between product use and efficacy

Immune correlates of cardiovascular co-morbidity in HIV infected participants from South India

Understanding the immune correlates of cardiovascular disease (CVD) risk in HIV infection is an important area of investigation in the current era of aging with HIV infection. Less is known about CVD risk and HIV infection in developing nations where additional risk factors may be playing a role in the CVD development. In this study, we assessed the effects of systemic inflammation, microbial translocation (MT), T cell immune activation (IA), and nadir CD4 counts on cardiac function and arterial stiffness as markers of subclinical atherosclerosis in HIV-infected individuals. People with HIV (PWH) who were ART naïve (n = 102) or virally suppressed on ART (n = 172) were stratified on nadir CD4 counts and compared to HIV-uninfected controls (n = 64). Determination was made of cardiac function via radial pulse wave and carotid intima thickness (C-IMT) measurements. Plasma biomarkers of inflammation and MT by ELISA or multiplex assays, and immune activation (IA) of T cells based HLA-DR and CD38 expression were investigated by flow cytometry. T-test, Mann-Whitney U test, and Spearman correlation were used to analyze study parameters. Reduction in cardiac function with lower cardiac ejection time (p < 0.001), stroke volume (p < 0.001), cardiac output (p = 0.007), higher arterial stiffness (p < 0.05) were identified in ART-naïve participants, compared to PWH on ART (p < 0.05). No significant difference in C-IMT values were noted. Higher inflammatory and MT markers were found in the ART-naïve group compared to treated group who were comparable to uninfected participants, except for having higher TNF-α (p < 0.001) and sCD14 (p < 0.001). Immune activation of CD4 and CD8 T-cells was greater in ART-naïve participants compared to ART-treated and uninfected controls (p < 0.05). Lower nadir CD4 counts, higher inflammation, and higher MT predicted poor cardiac measures in the ART-naïve with nadir CD4 < 200cells/mm manifesting the highest arterial stiffness, and lowest cardiac function, whereas ART-treated, even with nadir < 200 cells/mm were similar to uninfected in these measures. In HIV-infected individuals, initiation of ART even at nadir of < 200 cells/mm may prevent or reverse cardiovascular disease outcomes that are easily measurable in low income countries