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HIV Apheresis Tags (HIVAT) Aided Elimination of Viremia.

ABSTRACT: Introduction:HIV viremia is the essential element for progression of an initial HIV infection into AIDS and death. The currently approved management relies primarily on chemotherapy repressing the HIV replication in the infected CD4+ cells, although with severe systemic adverse effects. The problem is that it does not physically eliminate viruses, which then not only keep infecting healthy cells of these patients, but also promote infections of other people. Specific aim:An overall objective of our work is biomolecular engineering of virus apheresis tags (VAT) that eliminate viremias without adverse effects. The specific aim of this project was biomolecular engineering of Human Immunodeficiency Virus Apheresis Tags (HIVAT): CD4-Au-Fe3O4, CD4-SiO2-Fe3O4, anti-gp120-Au-Fe3O4, and anti-gp120-SiO2-Fe3O4. Healthy Donors and Patients:Per the Institutional Review Board's approval and in compliance with Declaration of Helsinki, healthy donors and patients were presented with Patient Bill of Rights and provided Patient Informed Consent, while all the procedures were pursued by the licensed physicians. Materials and Methods:CD4, gp120, gp41, gp160, anti-gp120, p24 were transgenomically expressed. Superparamagnetic core-shell particles (SPM-CSP) were synthesized. SPM-CSP were used as the nucleation centers for assembling the expressed molecules upon them to create virus apheresis tags (VAT). VAT were injected into the blood or lymph acquired from the HIV+ and HBV+ patients followed by apheresis at 0.47 - 9.4 T. VAT efficacy in eliminating viremia was determined through immunoblots, NMR and q-RT-PCR. Results:Treatment of blood or lymph of the HIV+ patients' with VAT followed by virus apheresis resulted in rapid elimination of the HIV viremia. Efficacy of apheresis was contingent upon the gravity of viremia versus doses and regimens of VAT. Importantly, administration of VAT also effectively improved levels of non-infected CD4+ lymphocytes. Discussion / Conclusions:Herein, we present the proof of concept for a new, effective treatment with virus apheresis tags (VAT), specifically Human Immunodeficiency Virus Apheresis Tags (HIVAT), of the HIV+ patients' blood and lymph, which is eliminating the HIV viremia.It can be easily adapted as treatments of viremias perpetrated by other deadly viruses, which we vigorously pursue.

SUBMITTER: Malecki M

PROVIDER: S-EPMC6438618 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:CD8+ and CD4+ T cells from HIV infected patients with HIV-RNA viremia of >50 copies/ml and CD8+ and CD4+ T cells from healthy controls were isolated by negative selection (Miltenyi Biotech, Auburn, CA). Cell sorting of the CD4 and CD8 T cell subsets were performed based on surface staining of CD3+CD8+ or CD3+CD4+ and na ve CD45RA+CD27+CD127highHLA-DRlow, and CD3+CD8+ or CD3+CD4+ and memory CD45RA-CD27+CD127highHLA-DRlow. Sorted cell populations were spun down and stored as dry pellets at -80M-BM-0C. Samples analyzed by transcript levels of genes related to cytokine signaling were determined by the JAK/STAT Signaling Pathway microarray. CD8+ and CD4+ T cells from HIV infected patients with HIV-RNA viremia of >50 copies/ml and CD8+ and CD4+ T cells from healthy controls were isolated by negative selection (Miltenyi Biotech, Auburn, CA). Cell sorting of the CD4 and CD8 T cell subsets were performed based on surface staining of CD3+CD8+ or CD3+CD4+ and naM-CM-/ve CD45RA+CD27+CD127highHLA-DRlow, and CD3+CD8+ or CD3+CD4+ and memory CD45RA-CD27+CD127highHLA-DRlow. Sorted cell populations were spun down and stored as dry pellets at -80M-BM-0C. Samples analyzed by transcript levels of genes related to cytokine signaling were determined by the JAK/STAT Signaling Pathway microarray (http://www.sabiosciences.com/rt_pcr_product/HTML/PAHS-039A.html, SABiosciences Frederick, MD). Briefly, total RNA was harvested from each individual T cell subset from each patient or healthy control and contaminating DNA was digested with DNase. Messenger RNA was converted to cDNA and loaded onto PCR array plates for quantitative real-time PCR. Quantification of transcript levels was determined by normalizing to 5 housekeeping genes from each individual sample. Relative gene expression levels for each subset were averaged and compared between cell populations from the patient group and healthy controls. Because of the multiple comparisons only p values M-bM-^IM-$ 0.01 were considered significant.

Project description:BackgroundLong-term viral load (VL) suppression among HIV-positive, reproductive-aged women on ART is key to eliminating mother-to-child transmission (MTCT) but few data exist from sub-Saharan Africa. We report trends in post-partum VL in Malawian women on ART and factors associated with detectable VL up to 24 months post-partum.Methods1-6 months post-partum mothers, screened HIV-positive at outpatient clinics in Malawi, were enrolled (2014-2016) with their infants. At enrollment, 12- and 24-months post-partum socio-demographic and PMTCT indicators were collected. Venous samples were collected for determination of maternal VL (limit of detection 40 copies/ml). Results were returned to clinics for routine management.Results596/1281 (46.5%) women were retained in the study to 24 months. Those retained were older (p<0.01), had higher parity (p = 0.03) and more likely to have undetectable VL at enrollment than those lost to follow-up (80.0% vs 70.2%, p<0.01). Of 590 women on ART (median 30.1 months; inter-quartile range 26.8-61.3), 442 (74.9%) with complete VL data at 3 visits were included in further analysis. Prevalence of detectable VL at 12 and 24 months was higher among women with detectable VL at enrollment than among those with undetectable VL (74 detectable VL results/66 women vs. 19/359; p<0.001). In multivariable analysis (adjusted for age, parity, education, partner disclosure, timing of ART start and self-reported adherence), detectable VL at 24 months was 9 times more likely among women with 1 prior detectable VL (aOR 9.0; 95%CI 3.5-23.0, p<0.001) and 226 times more likely for women with 2 prior detectable VLs (aOR 226.4; 95%CI 73.0-701.8, p<0.001).ConclusionsDetectable virus early post-partum strongly increases risk of ongoing post-partum viremia. Due to high loss to follow-up, the true incidence of detectable VL over time is probably underestimated. These findings have implications for MTCT, as well as for the mothers, and call for intensified VL monitoring and targeted adherence support for women during pregnancy and post-partum.

Project description:ImportanceViral suppression of HIV is an important treatment goal to decrease morbidity, mortality, and risk of transmission to others.ObjectiveTo characterize longitudinal HIV viral load outcomes among women enrolled in the Women's Interagency HIV Study (WIHS).Design, setting, and participantsA prospective cohort study of HIV-positive women with semiannual study visits and a minimum of 5 follow-up visits was conducted from 1994 to 2017. The WIHS sites included in this analysis are in Brooklyn and Bronx, New York; Chicago, Illinois; San Francisco, California; and Washington, DC.Main outcomes and measuresWomen were categorized into groups based on their probability of achieving viral load suppression below 200 copies/mL using logistic trajectory modeling. Multinomial regression analysis was used to identify factors associated with placement in the group with the highest probability of viremia.ResultsAt baseline, the mean (SD) age of the 1989 women was 36.9 (8.0) years, mean CD4+ T-lymphocyte count was 467/mm3, median (interquartile range) HIV RNA was 6200.0 (384.5-41 678.0) copies/mL, and 1305 women (65.6%) were African American. Three trajectory groups were identified with low (568 [28.6%]), intermediate (784 [39.4%]), and high (637 [32.0%]) probability of viremia above 200 copies/mL. The mean (SD) cumulative years of viral suppression were 18.7 (4.0) years, 12.2 (3.1) years, and 5.8 (2.9) years in the respective groups. Factors associated with high probability of viremia included younger age (odds ratio [OR]. 0.99; 95% CI, 0.98-0.99; P = .03), African American race (odds ratio [OR], 2.43; 95% CI, 1.75-3.37), P < .001), Hispanic race/ethnicity (OR, 1.50; 95% CI, 1.03-2.19; P = .04), increased levels of depressive symptoms (OR, 1.17; 95% CI, 1.01-1.36; P = .03), drug use (OR, 1.23; 95% CI, 1.01-1.51; P = .04), lower CD4+ T-lymphocyte counts (OR, 95% CI, 0.82; 0.80-0.85; P < .001), and unstable housing (OR, 1.25, 95% CI, 1.03-1.50; P = .02). Between 2015 and 2017, 71.2% of women demonstrated sustained viral suppression: 89.6% (310 of 346) of those with low viremia, 83.4% (346 of 415) with intermediate, and 35.2% (112 of 318) with high probability of viremia.Conclusions and relevanceThis longitudinal approach suggested that the probability of viremia decreased substantially over time for most participants, including among women with earlier histories of incomplete viral suppression. The findings from this study suggest that continued efforts are needed to address mental health, social, behavioral and structural factors that were identified as associated with high probability of HIV viremia over time.

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HIV Apheresis Tags (HIVAT) Aided Elimination of Viremia.

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