Impact of Integrase Inhibition compared to non-nucleoside inhibition on HIV reservoirs in Lymphoid Tissues

Fri, 15 Mar 2019 00:00:00 GMT-05:00 - Rothenberger, Meghan; Nganou-Makamdop, Krystelle; Kityo, Cissy; Ssali, Francis; Chipman, Jeffrey G; Beilman, Gregory J; Hoskuldsson, Torfi; Anderson, Jodi; Jasurda, Jake; Schmidt, Thomas E; Calisto, Samuel P; Pearson, Hope; Reimann, Thomas; David, Caitlin; Perkey, Katherine; Southern, Peter; Wietgrefe, Steve; Helgeson, Erika; Reilly, Cavan; Haase, Ashley T; Douek, Daniel C; Fletcher, Courtney V; Schacker, Timothy W
Εισαγωγή: HIV is produced in lymphoid tissues (LT) and stored on the follicular dendritic cell network in LT. When antiretroviral therapy (ART) is started, plasma viremia decays in two phases; the first within days of starting therapy and the second over weeks. Raltegravir (RAL), an integrase inhibitor, has been associated with only a single rapid phase of decay and we speculated this might be due to higher cell-associated concentration (IC) of RAL in LT. We have previously measured suboptimal ICs of ART agents in LT which was associated with slower decay of both vRNA+ cells and the FDCn pool. Setting: Outpatient clinic at the Joint Clinical Research Center in Kampala, Uganda
Μέθοδοι: We compared the rate of decay in LT in people starting RAL compared to efavirenz (EFV).
Αποτελέσματα: There was no difference in the rate of virus decay in LT. The ratio of the IC of RAL and EFV in LN to in vivo effective concentrations was 1 log lower in LN for EFV and > 3 logs lower for RAL.
Συμπέρασμα: These data further highlight the challenges of drug delivery to LT in HIV infection and demonstrate that RAL is not superior to EFV as judged by direct measurements of the source of virus in LT. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Corresponding Author: Timothy Schacker, MD Department of Medicine MMC250 420 Delaware Street SE Minneapolis, MN 55455 Phone: 612-624-9955 Schacker@UMN.edu Conflicts of interest. All authors involved in this manuscript do not have a commercial or other association that might pose a conflict of interest. Financial support. Funding for this research was provided by an unrestricted grant from Merck, R01-AI124965, and UL1TR000114. No sponsor or funder played a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author contributions. MR, KNM, CK, ATH, DCD, CVF, TWS provided the conceptualization; MR, KNM, FS, JA, EH, CR, DCD, TWS provided data curation; KNM, HP, TR, CD, KP, PS, SW, EH, CR, DCD, CVF provided formal analysis; TWS provided funding acquisition; MR, KNM, CK, JGC, GJB, TH, JA, JJ, TES, SPC, DCD, CVF, TWS provided investigation; KNM, JGC, GJB, TH, JA, ATH provided methodology; MR, CK, FS, JGC, GJB, TH, TWS provided project administration; TWS provided resources; CR, CVF provided supervision; CD, EH, CR, CVF provided validation; CD provided visualization; MR, KNM, CK, JGC, GJB, TH, JA, CR, ATH, DCD, CVF, TWS provided writing, review and editing. - Β© 2019

Increasing levels of serum heat shock protein 70 precede the development of AIDS-defining non-Hodgkin lymphoma among carriers of HLA-B8-DR3

Fri, 15 Mar 2019 00:00:00 GMT-05:00 - Aissani, Brahim; Martinez-Maza, Otoniel; Kaslow, Richard A.; Wiener, Howard W.; Bream, Jay H.; Stosor, Valentina; Martinson, Jeremy J.; Jacobson, Lisa P.; Shrestha, Sadeep
Εισαγωγή: We hypothesized that carriage of presumably high Hsp70 producing gene variants on a specific human major histocompatibilty complex haplotype, the 8.1 ancestral haplotype (8.1AH), may predispose HIV-infected individuals to AIDS-NHL. SETTING: We compared serum Hsp70 levels in the years preceding the diagnosis of AIDS-NHL in a matched case-control study (n=151 pairs) nested in the Multicenter AIDS Cohort Study (MACS).
Μέθοδοι: We tested the impact of 8.1AH-specific SNP and joint SNP-HLA extended haplotypes previously associated with AIDS-NHL in MACS on the circulating Hsp70 levels in mixed linear models.
Αποτελέσματα: We report elevated serum levels of Hsp70 in the 4 years preceding the diagnosis of AIDS-NHL in cases that carry 8.1AH but not in non-carrier cases and not in carrier or non-carrier matched controls. The strongest predictor of higher serum Hsp70 was haplotype A-G-A-C formed by SNPs rs537160(A) and rs1270942(G) in the complement factor CFB gene cluster and rs2072633(A) and rs6467(C) in nearby RDBP and CYP21A2 located 70 Kb apart from the Hsp70 gene cluster. The association with A-G-A-C haplotype (beta = 0.718; SE = 0.182; p = 0.0002) and with other 8.1AH-specific haplotypes including the high-producing TNFA haplotype rs909253(G) - rs1800629(A) (beta = 0.308; SE = 0.140; p = 0.032) were observed only with NHL identified as an AIDS-defining condition but not as a post-AIDS condition, nor in combined AIDS and post-AIDS cases.
Συμπέρασμα: Our combined genetic and functional approach suggests that altered level of Hsp70 is a correlate of 8.1AH-mediated AIDS-NHL. Further investigation of the Hsp70 gene cluster and nearby loci that are tagged by A-G-A-C could better elucidate the genetic determinants of the malignancy. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Correspondence to: Brahim Aissani: Department of Epidemiology University of Alabama at Birmingham 1665 University Blvd, RPHB Room 220A Birmingham, Alabama 35294-0022 Phone: (205) 902-4558 Fax: (205) 934-1640 baissani@uab.edu. Conflicts of Interest and Source of Funding: None declared. Parts of the data were presented at the 12th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI), Bethesda, April 26-27, 2010. Sources of support:Funding was provided by subcontract (BA) to NIH/NCI P30-AI045008 (PI: Hoxie). The Multicenter AIDS Cohort Study (MACS) is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and the National Heart, Lung and Blood Institute. UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041. This work was also supported by the Pendleton Charitable Trust and the McCarthy Family Foundation, and by the Quetelet Endowed Professor Research Fund. - Β© 2019

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