Effect of Raltegravir-containing Intensification on HIV Burden and T-cell Activation in Multiple Gut Sites of HIV-positive Adults on Suppressive Antiretroviral Therapy

Overview

Journal AIDS

Specialty Infectious Diseases

Date 2010 Sep 10

PMID 20827162

Citations 149

Authors

Steven A Yukl

Amandeep K Shergill

Kenneth McQuaid

Sara Gianella

Harry Lampiris

C Bradley Hare

Mark Pandori

Elizabeth Sinclair

Huldrych F Gunthard

Marek Fischer

Joseph K Wong

Diane V Havlir

Affiliations

Soon will be listed here.

Abstract

Objective: To determine whether raltegravir-containing antiretroviral therapy (ART) intensification reduces HIV levels in the gut.

Design: Open-label study in HIV-positive adults on ART with plasma HIV RNA below 40 copies/ml.

Methods: Seven HIV-positive adults received 12 weeks of ART intensification with raltegravir alone or in combination with efavirenz or darunavir. Gut cells were obtained by upper and lower endoscopy with biopsies from duodenum, ileum, colon, and rectum at baseline and 12 weeks. Study outcomes included plasma HIV RNA, HIV DNA and RNA from peripheral blood mononuclear cells (PBMC) and four gut sites, T-cell subsets, and activation markers.

Results: Intensification produced no consistent decrease in HIV RNA in the plasma, PBMC, duodenum, colon, or rectum. However, five of seven participants had a decrease in unspliced HIV RNA per 10 CD4(+) T cells in the ileum. There was a trend towards decreased T-cell activation in all sites, which was greatest for CD8(+) T cells in the ileum and PBMC, and a trend towards increased CD4(+) T cells in the ileum.

Conclusion: Most HIV RNA and DNA in the blood and gut is not the result of ongoing replication that can be impacted by short-term intensification with raltegravir. However, the ileum may support ongoing productive infection in some patients on ART, even if the contribution to plasma RNA is not discernible.

Citing Articles

The Human Milk Oligosaccharide Lacto-N-Fucopentaose III Conjugated to Dextran Inhibits HIV Replication in Primary Human Macrophages.

Media T, Ramesh M, Lee O, Ubaka L, Harn D, Norberg T Nutrients. 2025; 17(5).

PMID: 40077760 PMC: 11901455. DOI: 10.3390/nu17050890.

Controversies in the Design of Strategies for the Cure of HIV Infection.

de Gea-Grela A, Moreno S Pathogens. 2023; 12(2).

PMID: 36839593 PMC: 9961067. DOI: 10.3390/pathogens12020322.

Opposing roles of CLK SR kinases in controlling HIV-1 gene expression and latency.

Dahal S, Clayton K, Been T, Fernet-Brochu R, Villasmil Ocando A, Balachandran A Retrovirology. 2022; 19(1):18.

PMID: 35986377 PMC: 9389714. DOI: 10.1186/s12977-022-00605-4.

Inflammasomes as mediators of inflammation in HIV-1 infection.

Min A, Fortune T, Rodriguez N, Hedge E, Swartz T Transl Res. 2022; 252():1-8.

PMID: 35917903 PMC: 10160852. DOI: 10.1016/j.trsl.2022.07.008.

Quantification of Total HIV DNA as a Marker to Measure Viral Reservoir: Methods and Potential Implications for Clinical Practice.

Belmonti S, Di Giambenedetto S, Lombardi F Diagnostics (Basel). 2022; 12(1).

PMID: 35054206 PMC: 8774405. DOI: 10.3390/diagnostics12010039.

References

Swanson P, Huang S, Abravaya K, de Mendoza C, Soriano V, Devare S . Evaluation of performance across the dynamic range of the Abbott RealTime HIV-1 assay as compared to VERSANT HIV-1 RNA 3.0 and AMPLICOR HIV-1 MONITOR v1.5 using serial dilutions of 39 group M and O viruses. J Virol Methods. 2006; 141(1):49-57. DOI: 10.1016/j.jviromet.2006.11.026. View

Tang N, Huang S, Salituro J, Mak W, Cloherty G, Johanson J . A RealTime HIV-1 viral load assay for automated quantitation of HIV-1 RNA in genetically diverse group M subtypes A-H, group O and group N samples. J Virol Methods. 2007; 146(1-2):236-45. DOI: 10.1016/j.jviromet.2007.07.003. View

Shacklett B, Critchfield J, Lemongello D . Isolating mucosal lymphocytes from biopsy tissue for cellular immunology assays. Methods Mol Biol. 2008; 485:347-56. DOI: 10.1007/978-1-59745-170-3_23. View

Fischer M, Joos B, Hirschel B, Bleiber G, Weber R, Gunthard H . Cellular viral rebound after cessation of potent antiretroviral therapy predicted by levels of multiply spliced HIV-1 RNA encoding nef. J Infect Dis. 2004; 190(11):1979-88. DOI: 10.1086/425983. View

Sattentau Q . Avoiding the void: cell-to-cell spread of human viruses. Nat Rev Microbiol. 2008; 6(11):815-26. DOI: 10.1038/nrmicro1972. View

Ramratnam B, Ribeiro R, He T, Chung C, Simon V, Vanderhoeven J . Intensification of antiretroviral therapy accelerates the decay of the HIV-1 latent reservoir and decreases, but does not eliminate, ongoing virus replication. J Acquir Immune Defic Syndr. 2004; 35(1):33-7. DOI: 10.1097/00126334-200401010-00004. View

Haller C, Fackler O . HIV-1 at the immunological and T-lymphocytic virological synapse. Biol Chem. 2008; 389(10):1253-60. DOI: 10.1515/BC.2008.143. View

Grossman Z, Feinberg M, Kuznetsov V, Dimitrov D, Paul W . HIV infection: how effective is drug combination treatment?. Immunol Today. 1998; 19(11):528-32. DOI: 10.1016/s0167-5699(98)01353-x. View

Phillips D . The role of cell-to-cell transmission in HIV infection. AIDS. 1994; 8(6):719-31. DOI: 10.1097/00002030-199406000-00001. View

10.

Fischer M, Joos B, Niederost B, Kaiser P, Hafner R, von Wyl V . Biphasic decay kinetics suggest progressive slowing in turnover of latently HIV-1 infected cells during antiretroviral therapy. Retrovirology. 2008; 5:107. PMC: 2630982. DOI: 10.1186/1742-4690-5-107. View

11.

Hunt P, Martin J, Sinclair E, Bredt B, Hagos E, Lampiris H . T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003; 187(10):1534-43. DOI: 10.1086/374786. View

12.

Kolber M, Saenz M, Tanner T, Arheart K, Pahwa S, Liu H . Intensification of a suppressive HAART regimen increases CD4 counts and decreases CD8+ T-cell activation. Clin Immunol. 2007; 126(3):315-21. DOI: 10.1016/j.clim.2007.10.002. View

13.

Piguet V, Sattentau Q . Dangerous liaisons at the virological synapse. J Clin Invest. 2004; 114(5):605-10. PMC: 514595. DOI: 10.1172/JCI22812. View

14.

Hunt P, Brenchley J, Sinclair E, McCune J, Roland M, Page-Shafer K . Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. 2008; 197(1):126-33. PMC: 3466592. DOI: 10.1086/524143. View

15.

Kaiser P, Joos B, Niederost B, Weber R, Gunthard H, Fischer M . Productive human immunodeficiency virus type 1 infection in peripheral blood predominantly takes place in CD4/CD8 double-negative T lymphocytes. J Virol. 2007; 81(18):9693-706. PMC: 2045436. DOI: 10.1128/JVI.00492-07. View

16.

Anton P, Poles M, Elliott J, Mao S, McGowan I, Lenz H . Sensitive and reproducible quantitation of mucosal HIV-1 RNA and DNA viral burden in patients with detectable and undetectable plasma viral HIV-1 RNA using endoscopic biopsies. J Virol Methods. 2001; 95(1-2):65-79. DOI: 10.1016/s0166-0934(01)00295-6. View

17.

Havlir D, Strain M, Clerici M, Ignacio C, Trabattoni D, Ferrante P . Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years. J Virol. 2003; 77(20):11212-9. PMC: 224988. DOI: 10.1128/jvi.77.20.11212-11219.2003. View

18.

Critchfield J, Lemongello D, Walker D, Garcia J, Asmuth D, Pollard R . Multifunctional human immunodeficiency virus (HIV) gag-specific CD8+ T-cell responses in rectal mucosa and peripheral blood mononuclear cells during chronic HIV type 1 infection. J Virol. 2007; 81(11):5460-71. PMC: 1900284. DOI: 10.1128/JVI.02535-06. View

19.

Avettand-Fenoel V, Prazuck T, Hocqueloux L, Melard A, Michau C, Kerdraon R . HIV-DNA in rectal cells is well correlated with HIV-DNA in blood in different groups of patients, including long-term non-progressors. AIDS. 2008; 22(14):1880-2. DOI: 10.1097/QAD.0b013e32830fbdbc. View

20.

Koelsch K, Liu L, Haubrich R, May S, Havlir D, Gunthard H . Dynamics of total, linear nonintegrated, and integrated HIV-1 DNA in vivo and in vitro. J Infect Dis. 2008; 197(3):411-9. DOI: 10.1086/525283. View