Characteristics and Outcomes of Initial Virologic Suppressors During Analytic Treatment Interruption in a Therapeutic HIV-1 Gag Vaccine Trial

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Apr 6

PMID 22479542

Citations 4

Authors

Jonathan Z Li

Chanson J Brumme

Michael M Lederman

Zabrina L Brumme

Hongying Wang

John Spritzler

Mary Carrington

Kathleen Medvik

Bruce D Walker

Robert T Schooley

Daniel R Kuritzkes

Affiliations

Soon will be listed here.

Abstract

Background: In the placebo-controlled trial ACTG A5197, a trend favoring viral suppression was seen in the HIV-1-infected subjects who received a recombinant Ad5 HIV-1 gag vaccine.

Objective: To identify individuals with initial viral suppression (plasma HIV-1 RNA set point <3.0 log(10) copies/ml) during the analytic treatment interruption (ATI) and evaluate the durability and correlates of virologic control and characteristics of HIV sequence evolution.

Methods: HIV-1 gag and pol RNA were amplified and sequenced from plasma obtained during the ATI. Immune responses were measured by flow cytometric analysis and intracellular cytokine expression assays. Characteristics of those with and without initial viral suppression were compared using the Wilcoxon rank sum and Fisher's exact tests.

Results: Eleven out of 104 participants (10.6%) were classified as initial virologic suppressors, nine of whom had received the vaccine. Initial virologic suppressors had significantly less CD4+ cell decline by ATI week 16 as compared to non-suppressors (median 7 CD4+ cell gain vs. 247 CD4+ cell loss, P = 0.04). However, of the ten initial virologic suppressors with a pVL at ATI week 49, only three maintained pVL <3.0 log(10) copies/ml. HIV-1 Gag-specific CD4+ interferon-γ responses were not associated with initial virologic suppression and no evidence of vaccine-driven HIV sequence evolution was detected. Participants with initial virologic suppression were found to have a lower percentage of CD4+ CTLA-4+ cells prior to treatment interruption, but a greater proportion of HIV-1 Gag-reactive CD4+ TNF-α+ cells expressing either CTLA-4 or PD-1.

Conclusions: Among individuals participating in a rAd5 therapeutic HIV-1 gag vaccine trial, initial viral suppression was found in a subset of patients, but this response was not sustained. The association between CTLA-4 and PD-1 expression on CD4+ T cells and virologic outcome warrants further study in trials of other therapeutic vaccines in development.

Trial Registration: ClinicalTrials.gov NCT00080106.

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References

Autran B, Murphy R, Costagliola D, Tubiana R, Clotet B, Gatell J . Greater viral rebound and reduced time to resume antiretroviral therapy after therapeutic immunization with the ALVAC-HIV vaccine (vCP1452). AIDS. 2008; 22(11):1313-22. DOI: 10.1097/QAD.0b013e3282fdce94. View

Boritz E, Palmer B, Wilson C . Human immunodeficiency virus type 1 (HIV-1)-specific CD4+ T cells that proliferate in vitro detected in samples from most viremic subjects and inversely associated with plasma HIV-1 levels. J Virol. 2004; 78(22):12638-46. PMC: 525069. DOI: 10.1128/JVI.78.22.12638-12646.2004. View

Fagard C, Oxenius A, Gunthard H, Garcia F, Le Braz M, Mestre G . A prospective trial of structured treatment interruptions in human immunodeficiency virus infection. Arch Intern Med. 2003; 163(10):1220-6. DOI: 10.1001/archinte.163.10.1220. View

Johnston R . HIV cure: controversy, consensus, and a consortium. AIDS Res Hum Retroviruses. 2010; 26(9):943-6. DOI: 10.1089/aid.2010.0087. View

Day C, Kaufmann D, Kiepiela P, Brown J, Moodley E, Reddy S . PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006; 443(7109):350-4. DOI: 10.1038/nature05115. View

Folkers G, Fauci A . Controlling and ultimately ending the HIV/AIDS pandemic: a feasible goal. JAMA. 2010; 304(3):350-1. DOI: 10.1001/jama.2010.957. View

Brumme Z, John M, Carlson J, Brumme C, Chan D, Brockman M . HLA-associated immune escape pathways in HIV-1 subtype B Gag, Pol and Nef proteins. PLoS One. 2009; 4(8):e6687. PMC: 2723923. DOI: 10.1371/journal.pone.0006687. View

Kiepiela P, Leslie A, Honeyborne I, Ramduth D, Thobakgale C, Chetty S . Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature. 2004; 432(7018):769-75. DOI: 10.1038/nature03113. View

Ramduth D, Day C, Thobakgale C, Mkhwanazi N, de Pierres C, Reddy S . Immunodominant HIV-1 Cd4+ T cell epitopes in chronic untreated clade C HIV-1 infection. PLoS One. 2009; 4(4):e5013. PMC: 2661367. DOI: 10.1371/journal.pone.0005013. View

10.

Moing V, Chene G, Carrieri M, Alioum A, Brun-Vezinet F, Piroth L . Predictors of virological rebound in HIV-1-infected patients initiating a protease inhibitor-containing regimen. AIDS. 2001; 16(1):21-9. DOI: 10.1097/00002030-200201040-00004. View

11.

Pereyra F, Jia X, McLaren P, de Bakker P, Walker B, Ripke S . The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science. 2010; 330(6010):1551-7. PMC: 3235490. DOI: 10.1126/science.1195271. View

12.

Murphy R, Sunpath H, Lu Z, Chelin N, Losina E, Gordon M . Outcomes after virologic failure of first-line ART in South Africa. AIDS. 2010; 24(7):1007-12. PMC: 2902159. DOI: 10.1097/QAD.0b013e3283333639. View

13.

Babiker A, Castro nee Green H, Compagnucci A, Fiscus S, Giaquinto C, Gibb D . First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial. Lancet Infect Dis. 2011; 11(4):273-83. PMC: 3111069. DOI: 10.1016/S1473-3099(10)70313-3. View

14.

Prendergast A, Goodliffe H, Clapson M, Cross R, Tudor-Williams G, Riddell A . Gag-specific CD4+ T-cell responses are associated with virological control of paediatric HIV-1 infection. AIDS. 2011; 25(10):1329-31. DOI: 10.1097/QAD.0b013e3283478575. View

15.

Schooley R, Spritzler J, Wang H, Lederman M, Havlir D, Kuritzkes D . AIDS clinical trials group 5197: a placebo-controlled trial of immunization of HIV-1-infected persons with a replication-deficient adenovirus type 5 vaccine expressing the HIV-1 core protein. J Infect Dis. 2010; 202(5):705-16. PMC: 2916952. DOI: 10.1086/655468. View

16.

Lederman M, Penn-Nicholson A, Stone S, Sieg S, Rodriguez B . Monitoring clinical trials of therapeutic vaccines in HIV infection: role of treatment interruption. Curr Opin HIV AIDS. 2009; 2(1):56-61. DOI: 10.1097/COH.0b013e3280119264. View

17.

Honeyborne I, Prendergast A, Pereyra F, Leslie A, Crawford H, Payne R . Control of human immunodeficiency virus type 1 is associated with HLA-B*13 and targeting of multiple gag-specific CD8+ T-cell epitopes. J Virol. 2007; 81(7):3667-72. PMC: 1866034. DOI: 10.1128/JVI.02689-06. View

18.

Thompson M, Aberg J, Cahn P, Montaner J, Rizzardini G, Telenti A . Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010; 304(3):321-33. DOI: 10.1001/jama.2010.1004. View

19.

Fitzgerald D, Janes H, Robertson M, Coombs R, Frank I, Gilbert P . An Ad5-vectored HIV-1 vaccine elicits cell-mediated immunity but does not affect disease progression in HIV-1-infected male subjects: results from a randomized placebo-controlled trial (the Step study). J Infect Dis. 2011; 203(6):765-72. PMC: 3119328. DOI: 10.1093/infdis/jiq114. View

20.

Trigona W, Clair J, Persaud N, Punt K, Bachinsky M, Sadasivan-Nair U . Intracellular staining for HIV-specific IFN-gamma production: statistical analyses establish reproducibility and criteria for distinguishing positive responses. J Interferon Cytokine Res. 2003; 23(7):369-77. DOI: 10.1089/107999003322226023. View