Characteristics and outcomes of initial virologic suppressors during analytic treatment interruption in a therapeutic HIV-1 gag vaccine trial

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, AIDS Clinical Trials Group A5197 Study Team, 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, AIDS Clinical Trials Group A5197 Study Team

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.

Conflict of interest statement

Competing Interests: The authors have the following competing interests: Drs. Kuritzkes, Lederman, and Schooley are consultants to Merck; Dr. Kuritzkes has received research support from Merck. Mary Carrington is an employee of SAIC-Frederick, Inc. Dr. Li is the recipient of a Clinical Investigator Training Program Fellowship: Harvard/MIT Health Sciences and Technology - Beth Israel Deaconess Medical Center, in collaboration with Pfizer Inc. and Merck & Co. The authors appreciate Dr. Michael Robertson's (Merck Research Laboratories) input in the design of the study and review of the manuscript. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Viral load trends for individuals…
Figure 1. Viral load trends for individuals with ATI set point viral load
The light yellow highlighted region encompass the HIV-1 viral load measurements used to calculate the viral set point (mean of the ATI weeks 12 and 16 HIV-1 RNA copies/ml). Pre-ARV, pre-antiretroviral therapy; PID, patient identification number.
Figure 2. HIV-1 Gag-specific CD4+ IFN-γ-producing T…
Figure 2. HIV-1 Gag-specific CD4+ IFN-γ-producing T cells at weeks 8 and 38 categorized by initial virologic suppression and treatment arm.
Panel A, CD4+ IFN-γ response 8 weeks after receiving the first vaccine dose. Number of cells quantified by the intracellular cytokine staining assay in response to pooled HIV Gag peptides. Panel B, CD4+ IFN-γ response 38 weeks after receiving the first vaccine dose and immediately prior to initiating the analytic treatment interruption. Statistical comparison not provided for participants in the “Suppressors (Placebo)” group as only two participants fell into this category.
Figure 3. Expression of HIV-1 CD4+ T…
Figure 3. Expression of HIV-1 CD4+ T cells expressing either CTLA-4+ or PD-1+ by participants with and without initial virologic suppression.
Panel A, Percentage of CD4+ T cells expressing CTLA-4 at week 38 detected using flow cytometry. Panel B, Percentage of CD4+ T cells expressing PD-1 at week 38 detected using flow cytometry.
Figure 4. Expression of HIV-1 Gag-specific CD4+…
Figure 4. Expression of HIV-1 Gag-specific CD4+ TNF-α+ T cells expressing either CTLA-4+ or PD-1+ by participants with and without initial virologic suppression.
Panel A, Percentage of CD4+TNF-α+ T cells expressing CTLA-4 at week 38. Panel B, Percentage of CD4+TNF-α+ T cells expressing PD-1 at week 38.

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