Expression profile of host restriction factors in HIV-1 elite controllers

Mohamed Abdel-Mohsen,Manqing Li,Teri Liegler,Satish K Pillai,Joseph K Wong,Rebecca Hoh,Steven G Deeks,Michael David,Mohamed S Salama,Hussam El-Din A Ghanem,Elizabeth Sinclair,Douglas F Nixon,Xutao Deng,Rui André Saraiva Raposo

doi:10.1186/1742-4690-10-106

Abstract

BackgroundSeveral host-encoded antiviral factors suppress HIV-1 replication in a cell-autonomous fashion in vitro. The relevance of these defenses to the control of HIV-1 in vivo remains to be elucidated. We hypothesized that cellular restriction of HIV-1 replication plays a significant role in the observed suppression of HIV-1 in "elite controllers", individuals who maintain undetectable levels of viremia in the absence of antiretroviral therapy (ART). We comprehensively compared the expression levels of 34 host restriction factors and cellular activation levels in CD4+ T cells and sorted T cell subsets between elite controllers, HIV-1-infected (untreated) non-controllers, ART-suppressed, and uninfected individuals.ResultsExpression of schlafen 11, a codon usage-based inhibitor of HIV-1 protein synthesis, was significantly elevated in CD4+ T cells from elite controllers as compared to both non-controllers (p = 0.048) and ART-suppressed individuals (p = 0.024), with this effect most apparent in central memory CD4+ T cells. Schlafen 11 expression levels were comparable between controllers and uninfected individuals. Cumulative restriction factor expression was positively correlated with CD4+ T cell activation (r2 = 0.597, p < 0.0001), viral load (r2 = 0.34, p = 0.015), and expression of ISG15 (r2 = 0.73, p < 0.0001), a marker of interferon exposure. APOBEC3C, APOBEC3D, CTR9, TRIM26, and TRIM32 were elevated in elite controllers with respect to ART-suppressed individuals, while levels were comparable to uninfected individuals and non-controllers.ConclusionsHost restriction factor expression typically scales with cellular activation levels. However, the elevated mRNA and protein expression of schlafen 11, despite low activation and viral load, violates the global pattern and may be a signature characteristic of HIV-1 elite control.

Highlights

Several host-encoded antiviral factors suppress HIV-1 replication in a cell-autonomous fashion in vitro
Schlafen 11 expression is elevated in elite controllers We implemented the “CuRe” (Cumulative Restriction) TaqMan® Low Density Arrays (TLDA) to measure the mRNA expression of 34 anti-HIV-1 genes in CD4+ T cells from 48 subjects representing four HIV-1 disease states (12 elite controllers, 12 noncontrollers, 12 antiretroviral therapy (ART)-suppressed, and 12 HIV-1-uninfected individuals)
The complete list of surveyed genes along with their respective reported anti-HIV-1 roles is presented in Table 1, precise disease state definitions are described in Table 2, and individual subject characteristics are documented in Additional file 1: Table S1

Summary

Introduction

Several host-encoded antiviral factors suppress HIV-1 replication in a cell-autonomous fashion in vitro. The relevance of these defenses to the control of HIV-1 in vivo remains to be elucidated. We hypothesized that cellular restriction of HIV-1 replication plays a significant role in the observed suppression of HIV-1 in “elite controllers”, individuals who maintain undetectable levels of viremia in the absence of antiretroviral therapy (ART). We comprehensively compared the expression levels of 34 host restriction factors and cellular activation levels in CD4+ T cells and sorted T cell subsets between elite controllers, HIV-1-infected (untreated) non-controllers, ART-suppressed, and uninfected individuals. Antiretroviral therapy (ART) has dramatically decreased the morbidity and mortality associated with HIV-1 infection.

Methods

Results

Discussion

Conclusion