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

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.

Effects of Alpha Interferon Treatment on Intrinsic Anti-HIV-1 Immunity In Vivo

“…The contribution of non-cell-intrinsic mechanisms to IFN-␣ anti-HIV-1 effects should be explored in greater detail. These data support the concept that the induction of particular intrinsic immune mechanisms may constitute a promising antiretroviral strategy, complementing our previous in vitro work (21) and our translational studies of restriction mechanisms in HLA-B*57-positive individuals (22) and HIV-1 elite controllers (11).…”

“…We designed and implemented a custom TLDA to measure the expression of 34 anti-HIV-1 restriction genes (11). We relied on the following two minimal criteria for inclusion in our CuRe TLDA: (i) peer-reviewed, published evidence of direct inhibition of HIV-1 replication in vitro and (ii) detectable expression in human peripheral blood mononuclear cells.…”

Dynamic Regulation of Host Restriction Factor Expression over the Course of HIV-1 Infection In Vivo

“…More recently, we comprehensively quantified the overall restriction factor expression profile of primary cells in healthy individuals and demonstrated that cellular activation strongly induced the expression of anti-HIV-1 genes and that increased gene expression correlated with decreased ex vivo HIV-1 replication (11). We have also used this platform to analyze host restriction factor gene expression in a cross-sectional study of HIV-1 patients at different stages of disease (13).…”

“…We quantified the expression of 32 different anti-HIV-1 genes using a custom-made TaqMan array (11,13) and measured the levels of CD4 ϩ T cell activation over 7 years. We found that overall, restriction factor gene expression consistently increased over time and was significantly associated with systemic CD4 ϩ T cell activation and viral load.…”

IFITM1 targets HIV-1 latently infected cells for antibody-dependent cytolysis

“…We utilized latency models to obtain unique mechanistic insights into the role of intrinsic cellular immunity during ART. Previous work by our group led to the development of a quantitative PCR-based (qPCR-based) array capable of examining the expression of a predefined set of antiviral genes in primary cells (12,21). In this work, we hypothesized that transcriptional HIV-1 persistence in latent reservoirs during antiretroviral therapy (ART) is the main obstacle to virus eradication.…”