Preservation of Lymphopoietic Potential and Virus Suppressive Capacity by CD8+ T Cells in HIV-2–Infected Controllers

Abstract

Compared with HIV-1, HIV-2 infection is characterized by a larger proportion of slow or nonprogressors. A better understanding of HIV-2 pathogenesis should open new therapeutic avenues to establish control of HIV-1 replication in infected patients. In this study, we studied the production of CD8+ T cells and their capacity for viral control in HIV-2 controllers from the French ANRS CO5 HIV-2 cohort. HIV-2 controllers display a robust capacity to support long-term renewal of the CD8+ T cell compartment by preserving immune resources, including hematopoietic progenitors and thymic activity, which could contribute to the long-term maintenance of the CD8+ T cell response and the avoidance of premature immune aging. Our data support the presence of HIV-2 Gag–specific CD8+ T cells that display an early memory differentiation phenotype and robust effector potential in HIV-2 controllers. Accordingly, to our knowledge, we show for the first time that HIV-2 controllers possess CD8+ T cells that show an unusually strong capacity to suppress HIV-2 infection in autologous CD4+ T cells ex vivo, an ability that likely depends on the preservation of host immune resources. This effective and durable antiviral response probably participates in a virtuous circle, during which controlled viral replication permits the preservation of potent immune functions, thus preventing HIV-2 disease progression.

Optimal maturation of the SIV-specific CD8+T-cell response after primary infection is associated with natural control of SIV. ANRS SIC study

“…SIV controllers decreased plasma viral load (VL) to levels below 400 SIV-RNA copies/mL, at least twice, over a follow up period of 18 months, while VIRs consistently maintained VL above 400 SIV-RNA copies/mL. The threshold of 400 RNA copies/mL was chosen in coherence with our studies in human cohorts of natural HIV control (Angin et al, 2016; Noel et al, 2016; Saez-Cirion et al, 2013; Saez-Cirion et al, 2007; Saez-Cirion et al, 2009). Ten SICs achieved control of viremia within 3 months.…”

“…CD8 + T-cells from HICs typically suppress ex vivo infection of autologous CD4 + T-cells (Angin et al, 2016; Buckheit et al, 2012; Julg et al, 2010; Saez-Cirion et al, 2007; Saez-Cirion et al, 2009; Tansiri et al, 2015). We therefore investigated this property as a potential discriminant between SICs and VIRs.…”

“…The capacity of CD8 + T-cells to suppress infection of autologous CD4 + T-cells directly ex vivo is a particular feature of HICs (Almeida et al, 2009; Angin et al, 2016; Buckheit et al, 2012; Julg et al, 2010; Saez-Cirion et al, 2007; Saez-Cirion et al, 2009; Tansiri et al, 2015) that is mediated by the rapid elimination of infected CD4+ T-cells (Saez-Cirion et al, 2007). Irrespective of subsequent outcome, we detected relatively weak CD8 + T-cell-mediated SIV-suppressive activity during primary infection, despite the vigorous mobilization of SIV-specific CD8 + T-cells.…”

“…These observations suggest that naturally generated HIV/SIV-specific CD8 + T-cells are frequently suboptimal in terms of antiviral efficacy, potentially reflecting limited cross-reactivity and/or intrinsic defects in the arsenal of effector functions required to eliminate infected CD4 + T-cells (Du et al, 2016; Lecuroux et al, 2013). The latter possibility is especially intriguing in light of ex vivo experiments showing that effective suppression of viral replication is a particular feature of CD8 + T-cells isolated from HIV controllers (HICs) (Angin et al, 2016; Saez-Cirion et al, 2007; Saez-Cirion et al, 2009; Tansiri et al, 2015).…”

Delayed disease progression in HIV-2: the importance of TRIM5α and the retroviral capsid

“…Gag-specific CTL responses were shown to correlate strongly and inversely with viral load in HIV-2-infected subjects, with most viraemic patients lacking gag-specific responses (which would be rare in HIV-1 infection) [80]. CD8 + cells from aviraemic patients can potently suppress viral replication in CD4 + cells; these CD8 + cells have an early differentiation phenotype and are potent effectors [81]. Therefore, there are both quantitative and qualitative differences between CTL responses in HIV-2-infected subjects with and without detectable viraemia, suggesting that the generation of a potent and effective CTL response is central to limiting HIV-2 replication.…”