CD8+ T-Cell Mediated Control of HIV-1 in a Unique Cohort With Low Viral Loads

Abstract

A unique population of HIV-1 infected individuals can control infection without antiretroviral therapy. These individuals fall into a myriad of categories based on the degree of control (low or undetectable viral load), the durability of control over time and the underlying mechanism (i.e., possession of protective HLA alleles or the absence of critical cell surface receptors). In this study, we examine a cohort of HIV-1 infected individuals with a documented history of sustained low viral loads in the absence of therapy. Through in vitro analyses of cells from these individuals, we have determined that infected individuals with naturally low viral loads are capable of controlling spreading infection in vitro in a CD8+ T-cell dependent manner. This control is lost when viral load is suppressed by antiretroviral therapy and correlates with a clinical CD4:CD8 ratio of <1. Our results support the conclusion that HIV-1 controllers with low, but detectable viral loads may be controlling the virus due to an effective CD8+ T-cell response. Understanding the mechanisms of control in these subjects may provide valuable understanding that could be applied to induce a functional cure in standard progressors.

HIV-1 controllers possess a unique CD8+ T-cell activation phenotype and loss of control is associated with increased expression of exhaustion markers

“…During chronic infection, increased upregulation of ICRs results in T-cell exhaustion, a spectrum of progressively impaired effector functions which cause a hierarchical loss of T cell functionality. Our group previously demonstrated that in vivo viral control corresponds to ex vivo suppression of viral replication in a cohort of HIV-1 controllers (51). In the current study, a cohort of HIV-1 controllers who lost the ability to control viral replication, and were subsequently placed on ART after enrollment, presents a unique opportunity to observe real time changes associated with HIV-1 viral replication and T cell exhaustion within the same subject.…”

“…This ex vivo control was shown to be mediated by CD8+ T-cells. Further, CD8+ T-cells in these controllers maintained levels of activation markers and the exhaustion marker PD-1 equivalent to uninfected individuals, unlike PLWH without a history of control who exhibited the expected increase in activation and PD-1 (51).…”

“…This ex vivo control was shown to be mediated by CD8+ T-cells. Further, CD8+ T-cells in these controllers maintained levels of activation markers and the exhaustion marker PD-1 equivalent to uninfected individuals, unlike PLWH without a history of control who exhibited the expected increase in activation and PD-1 (51). Despite their initial inherent ability to suppress viral replication in the absence of ART, mechanisms that are poorly understood cause HIV-1 controllers to eventually lose the ability to control viral replication as measured by an increase in HIV plasma viral load.…”