Loss of Viral Control in Early HIV‐1 Infection Is Temporally Associated with Sequential Escape from CD8⁺T Cell Responses and Decrease in HIV–1–Specific CD4⁺and CD8⁺T Cell Frequencies

Abstract

The outcome of human immunodeficiency virus type 1 (HIV-1) infection is related to the set-point plasma virus load (pVL) that emerges after primary HIV-1 infection (PHI). This set-point pVL generally remains stable but eventually increases with progression to disease. However, the events leading to loss of viremic control are poorly understood. Here, we describe an individual who presented with symptomatic PHI and subsequently progressed rapidly, after an initial period of 1 year during which viral replication was well controlled. Escalation of viral replication in this atypical case was preceded by the emergence of escape variants in many epitopes targeted by dominant CD8 + T cell responses and a marked decrease in HIV-1-specific CD4 + and CD8 + T cell frequencies. There were no changes in viral tropism, replication kinetics, or neutralizing antibody titers. These findings demonstrate the temporal relationship between viral escape from CD8 + T cell activity, decrease in HIV-1-specific T cell frequencies, and loss of control of viral replication.Substantial evidence indicates that the adaptive immune system plays a major role in containing viral replication during HIV-1 infection [1,2]. In particular, HIV-1-specific CD8 + T cell responses are thought to mediate the decrease in the initial viremia during primary HIV-1 infection (PHI) [3,4]. After PHI, a setpoint plasma virus load (pVL) emerges that, in general, remains relatively stable throughout the chronic asymptomatic phase of infection. The magnitude of this setpoint pVL, which is likely determined by early interactions between the virus and the immune system, is inversely related to the rate of progression to AIDS [5]. However, the factors that are responsible for the maintenance of the established set-point pVL are less well defined, and it is not clear which events eventually lead to loss of control of viremia. Identification of such events requires longitudinal and comprehensive analysis of adaptive immune responses and viral evolution in patients with untreated HIV-1 infection.Here, we studied the natural course of HIV-1 infection over a period of 2 years in an individual who presented with symptomatic PHI. Initially, viral replication

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

“…It is possible that detection of HLA-associated polymorphisms at the population level is inherently biased toward detection of "straightforward" escape mutations such as those directly affecting binding to HLA, while escape mutations resulting from more complex and/or "secondary" interactions (e.g., escape from populations of TCRs capable of interacting with HLA-bound peptide) may be more challenging to detect. Indeed, numerous examples exist where an escape variant selected in one individual is highly recognized by another's immune response (38,47,63,90). Despite these caveats, recent large-scale studies of immune escape indicate that data sets of the present size have sufficient power to detect even rare escape mutations (26), as well as to detect cases where escape from one HLA allele represents the susceptible form for another (19).…”

Structural and Biological Basis of CTL Escape in Coronavirus-Infected Mice

“…These CTL escape viruses contribute to enhanced pathogenesis and disease progression (2,3). Such escape viruses have been identified in humans infected with HIV and hepatitis C virus (HCV) 4 , and in nonhuman primates infected with SIV and HCV (reviewed in Ref.…”

Preemptive priming readily overcomes structure-based mechanisms of virus escape

“…Although the NPM6I and NPM6T CTLs detected following primary infection were minimal, the homologous recall responses were substantial, similar to what happens with HIV variants (33)(34)(35). Although variation at prominent pMHCI residues may manifest as diminished recognition by existing CD8 + T cells, such mutants can recruit their own TCR repertoires, though with different degrees of effectiveness.…”