Limited Sequence Evolution within Persistently Targeted CD8 Epitopes in Chronic Human Immunodeficiency Virus Type 1 Infection

Abstract

Studies in acute human immunodeficiency virus type 1 (HIV-1) infection indicate viral evolution under CD8T-cell immune selection pressure, but the effects of ongoing immune pressure on epitope evolution during chronic infection are not well described. In this study, we performed a detailed longitudinal analysis of viral sequence variation within persistently targeted cytotoxic T-lymphocyte (CTL) epitopes in two HIV-1-infected persons during 6 years of persistent viremia. Responses were quantitated using freshly isolated peripheral blood lymphocytes in direct lytic assays as well as by gamma interferon (IFN-␥) Elispot assays on cryopreserved cells. Seven targeted epitopes were identified in each person. In the majority of cases, the dominant epitope sequence did not change over time, even in the presence of responses of sufficient magnitude that they were detectable using fresh peripheral blood mononuclear cells in direct lytic assays. Only 4 of the 14 autologous epitopes tested represented potential CTL escape variants; however, in most cases strong responses to these epitopes persisted for the 6 years of study. Although persistent IFN-␥ responses were detected to all epitopes, direct lytic assays demonstrated declining responses to some epitopes despite the persistence of the targeted sequence in vivo. These data indicate limited viral evolution within persistently targeted CD8 T-cell epitopes during the chronic phase of infection and suggest that these regions of the virus are either refractory to sequence change or that persistently activated CD8 T-cell responses in chronic infection exert little functional selection pressure.

CD8 T-Cell Recognition of Multiple Epitopes within Specific Gag Regions Is Associated with Maintenance of a Low Steady-State Viremia in Human Immunodeficiency Virus Type 1-Seropositive Patients

“…It is noteworthy that the three subjects that possess protective allele B8101, but with high viral loads, also targeted this epitope. The persistence of unaltered yet targeted epitopes during the course of chronic HIV infection has also been demonstrated in two recent studies (9,19).…”

“…IFN-␥ is a sensitive marker for HIV-specific CD8 T-cell activation; however, virus-specific cytolytic activity and IFN-␥ secretion upon restimulation do not necessarily correlate during chronic HIV infection (3,9,19). This dislinkage of cytolytic activity and IFN-␥ secretion has been ascribed to a phenomenon known as the "partial functional exhaustion" of T cells.…”

The Impairment of CD8 Responses Limits the Selection of Escape Mutations in Acute Hepatitis C Virus Infection

“…To investigate the role of this mechanism in HCV pathobiology, particular attention was paid in our study to analyze the global T cell reactivity to identify the most dominant CD8 epitopes and to follow their evolution over time, because immunodominant CD8 responses are more likely to exert a strong selective pressure on the virus and to drive escape (32,(35)(36)(37)(38). Moreover, the quality of the different epitope-specific CD8 responses was carefully characterized because it is increasingly clear that not all Ag-specific CD8 ϩ cells are equally effective in viral clearance and that the avidity of these cells is one of the variables that can greatly impact on their antiviral efficacy (29 -32).…”

The Rate of Immune Escape Vanishes When Multiple Immune Responses Control an HIV Infection

“…All in all, this was taken as evidence suggesting that the virus is largely controlled by other mechanisms during chronic infection (12). However, it is known that CTL responses persist (14,15), and that new CTL responses develop in chronically infected patients (11). Another major aim of this work is to show that the minor selection pressure was to be expected when several CTL clonotypes together control the infection, and, although each of them has very little impact on the control of the infection, they together can play an essential role.…”

“…Several studies have documented very slow escapes and slow sequence evolution during chronic infection (12)(13)(14)(15)(16). The consensus interpretation of these slow takeover rates during chronic infection is that even the dominant CTL clonotypes impose a very minor selection pressure and play a very minor role in controlling the virus (12).…”