Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection

Abstract

Cytotoxic T-lymphocyte (CTL) responses peak coincident with the decline in acute HIV viremia. Despite two reports of CTL-resistant HIV variants emerging during acute infection, the contribution of acute CTL escape to HIV pathogenesis remains unclear. Difficulties inherent in studying acute HIV infection can be overcome by modeling virus-host interactions in SIV-infected rhesus macaques. We sequenced 21 complete simian immunodeficiency virus (SIV)mac239 genomes at four weeks post-infection to determine the extent of acute CTL escape. Here we show that viruses from 19 of 21 macaques escaped from CTLs during acute infection and that these escape-selecting CTLs were responsive to lower concentrations of peptide than other SIV-specific CTLs. Interestingly, CTLs that require low peptide concentrations for stimulation (high 'functional avidity') are particularly effective at controlling other viral infections. Our results suggest that acute viral escape from CTLs is a hallmark of SIV infection and that CTLs with high functional avidity can rapidly select for escape variants.

Long-term protection against SHIV89.6P replication in HIV-1 Tat vaccinated cynomolgus monkeys

“…In a SIV model utilizing a molecular clone for the challenge, a strong correlation was found between the resolution of plasma viremia and the detection of a dominant CTL response against a Tat epitope (Tat 28-35 SL8) leading to the appearance of viral variants with an apparently reduced fitness [31]. Subsequent studies demonstrated that CTLs with high functional avidity for the early and intermediate proteins Tat, Nef and Vpr were the major factor driving the selection of immune escape variants during acute SIV infection [63]. More recent data measuring inhibition of HIV-1 replication by CTLs clones with known avidity and specificity indicate that, in vitro, the fine epitope specificity might be the most important factor at determining control of virus replication and selection of virus variants [64].…”

Simian-Human Immunodeficiency Virus Escape from Cytotoxic T-Lymphocyte Recognition at a Structurally Constrained Epitope

“…If, as some have suggested, CTL initially target early gene products, such as Tat and Nef, and only later in the course of infection target structural gene products (14), then the selection pressure will be greatest on early gene products during primary infection and on structural proteins during chronic infection. It has been suggested that early high-avidity CTL specific for Tat and Nef select for escape viruses more frequently than do late lowavidity CTL specific for Gag (26). This paradigm has, however, not been confirmed in in vitro studies with CTL clones with different avidities for the same epitope (37).…”

Engineering RENTA, a DNA prime-MVA boost HIV vaccine tailored for Eastern and Central Africa

“…Despite initial successful reports, 31,32 subsequent studies failed to demonstrate protective efficacy of Tat-specific CTL only. 33,34 Nevertheless, simian immunodeficiency virus (SIV) Tat is an early protein against which responses impose a selective pressure on incoming virus, 35 and therefore it is an important component for a prophylactic vaccine. RT was included into the RENTA immunogen because it is a relatively conserved protein with a large number of identified CTL epitopes.…”