Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia

Abstract

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by early peaks of viraemia that decline as strong cellular immune responses develop. Although it has been shown that virus-specific CD8-positive cytotoxic T lymphocytes (CTLs) exert selective pressure during HIV and SIV infection, the data have been controversial. Here we show that Tat-specific CD8-positive T-lymphocyte responses select for new viral escape variants during the acute phase of infection. We sequenced the entire virus immediately after the acute phase, and found that amino-acid replacements accumulated primarily in Tat CTL epitopes. This implies that Tat-specific CTLs may be significantly involved in controlling wild-type virus replication, and suggests that responses against viral proteins that are expressed early during the viral life cycle might be attractive targets for HIV vaccine development.

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].…”

“…Of importance, Tat is conserved in its immunogenic regions among all M subtypes, and Tat B clade is recognized to the same extent by sera from South African, Ugandan and Italian individuals infected with A, B, C and D virus clades [28]. Further, studies in humans [29,30] and in monkeys indicate that anti-Tat CTLs are key to control virus replication early after primary infection, and that they exert a selective immune pressure on the virus leading to the appearance of slowly replicating and apparently less pathogenic escape mutants [31].…”

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.…”

Cellular immune responses against hepatitis C virus: the evidence base 2002

“…A response which is highly vigorous and efficient may rapidly lose its efficacy in vivo if viral load is not quickly contained, as this will generate escape mutation, which has been very clearly illustrated in the LCMV and SIV challenge systems [74,75]. How many effective epitopes need to be targeted is an important question, and one that is critical to vaccine design.…”