Broad Recognition of Circulating HIV-1 by HIV-1-Specific Cytotoxic T-Lymphocytes with Strong Ability to Suppress HIV-1 Replication

Abstract

HIV-1-specific cytotoxic T-lymphocytes (CTLs) with strong abilities to suppress HIV-1 replication and recognize most circulating HIV-1 strains are candidates for effector T cells for cure treatment and prophylactic AIDS vaccine. Previous studies demonstrated that the existence of CTLs specific for 11 epitopes was significantly associated with good clinical outcomes in Japan, although CTLs specific for one of these epitopes select for escape mutations. However, it remains unknown whether the CTLs specific for the remaining 10 epitopes suppress HIV-1 replication in vitro and recognize circulating HIV-1. Here, we investigated the abilities of these CTLs to suppress HIV-1 replication and to recognize variants in circulating HIV-1. CTL clones specific for 10 epitopes had strong abilities to suppress HIV-1 replication in vitro. The ex vivo and in vitro analyses of T-cell responses to variant epitope peptides showed that the T cells specific for 10 epitopes recognized mutant peptides which are detected in 84.1% to 98.8% of the circulating HIV-1 strains found in HIV-1-infected Japanese individuals. In addition, the T cells specific for 5 epitopes well recognized target cells infected with 7 mutant viruses that had been detected in >5% of tested individuals. Taken together, these results suggest that CTLs specific for the 10 epitopes effectively suppress HIV-1 replication and broadly recognize the circulating HIV-1 strains in the HIV-1-infected individuals. This study suggests the use of these T cells in clinical trials. IMPORTANCE In recent T-cell AIDS vaccine trials, the vaccines did not prevent HIV-1 infection, although HIV-1-specific T cells were induced in the vaccinated individuals, suggesting that the T cells have a weak ability to suppress HIV-1 replication and fail to recognize circulating HIV-1. We previously demonstrated that the T-cell responses to 10 epitopes were significantly associated with good clinical outcome. However, there is no direct evidence that these T cells have strong abilities to suppress HIV-1 replication and recognize circulating HIV-1. Here, we demonstrated that the T cells specific for the 10 epitopes had strong abilities to suppress HIV-1 replication in vitro. Moreover, the T cells cross-recognized most of the circulating HIV-1 in HIV-1-infected individuals. This study suggests the use of T cells specific for these 10 epitopes in clinical trials of T-cell vaccines as a cure treatment.

Non-synonymous Substitutions in HIV-1 GAG Are Frequent in Epitopes Outside the Functionally Conserved Regions and Associated With Subtype Differences

“…However, a non-synonymous substitution, E203D, was observed in CTL epitope DTINEEAAEWDR. The selection of this epitope for immune escape strains has been previously described ( Murakoshi et al, 2019 ). However, the substitution has also been shown not to impact the epitope’s immunogenicity as a vaccine construct ( Ondondo et al, 2016 ).…”

“…Despite the West African epicenter having one of the highest numbers of diverse circulating HIV-1 strains, very few longitudinal studies on HIV-1 have been reported from the region. Escape due to CTL epitopes, which is driven by frequencies of non-synonymous and synonymous substitutions ( Kosakovsky Pond et al, 2008 ; Garcia-knight et al, 2016 ), outside the functionally conserved region may be a crucial factor to consider in the design of therapeutic and universal HIV vaccines ( Murakoshi et al, 2019 ). They may also provide opportunities for compensatory mutations on replicative fitness ( Crawford et al, 2011 ).…”

Effect of Difference in Consensus Sequence between HIV-1 Subtype A/E and Subtype B Viruses on Elicitation of Gag-Specific CD8+T Cells and Accumulation of HLA-Associated Escape Mutations

“…These mutations critically affect suppression of HIV-1 replication by T cells specific for these protective epitopes (4,(26)(27)(28), suggesting a critical effect of these mutations on HIV-1 control by T cells specific for these protective epitopes. On the other hand, recent studies showed that HLA-APs are not present in 10 of 11 protective T cell epitopes among HIV-1 subtype B-infected Japanese individuals (13,29). Thus, the accumulation of escape mutations in the protective epitopes is a rare event in subtype B-infected Japanese individuals.…”

Role of Escape Mutant-Specific T Cells in Suppression of HIV-1 Replication and Coevolution with HIV-1

“…Recent studies on HIV-1 subtype B-infected Japanese individuals demonstrated that HLA-B*52:01-restricted HIV-1-specific CD8 + T cells for 4 epitopes (GagMI8 [Gag 198 to 205], GagWV8 [Gag 316 to 323], GagRI8 [Gag 275 to 282], and PolSI8 [Pol 654 to 661]) have the ability to suppress HIV-1 replication both in vivo and in vitro ( 6 , 44 ). Of these epitopes, GagMI8, GagWV8, and PolSI8 are conserved ones among the subtype B viruses, whereas GagRI8 has 3 substitutions at Gag280 (Gag280S, Gag280A, and Gag280V) in 26% of HIV-1 subtype B-infected Japanese individuals ( 6 , 45 ). A previous study on HLA-associated HIV-1 polymorphisms in HIV-1 subtype B-infected Japanese individuals showed that Gag280S and Gag280A accumulate in HLA-B*52:01 + individuals, whereas Gag280V do not ( 46 ), suggesting that Gag280S and Gag280A are escape mutations selected by HLA-B*52:01-restricted RI8-specific T cells.…”