Different Abilities of Escape Mutant-Specific Cytotoxic T Cells To Suppress Replication of Escape Mutant and Wild-Type Human Immunodeficiency Virus Type 1 in New Hosts

Abstract

There is much evidence that in human immunodeficiency virus type 1 (HIV-1)-infected individuals, strong cytotoxic T lymphocyte (CTL)-mediated immune pressure results in the selection of HIV-1 mutants that have escaped from wild-type-specific CTLs. If escape mutant-specific CTLs are not elicited in new hosts sharing donor HLA molecules, the transmission of these mutants results in the accumulation of escape mutants in the population. However, whether escape mutant-specific CTLs are definitively not elicited in new hosts sharing donor HLA molecules still remains unclear. A previous study showed that a Y-to-F substitution at the second position (2F) of the Nef138-10 epitope is significantly detected in HLA-A*2402 ؉ hemophilic donors. Presently, we confirmed that this 2F mutant was an escape mutant by demonstrating strong and weak abilities of Nef138-10-specific CTL clones to suppress replication of the wild-type and 2F mutant viruses, respectively. We demonstrated the existence of the 2F-specific CTLs in three new hosts who had been primarily infected with the 2F mutant. The 2F-specific CTL clones suppressed the replication of both wild-type and mutant viruses. However, the abilities of these clones to suppress replication of the 2F virus were much weaker than those of wild-type-specific and the 2F-specific ones to suppress replication of the wild-type virus. These findings indicate that the 2F mutant is conserved in HIV-1-infected donors having HLA-A*2402, because the 2F-specific CTLs failed to completely suppress the 2F mutant replication and effectively prevented viral reversion in new hosts carrying HLA-A*2402.

Host-Specific Adaptation of HIV-1 Subtype B in the Japanese Population

“…An interesting feature of the Japanese population is that approximately 70% of individuals carry HLA-A*24:02 (23). Despite sufficient statistical power to detect HLA-A*24:02-associated polymorphisms in our cohort, we identified only 9 of them, 6 of which were located in epitopes identified by our group (33)(34)(35). A possible explanation for the relatively low number of A*24:02-associated polymorphisms in Japan is that they have accumulated over time in circulating sequences so that they are no longer significantly enriched among persons expressing HLA-A*24:02.…”

CTL recognition of HIV‐1‐infected cells via cross‐recognition of multiple overlapping peptides from a single 11‐mer Pol sequence

“…HIV-1-specific CD8 + T cells recognize peptides derived from HIV-1 proteins presented by HLA class I molecules on HIV-1-infected cells, and effectively although not completely control the replication of HIV-1 [1,5,11,12]. Although any given HLA class I allele presents 8-mer to 11-mer peptides derived from different parts of HIV-1, it is also known that overlapping HIV-1 epitope Correspondence: Prof. Masafumi Takiguchi e-mail: masafumi@kumamoto-u.ac.jp peptides of different lengths from 8-mer to 11-mer from a given region can be presented by the same HLA class I molecule [13][14][15][16][17][18][19][20][21].…”

“…HIV-1-specific CD8 + T cells recognize peptides derived from HIV-1 proteins presented by HLA class I molecules on HIV-1-infected cells, and effectively although not completely control the replication of HIV-1 [1, 5,11,12]. Although any given HLA class I allele presents 8-mer to 11-mer peptides derived from different parts of HIV-1, it is also known that overlapping HIV-1 epitope processed peptides eluted from HIV-1 Nef-expressing cells [17]; and cells pulsed with proteasomal digests of HIV-1 protein derived fragments [16,17].…”

DifferentIn VivoEffects of HIV-1 Immunodominant Epitope-Specific Cytotoxic T Lymphocytes on Selection of Escape Mutant Viruses

“…These may include the appearance of HIV-1 carrying escape mutations in its immunodominant CTL epitopes as well as Nef-mediated downregulation of HLA class I molecules. There is a growing body of evidence for the former mechanism, i.e., that CTLs targeting immunodominant HIV-1 epitopes select escape mutants in chronically HIV-1-infected individuals (18,20,36), whereas the latter mechanism was proved by demonstrating that HIV-1-specific CTLs fail to kill Nef-positive-HIV-1-infected CD4 ϩ T cells but effectively kill Nef-defective-HIV-1-infected ones or that they suppress the replication of Nef-defective HIV-1 much more than that of Nef-positive HIV-1 (12,13,42,45).…”

“…However, the results obtained from such experiments do not reflect the ability of the CTLs to exert immune pressure in vivo. We and other groups previously utilized an assay to directly evaluate the ability of the CTLs to suppress HIV-1 replication in vitro (1,17,18,42,43). This assay may be better for evaluation of immune pressure by HIV-1-specific CTLs than other assays, because the ability of the CTLs to suppress HIV-1 replication is directly measured in cultures of HIV-1-infected CD4 ϩ T cells incubated with HIV-1-specific CTL clones.…”