Long-Term Control of HIV-1 in Hemophiliacs Carrying Slow-Progressing Allele HLA-B*5101

Abstract

HLA-B*51 alleles are reported to be associated with slow disease progression to AIDS, but the mechanism underlying this association is still unclear. In the present study, we analyzed the effect of HLA-B*5101 on clinical outcome for Japanese hemophiliacs who had been infected with HIV-1 before 1985 and had been recruited in 1998 for this study. HLA-B*5101+ hemophiliacs exhibited significantly slow progression. The analysis of HLA-B*5101-restricted HIV-1-specific cytotoxic T-lymphocyte (CTL) responses to 4 HLA-B*-restricted epitopes in 10 antiretroviral-therapy (ART)-free HLA-B*5101+ hemophiliacs showed that the frequency of Pol283-8-specific CD8+ T cells was inversely correlated with the viral load, whereas the frequencies of CD8+ T cells specific for 3 other epitopes were positively correlated with the viral load. The HLA-B*5101+ hemophiliacs whose HIV-1 replication had been controlled for approximately 25 years had HIV-1 possessing the wild-type Pol283-8 sequence or the Pol283-8V mutant, which does not critically affect T-cell recognition, whereas other HLA-B*5101+ hemophiliacs had HIV-1 with escape mutations in this epitope. The results suggest that the control of HIV-1 over approximately 25 years in HLA-B*5101-positive hemophiliacs is associated with a Pol283-8-specific CD8+ T-cell response and that lack of control of HIV-1 is associated with the appearance of Pol283-8-specific escape mutants.

Selection of TI8-8V Mutant Associated with Long-Term Control of HIV-1 by Cross-Reactive HLA-B*51:01–Restricted Cytotoxic T Cells

“…A previous study showed that the 8V mutation weakly reduced the recognition of TI8-specific CTL clones established from KI-051 in July 2002 (34,35). We first reconfirmed this finding by using three TI8-specific CTL clones (2B5, 2C6, and 2D1), which were established from KI-051 in July 2002 when the WT virus was still detectable.…”

“…HLA class I-peptide tetrameric complexes (tetramers) were generated as described previously (34). CTL clones were stained with PE-conjugated tetramers at 37˚C for 30 min.…”

“…A previous study showed that the HLA-B*51:01 allele was associated with long-term control of HIV-1 in HIV-1-infected Japanese hemophiliacs, and the frequency of HLA-B*51:01-restricted Pol283-290 (TI8: TAFTIPSI)-specific CD8 + T cells was inversely associated with plasma VL in HIV-1-infected ones (34), suggesting an important role of TI8-specific CD8 + T cells in the long-term control of HIV-1 infections. Four mutations (8T, 8L, 8R, and 8V) at position 8 of the TI8 epitope were significantly detectable in HLA-B*51 + individuals more than in HLA-B*51 2 individuals, suggesting that these mutations were selected by TI8-specific CTLs (35).…”

“…TI8-specific CTLs have a strong ability to suppress the replication of wild-type (WT) and the 8V mutant viruses in vitro but fail to suppress that of the 8T, 8L, and 8R mutant viruses (35,36). A study using a Japanese hemophiliac cohort showed that the 8V mutation is found in only HLA-B*B51:01 + elite controllers (34), suggesting that the selection of the 8V mutant virus is a critical factor for long-term control of HIV-1 in Japanese hemophiliacs. However, the mechanism underlying selection of the 8V virus in HLA-B*51:01 + elite controllers remains unclear.…”

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

“…Cross-recognition r CTL r HIV r Peptides r T cells Supporting Information available online Introduction CD8 + T cells play important roles in controlling HIV-1 [1][2][3][4][5][6][7][8][9][10]. 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].…”