Summary of the publications

Summary of the publications

2017-2018

Hayato Murakoshi, Madoka Koyanagi, Tomohiro Akahoshi, Takayuki Chikata, Nozomi Kuse, Hiroyuki Gatanaga, Sarah L Rowland-Jones, Shinichi Oka, and Masafumi Takiguchi, Impact of a Single HLA-A*24:02-associated Escape Mutation on the Detrimental Effect of HLA-B*35:01 in HIV-1 Control, EBioMedicine 36:103-112, 2018

BACKGROUND: HLA-B*35 is an HLA allele associated with rapid progression to AIDS. However, a mechanism underlying the detrimental effect of HLA-B*35 on disease outcome remains unknown. Recent studies demonstrated that most prevalent subtype HLA-B*35:01 is a detrimental allele in HIV-1 clade B-infected individuals. We here investigated the effect of mutations within the epitopes on HLA-B*35:01-restricted CD8+ T cells having abilities to suppress HIV-1 replication.
METHODS: We analyzed 16 HLA-B*35:01-restricted epitope-specific T cells in 63 HIV-1 clade B-infected Japanese B*35:01+ individuals and identified HLA-B*35:01-restricted CD8+ T cells having abilities to suppress HIV-1 replication. We further analyzed the effect of HLA-associated mutations on the ability of these T cells.
FINDINGS: The breadth of T cell responses to 4 epitopes was inversely associated with plasma viral load (pVL). However, the accumulation of an Y135F mutation in NefYF9 out of the 4 epitopes, which is selected by HLA-A*24:02-restricted T cells, affected the ability of YF9-specific T cells to suppress HIV-1 replication. HLA-B*35:01+ individuals harboring this mutation had much higher pVL than those without it. YF9-specific T cells failed to suppress replication of the Y135F mutant in vitro. These results indicate that this mutation impairs suppression of HIV-1 replication by YF9-specific T cells.
INTERPRETATION: These findings indicate that the Y135F mutation is a key factor underlying the detrimental effect of HLA-B*35:01 on disease outcomes in HIV-1 clade B-infected individuals.

Takayuki Chikata*, Giang Van Tran*, Hayato Murakoshi, Tomohiro Akahoshi, Ying Qi, Vivek Naranbhai, Nozomi Kuse, Yoshiko Tamura, Madoka Koyanagi, Sachiko Sakai, Dung Hoai Nguyen, Dung Thi Nguyen, Ha Thu Nguyen, Trung Vu Nguyen, Shinichi Oka, Maureen P. Martin, Mary Carrington, Keiko Sakai, Kinh Van Nguyen, and Masafumi Takiguchi (*Equal contribution), HLA class I-mediated HIV-1 control in Vietnamese infected with HIV-1 subtype A/E, J. Virol. 92:e01749-17, 2018

HIV-1-specific cytotoxic T cells (CTLs) play an important role in the control of HIV-1 subtype B or C infection. However, the role of CTLs in HIV-1 subtype A/E infection still remains unclear. Here we investigated the association of HLA class I alleles with clinical outcome in treatment-naive Vietnamese infected with subtype A/E. We found that HLA-C*12:02 was significantly associated with lower pVL and higher CD4 count and that the HLA-A*29:01-B*07:05-C*15:05 haplotype was significantly associated with higher pVL and lower CD4 count as compared to individuals without these respective genotypes. Nine Pol and three Nef mutations were associated with at least one HLA allele in the HLA-A*29:01-B*07:05-C*15:05 haplotype, where a strong negative correlation between the number of HLA-associated Pol mutations and CD4 count as well as a positive correlation with pVL in individuals with these HLA alleles were observed. The results suggest that the accumulation of mutations selected by CTLs restricted by these HLA alleles affect HIV control.ImportanceMost previous studies on HLA association with disease progression after HIV-1 infection have been performed in cohorts infected with HIV-1 subtypes B and C, whereas few such population-based studies have reported in cohorts infected with the Asian subtype A/E virus. In this study, we analyzed the association of HLA class I alleles with clinical outcomes in 536 HIV-1 subtype A/E infected Vietnamese individuals. We found that HLA-C*12:02 is protective while the HLA haplotype HLA-A*29:01-B*07:05-C*15:05 is deleterious. The individuals with HIV-1 mutations associated with at least one of the HLA alleles in the deleterious HLA haplotype had higher plasma viral load and lower CD4 counts than those without the mutations, suggesting viral adaptation and escape from HLA-mediated immune control. The present study identified a protective allele and a deleterious haplotype in the subtype A/E infection, which are different from those identified in cohorts infected with HIV-1 subtypes B and C.

Center for AIDS Research Best Paper Award 2017
Takayuki Chikata*, Hayato Murakoshi,* Madoka Koyanagi, Kazutaka Honda, Hiroyuki Gatanaga, Shinichi Oka, and Masafumi Takiguchi　(*Equal contribution), Control of HIV-1 by an HLA-B*52:01-C*12:02 protective haplotype, J. Infect. Dis. 216:1415-1424, 2017

HLA-B*52:01-C*12:02, which is found in approximately 20% of all Japanese persons, is well known to be associated with ulcerative colitis and Takayasu arteritis. This haplotype is also known to be protective in individuals infected with human immunodeficiency virus (HIV) type 1. Recent studies showed that HLA-B*52:01-restricted HIV-1-specific T cells suppress HIV-1 and that HLA-C*12:02 together with KIR2DL2 play an important role in natural killer cell-mediated control of HIV-1. However, the role of HLA-C*12:02-restricted cytotoxic T lymphocytes (CTLs) in suppressing HIV-1 replication remains unknown. In the present study, we demonstrated that HLA-C*12:02-restricted CTLs specific for 2 immunodominant epitopes, Pol IY11 and Nef MY9, contributed to the suppression of HIV-1 replication in HIV-1-infected individuals. Further analysis demonstrated that these 2 HLA-C*12:02-restricted CTLs together with 4 HLA-B*52:01-restricted ones effectively suppressed HIV-1 in individuals with the HLA-B*52:01-C*12:02 haplotype. Thus, both HLA-C*12:02 and HLA-B*52:01 alleles contribute to HIV-1 suppression via both HIV-1-specific CTLs and natural killer cells in individuals with this haplotype.

Hayato Murakoshi,* Madoka Koyanagi,* Takayuki Chikata, Mohammad Arif Rahman, Nozomi Kuse, Keiko Sakai, Hiroyuki Gatanaga, Shinichi Oka, and Masafumi Takiguchi (*Equal contribution), Accumulation of Pol mutations selected by HLA-B*52:01-C*12:02 protective haplotype-restricted CTLs causes low plasma viral load due to low viral fitness of mutant viruses, J. Virol, 91:e02082-16, 2017

HLA-B*52:01-C*12:02, which is the most abundant haplotype in Japan, has a protective effect on disease progression in HIV-1-infected Japanese individuals, whereas HLA-B*57 and -B*27 protective alleles are very rare in Japan. A previous study on HLA-associated polymorphisms demonstrated that the number of HLA-B*52:01-associated mutations at four Pol positions was inversely correlated with plasma viral load (pVL) in HLA-B*52:01-negative individuals, suggesting that the transmission of HIV-1 with these mutations could modulate the pVL in the population. However, it remains unknown whether these mutations were selected by HLA-B*52:01-restricted CTLs and also reduced viral fitness. In this study, we identified two HLA-B*52:01-restricted and one HLA-C*12:02-restricted novel cytotoxic T-lymphocyte (CTL) epitopes in Pol. Analysis using CTLs specific for these three epitopes demonstrated that these CTLs failed to recognize mutant epitopes or more weakly recognized cells infected with mutant viruses than wild-type virus, supporting the idea that these mutations were selected by the HLA-B*52:01- or HLA-C*12:02-restricted T cells. We further showed that these mutations reduced viral fitness, although the effect of each mutation was weak. The present study demonstrated that the accumulation of these Pol mutations selected by HLA-B*52:01- or HLA-C*12:02-restricted CTLs impaired viral replication capacity and thus reduced the pVL. The fitness cost imposed by the mutations partially accounted for the effect of the HLA-B*52:01-C*12:02 haplotype on clinical outcome, together with the effect of HLA-B*52:01-restricted CTLs on viral replication, which had been previously demonstrated.
IMPORTANCE: Numerous population-based studies identified HLA-associated HIV-1 mutations to predict HIV-1 escape mutations from cytotoxic T lymphocytes (CTLs). However, the majority of these HLA-associated mutations have not been identified as CTL escape mutations. Our previous population-based study showed that five HLA-B*52:01-associated mutations at four Pol positions were inversely correlated with the plasma viral load in HLA-B*52:01-negative Japanese individuals. In the present study, we demonstrated that these mutations were indeed selected by CTLs specific for novel B*52:01- and C*12:02-restricted epitopes and that the accumulation of these mutations reduced the viral fitness in vitro This study elucidated the mechanism by which the accumulation of these CTL escape mutations contributed to the protective effect of the HLA-B*52:01-HLA-C*12:02 haplotype on disease progression in HIV-1-infected Japanese individuals.

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