Collaboration of a Detrimental HLA-B*35:01 Allele with HLA-A*24:02 in Coevolution of HIV-1 with T Cells Leading to Poorer Clinical Outcomes

Abstract

Although mutant-specific T-cells are elicited in some individuals infected with HIV-1 mutant viruses, the detailed characteristics of these T-cells remain unknown. A recent study showed that the accumulation of strains expressing Nef135F, which were selected by HLA-A*24:02-restricted T-cells, was associated with poor outcomes in individuals with the detrimental HLA-B*35:01 allele, and that HLA-B*35:01-restricted NefYF9(Nef135-143)-specific T-cells failed to recognize target cells infected with Nef135F mutant viruses. Here we investigated HLA-B*35:01-restricted T-cells specific for the NefFF9 epitope incorporating the Nef135F mutation. Longitudinal TCR clonotype analysis demonstrated that 3 types of HLA-B*35:01-restricted T-cells (wild type-specific, mutant-specific, and cross-reactive) with different T-cell repertoires were elicited during the clinical course. HLA-B*35:01 + individuals possessing wild type-specific T-cells had a significantly lower pVL than those with mutant-specific and/or cross-reactive T-cells, even though the latter T-cells effectively recognized the mutant virus-infected cells. These results suggest that mutant-specific and cross-reactive T-cells could only partially suppress HIV-1 replication in vivo. Ex vivo analysis of the T-cells showed higher expression of PD-1 on cross-reactive T-cells and lower expression of CD160/2B4 on the mutant-specific T cells than other T-cells, implying that these inhibitory and stimulatory molecules are key to the reduced function of these T-cells. In the present study, we demonstrate that mutant-specific and cross-reactive T-cells do not contribute to suppression of HIV-1 replication in HIV-1-infected individuals, even though they have the capacity to recognize mutant virus-infected cells. Thus, the collaboration of HLA-A*24:02 with the detrimental allele HLA-B*35:01 resulted in the co-evolution of HIV-1 alongside virus-specific T-cells, leading to poorer clinical outcomes. Importance HIV-1 escape mutations are selected under pressure from HIV-1-specific CD8 + T-cells. Accumulation of these mutations in circulating viruses impairs control of HIV-1 by HIV-1-specific T-cells. Although it is known that HIV-1-specific T-cells recognizing mutant virus were elicited in some individuals infected with mutant virus, the role of these T-cells remains unclear. Accumulation of Phenylalanine at HIV-1 Nef135 (Nef135F), which is selected by HLA-A*24:02-restricted T-cells, led to poor clinical outcome in individuals carrying the detrimental HLA-B*35:01 allele. In the present study, we found that HLA-B*35:01-restricted mutant-specific and cross-reactive T-cells were elicited in HLA-B*35:01 + individuals infected with Nef135F mutant virus. These T-cells could not effectively suppress HIV-1 replication in vivo even though they could recognize mutant virus-infected cells in vitro . Mutant-specific and cross-reactive T-cells expressed lower levels of stimulatory molecules and higher levels of inhibitory molecules, respectively, suggesting a potential mechanism whereby these T-cells fail to suppress HIV-1 replication in HIV-1-infected individuals.

Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant

“…However, our finding that concurrent treatment with ganciclovir is associated with a lower response rate raises concerns that the reported immunosuppressive effects of this antiviral (7,42,43) Conversely, the consistent failure (0/7) of subjects treated with CMVpp65-VSTs restricted by allelic variants of HLA B35 to respond was highly significant (p=<0.001). Previously, inheritance of B35 has been associated with rapid progression of HIV (47)(48)(49) postulated to be due to the reduced antiviral activity of T-cells specific for particular epitopes presented by HLA B35 alleles (50,51). However, the mechanisms contributing to the altered activity observed are not well defined.…”

Contribution of the HIV-1 Envelope Glycoprotein to AIDS Pathogenesis and Clinical Progression

“…This control is the result of many elements and the activity of different cell types, such as CD4+ and CD8+ T cells, natural killers (NKs), dendritic cells (DCs), different types of antibodies (Abs), cell restrictions factors, human leucocyte antigens (HLAs) genotypes and/or host factors like CCR5 protective mutations [ 26 , 44 , 45 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 56 , 61 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ], as summarized in Figure 1 . In addition, HLA-B genotypes HLA-B57/B58 or -B27 [ 63 ], HLA-B*35:01 [ 74 , 75 ] and HLA-C [ 26 , 76 , 77 ], such as the HLA-C*03:02 1 in an African Pediatric Population [ 78 ], are linked with the control of HIV-1 infection ( Figure 1 , non-progressors bottom box). In some LTNP individuals [ 79 ] that harbor viruses with low replication capacity [ 80 , 81 , 82 , 83 ], the HIV-1 LTNP phenotype has been associated with the presence of potent and broad cytotoxic T lymphocyte (CTL) responses [ 66 , 84 ] ( Figure 1 , non-progressors bottom box) and active NK cells.…”