Nef interference with HIV-1–specific CTL antiviral activity is epitope specific

Adnan, Sama; Balamurugan, Arumugam; Trocha, Alicja; Bennett, Michael S.; Ng, Hwee L.; Ali, Ayub; Berthou, Christian; Yang, Otto O.

doi:10.1182/blood-2006-06-030668

Cited by 55 publications

(60 citation statements)

References 49 publications

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“…The ability of CAR-transduced CD8 ϩ T lymphocytes to suppress the replication of HIV-1 was tested as previously described in detail (2,9,11,12,(22)(23)(24). HIV-1 strains tested were obtained from the NIH AIDS Reference and Reagent Repository, including 94US_33931N (catalog number 11250), 90_US873 (catalog number 11251), 96TH_NP1538 (catalog number 11252), and 00TZ_A246 (catalog number 11256).…”

Section: Cells and Mediamentioning

confidence: 99%

HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies

Ali

Kitchen

Chen

et al. 2016

J Virol

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Although the use of chimeric antigen receptors (CARs) based on single-chain antibodies for gene immunotherapy of cancers is increasing due to promising recent results, the earliest CAR therapeutic trials were done for HIV-1 infection in the late 1990s. This approach utilized a CAR based on human CD4 as a binding domain and was abandoned for a lack of efficacy. The growing number of HIV-1 broadly neutralizing antibodies (BNAbs) offers the opportunity to generate novel CARs that may be more active and revisit this modality for HIV-1 immunotherapy. We used sequences from seven well-defined BNAbs varying in binding sites and generated single-chain-antibody-based CARs. These CARs included 10E8, 3BNC117, PG9, PGT126, PGT128, VRC01, and X5. Each novel CAR exhibited conformationally relevant expression on the surface of transduced cells, mediated specific proliferation and killing in response to HIV-1-infected cells, and conferred potent antiviral activity (reduction of viral replication in log 10 units) to transduced CD8 ؉ T lymphocytes. The antiviral activity of these CARs was reproducible but varied according to the strain of virus. These findings indicated that BNAbs are excellent candidates for developing novel CARs to consider for the immunotherapeutic treatment of HIV-1. R ecent years have seen a surge in immunotherapeutic approaches for treating malignancy, including numerous promising human trials of chimeric antigen receptor (CAR) gene therapy to generate tumor-specific T cells, based on the importance of CD8 ϩ T lymphocytes (CTLs) in tumor surveillance and malignant cell clearance through cytotoxicity. The general approach has been to identify monoclonal antibodies that bind a tumor cell surface antigen and use a single-chain version of the antibody as an artificial T cell receptor by genetic fusion to the CD3 chain signaling domain. As opposed to native T cell receptors (TCRs), CARs have the advantage of being major histocompatibility complex (MHC) unrestricted and therefore broadly applicable across human individuals and are also unaffected by tumor cell immune evasion through MHC downregulation. IMPORTANCE While chimeric antigen receptors (CARsNotably, one of the earliest tested clinical applications of CARs was for the treatment of HIV-1 infection. In 1994, Roberts et al. designed two virus-specific CARs using CD4 or a single-chain antibody as the binding domain for recombinant gp120 on the surface of cells (1), and these CARs were shown subsequently to have the direct capacity to kill HIV-1-infected cells and suppress viral replication at levels similar to those of HIV-1-specific CTL clones isolated from infected persons (2). Based on these data, the CD4-based CAR, consisting of the CD4 extracellular and transmembrane domains fused to the CD3 intracellular signaling domain (CD4 Ϫ ), was advanced to clinical trials starting in the late 1990s, using retroviral transduction of autologous peripheral blood T lymphocytes and reinfusion. Unfortunately, this effort was abandoned after these trials showed...

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Section: Cells and Mediamentioning

confidence: 99%

HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies

Ali

Kitchen

Chen

et al. 2016

J Virol

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“…HIV-infected cells expressing viral epitopes presented by HLA-C continue to be susceptible to lysis by HLA-C-restricted CTL. Prior studies using T-cell clones have shown that HLA-C-restricted CTL have equivalent cytotoxic activity relative of HLA-A-and HLA-B-restricted CTL [19,20]. There have been fewer data reported on the quantitative and qualitative characteristics of HLA-C-restricted CTL ex vivo in chronic HIV infection.…”

Section: The Phenotype Of Hla-c-restricted Ctl Is Similar To That Of mentioning

confidence: 99%

Characterization of an HLA‐C‐restricted CTL response in chronic HIV infection

et al. 2010

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HIV‐specific CTL play an important role in the host control of HIV infection. HIV‐nef may facilitate escape of HIV‐infected cells from CTL recognition by selectively downregulating the expression of HLA‐A and HLA‐B molecules, while surface expression of HLA‐C is unaffected. The HLA‐C‐restricted CTL responses have previously been largely ignored and poorly characterized. We examined the frequency, function, and phenotype of HLA‐C‐restricted CTL in ten antiretroviral therapy‐naïve Caucasian and African individuals with chronic HIV‐1 infection (for at least 8 years; CD4 cell counts in the range of 50–350) who carried the HLA‐Cw04 allele. HLA‐Cw04‐restricted CTL that recognize a conserved epitope within HIV‐1 envelope (aa 375‐383 SF9) were analyzed using IFN‐γ ELISPOT assays and phenotypic analysis was carried out by flow cytometry. HLA‐C‐restricted CTL play an important role in the HIV‐specific response, and can account for as much as 54% of the total response. HLA‐C‐restricted CTL are functionally and phenotypically identical to HLA‐A‐ and HLA‐B‐restricted CTL. HLA‐C‐restricted CTL in chronic HIV infection are memory cells of an intermediate phenotype, characterized by high CD27 and low CD28 expression and lack of perforin production.

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“…Direct evidence shows that HLA-C*07:02 presenting this peptide explicitly resists any downregulation of the complex by HIV-1 Nef, and cells presenting this complex retain susceptibility to a specific CTL attack (22). Additional reports demonstrated that only a limited number of mutations have been observed in this peptide [only V114I or D108E in early stage of infection and either K105R/Q or Q107R in a more elaborated study (23,42,43)] making it an excellent candidate for targeting.…”

Section: Discussionmentioning

confidence: 99%

“…293T (human embryonic kidney) cells were maintained in DMEM high-glucose medium containing 10% FCS, 100 U penicillin, and 100 mg/ml streptomycin. The peptides used in this study were Nef1 (residues 105-115 of HIV-1 Nef), KRQDILDLWVY (22); gp120 (residues 45-55 of HIV-1 Env), VYYGVPVWKEA (24); Conpep, KYFDEHYEY (25); and Nef2 (residues 90-97 of HIV-1 Nef), FLKEKGGL (26). Nef1 and gp120 were synthesized by M. Fridkin (Weizmann Institute of Science, Rehovot, Israel), Conpep by Genemed Synthesis (San Antonio, TX), and Nef2 by GL Biochem (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

“…Notably, the same Nef1 sequence was the consensus sequence in two independent reports that analyzed the variation of HIV-1 Nef in different patients (20,21). Moreover, HLA-C*07:02 presenting the specific Nef-derived peptide (that is identical to Nef1 but with an Arg instead of a Lys residue in the first position) is the only HLA complex that has ever been shown to resist specifically any downregulation from the cell surface by HIV-1 Nef (22). The Nef1 epitope was also reported to be within a frequently targeted and immunodominant region in different human ethnicities (17).…”

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