Identification of type-specific cytotoxic T lymphocyte responses to homologous viral proteins in laboratory workers accidentally infected with HIV-1.

Sipsas, Nikolaos V.; Kalams, Spyros A.; Trocha, Alicja; He, Suqin; Blattner, William A.; Walker, Bruce D.; Johnson, R. Paul

doi:10.1172/jci119221

Cited by 63 publications

(34 citation statements)

References 54 publications

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“…1b and indicates that these polymorphisms cluster near capsid helix VI (T 242 N, G 248 A, and N 252 H) or within the CypA-binding loop (H 219 Q, I 223 V, and M 228 I). This loop region does not contain putative HLA-B57 epitopes based on binding motif analysis (15), although a subdominant HLA-B7-restricted epitope does lie in this area of the capsid (4,59). Since identical T 242 Nassociated polymorphisms in the CypA loop region were observed in B7 ϩ and B7-negative individuals in this cohort (data not shown), mutations in this area are unlikely to be related to immune pressure mediated by HLA-B7.…”

Section: Resultsmentioning

confidence: 87%

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

Brockman

Schneidewind

Lahaie

et al. 2007

J Virol

243

338

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Certain histocompatibility leukocyte antigen (HLA) alleles are associated with improved clinical outcomes for individuals infected with human immunodeficiency virus type 1 (HIV-1), but the mechanisms for their effects remain undefined. An early CD8؉ T-cell escape mutation in the dominant HLA-B57-restricted Gag epitope TW10 (TSTLQEQIGW) has been shown to impair HIV-1 replication capacity in vitro. We demonstrate here that this T 242 N substitution in the capsid protein is associated with upstream mutations at residues H 219 , I 223 , and M 228 in the cyclophilin A (CypA)-binding loop in B57؉ individuals with progressive disease. In an independent cohort of epidemiologically linked transmission pairs, the presence of these substitutions in viruses encoding T 242 N was associated with significantly higher plasma viremia in donors, further suggesting that these secondary mutations compensated for the replication defect of T 242 N. Using NL4-3 constructs, we illustrate the ability of these CypA loop changes to partially restore replication of the T 242 N variant in vitro. Notably, these mutations also enhanced viral resistance to the drug cyclosporine A, indicating a reduced dependence of the compensated virus on CypA that is normally essential for optimal infectivity. Therefore, mutations in TW10 allow HIV-1 to evade a dominant early CD8 ؉ T-cell response, but the benefits of escape are offset by a defect in capsid function. These data suggest that TW10 escape variants undergo a postentry block that is partially overcome by changes in the CypA-binding loop and identify a mechanism for an HIV-1 fitness defect that may contribute to the slower disease progression associated with HLA-B57.

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Section: Resultsmentioning

confidence: 87%

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

Brockman

Schneidewind

Lahaie

et al. 2007

J Virol

243

338

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“…This observation also adds to the growing notion to include virus sequencing data in order to fully appreciate functional epitope information. The latter has been elegantly demonstrated by Sipsas et al (1997) who reported that the actual epitope sequence in autologous viruses may be quite different from the virus index sequence (e.g. HIV-1 LAI ) which is widely used to screen for CTL activity.…”

Section: Discussionmentioning

confidence: 99%

Characterization of HLA-B57-restricted human immunodeficiency virus type 1 Gag- and RT-specific cytotoxic T lymphocyte responses.

Klein

Burg

Hovenkamp

et al. 1998

Journal of General Virology

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“…51 Crrelease assays were performed as described elsewhere [31]. Briefly, HLA-matched antigen-presenting cells (T2 cells, TAPdeficient human lymphoblastoid hybridoma [32]) were labeled for 1 h with 200 lCi of Na 2 51 CrO 4 (DuPont NEN).…”

Section: Clone Generation and In Vitro Ctl Assaysmentioning

confidence: 99%

Discovery and characterization of highly immunogenic and broadly recognized mimics of the HIV‐1 CTL epitope Gag_77–85

et al. 2005

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Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) play an important role in HIV infection. Given the viral genetic diversity, the selection of suitable antigens and epitope variants will be important in the design of an effective vaccine. We have previously shown that combinatorial libraries are useful tools to identify epitope mimics as well as potentially cross-reactive natural sequences in protein databases. We have applied this approach to the HIV Gag p17-derived epitope SL9 (SLYNTVATL) to identify broadly recognized SL9 mimics and to assess the cross-recognition of naturally occurring SL9 variants. Nine nonapeptides were identified that were up to one order of magnitude more effective than SL9 in stimulating CTL responses in PBMC from HIVinfected subjects. Using transgenic mice, we demonstrate that a number of these epitope mimics were able to generate de novo T cell responses that cross-reacted with the original SL9 sequence. Particularly, mimics with changes at the relatively conserved Fpocket anchor residue were frequently cross-recognized. This approach may lead to vaccine candidates with higher in vivo immunogenicity and increased potential for cross-recognition of naturally occurring SL9 variants.

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Identification of type-specific cytotoxic T lymphocyte responses to homologous viral proteins in laboratory workers accidentally infected with HIV-1.

Cited by 63 publications

References 54 publications

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

Characterization of HLA-B57-restricted human immunodeficiency virus type 1 Gag- and RT-specific cytotoxic T lymphocyte responses.

Discovery and characterization of highly immunogenic and broadly recognized mimics of the HIV‐1 CTL epitope Gag_77–85

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Identification of type-specific cytotoxic T lymphocyte responses to homologous viral proteins in laboratory workers accidentally infected with HIV-1.

Cited by 63 publications

References 54 publications

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

Characterization of HLA-B57-restricted human immunodeficiency virus type 1 Gag- and RT-specific cytotoxic T lymphocyte responses.

Discovery and characterization of highly immunogenic and broadly recognized mimics of the HIV‐1 CTL epitope Gag77–85

Contact Info

Product

Resources

About

Discovery and characterization of highly immunogenic and broadly recognized mimics of the HIV‐1 CTL epitope Gag_77–85