Person:
Leitman, Ellen

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Leitman

First Name

Ellen

Name

Leitman, Ellen
Author's Publications: search.filters.isAuthorOfPublication.bf684fe7-2976-4558-bee7-e594982f91c7

Search Results

Now showing 1 - 3 of 3
  • Thumbnail Image
    Publication
    Post-treatment control or treated controllers? Viral remission in treated and untreated primary HIV infection
    (Lippincott Williams & Wilkins, 2017) Martin, Genevieve E.; Gossez, Morgane; Williams, James P.; Stöhr, Wolfgang; Meyerowitz, Jodi; Leitman, Ellen; Goulder, Philip; Porter, Kholoud; Fidler, Sarah; Frater, John
    Objective(s): An HIV cure will impose aviraemia that is sustained following the withdrawal of antiretroviral therapy (ART). Understanding the efficacy of novel interventions aimed at curing HIV requires characterization of both natural viral control and the effect of ART on viral control after treatment interruption. Design: Analysis of transient viral control in recent seroconverters in the Short Pulse AntiRetroviral Therapy at Acute Seroconversion trial. Methods: We compared untreated and treated HIV seroconverters (n = 292) and identified periods of control (plasma HIV RNA < 400 copies/ml for ≥16 weeks off therapy) in 7.9% of ART-naive participants, and in 12.0% overall. HIV DNA was measured by qPCR, and HIV-specific CD8+ responses were measured by enzyme-linked immunosorbent spot assay (ELISpot). T-cell activation and exhaustion were measured by flow cytometry. Results: At baseline, future controllers had lower HIV DNA, lower plasma HIV RNA, higher CD4+ : CD8+ ratios (all P < 0.001) and higher CD4+ cell counts (P < 0.05) than noncontrollers. Among controllers, the only difference between the untreated and those who received ART was higher baseline HIV RNA in the latter (P = 0.003), supporting an added ART effect. Conclusion: Consideration of spontaneous remission in untreated individuals will be critical to avoid overestimating the effect size of new interventions used in HIV cure studies.
  • Thumbnail Image
    Publication
    Saporin-conjugated tetramers identify efficacious anti-HIV CD8+ T-cell specificities
    (Public Library of Science, 2017) Leitman, Ellen; Palmer, Christine D.; Buus, Søren; Chen, Fabian; Riddell, Lynn; Sims, Stuart; Klenerman, Paul; Sáez-Cirión, Asier; Walker, Bruce; Hess, Paul R.; Altfeld, Marcus; Matthews, Philippa C.; Goulder, Philip J. R.
    Antigen-specific T-cells are highly variable, spanning potent antiviral efficacy and damaging auto-reactivity. In virus infections, identifying the most efficacious responses is critical to vaccine design. However, current methods depend on indirect measures or on ex vivo expanded CTL clones. We here describe a novel application of cytotoxic saporin-conjugated tetramers to kill antigen-specific T-cells without significant off-target effects. The relative efficacy of distinct antiviral CD8+ T-cell specificity can be directly assessed via antigen-specific CD8+ T-cell depletion. The utility of these reagents is demonstrated here in identifying the CD8+ T-cell specificity most effective in preventing HIV progression in HIV-infected HLA-B*27-positive immune controllers.
  • Thumbnail Image
    Publication
    HLA-B*14:02-Restricted Env-Specific CD8+ T-Cell Activity Has Highly Potent Antiviral Efficacy Associated with Immune Control of HIV Infection
    (American Society for Microbiology, 2017) Leitman, Ellen; Willberg, Christian B.; Tsai, Ming-Han; Chen, Huabiao; Buus, Søren; Chen, Fabian; Riddell, Lynn; Haas, David; Fellay, Jacques; Goedert, James J.; Piechocka-Trocha, Alicja; Walker, Bruce; Martin, Jeffrey; Deeks, Steven; Wolinsky, Steven M.; Martinson, Jeremy; Martin, Maureen; Qi, Ying; Sáez-Cirión, Asier; Yang, Otto O.; Matthews, Philippa C.; Carrington, Mary; Goulder, Philip J. R.
    ABSTRACT Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B*14, which protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B*14-EL9). A subdominant HLA-B*14-restricted response targets Gag (DRYFKTLRA, HLA-B*14-DA9). Using HLA-B*14/peptide-saporin-conjugated tetramers, we show that HLA-B*14-EL9 is substantially more potent at inhibiting viral replication than HLA-B*14-DA9. HLA-B*14-EL9 also has significantly higher functional avidity (P < 0.0001) and drives stronger selection pressure on the virus than HLA-B*14-DA9. However, these differences were HLA-B*14 subtype specific, applying only to HLA-B*14:02 and not to HLA-B*14:01. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV. IMPORTANCE: In HIV infection, although cytotoxic T lymphocytes (CTL) play a potentially critical role in eradication of viral reservoirs, the features that constitute an effective response remain poorly defined. We focus on HLA-B*14, unique among HLAs associated with control of HIV in that the dominant CTL response is Env specific, not Gag specific. We demonstrate that Env-specific HLA-B*14-restricted activity is substantially more efficacious than the subdominant HLA-B*14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV are observed only in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This reflects the increased functional avidity of the Env response over Gag, substantially more marked for HLA-B*14:02. Finally, we show that HLA-B*14:02 is significantly more strongly associated with viremic control than HLA-B*14:01. These findings indicate that, although Gag-specific CTL may usually have greater anti-HIV efficacy than Env responses, factors independent of protein specificity, including functional avidity, may carry greater weight in mediating effective control of HIV.