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AIDS (London, England)
 
AIDS. 2016 March 27; 30(6): 972–974.
Published online 2016 March 7. doi:  10.1097/QAD.0000000000001022
PMCID: PMC4788062
NIHMSID: NIHMS755591

Subdominant Gag-specific anti-HIV efficacy in an HLA-B*57-positive elite controller

Despite the discovery of HIV over three decades ago, the 2008 ‘Berlin patient’ is the only case of sustained HIV remission. Other cases of apparent ‘cure’ eventually relapsed [1] and although early antiretroviral therapy (ART) has recently gained traction as a factor contributing to remission [2,3], most cases are likely to relapse [4]. In contrast, relapse in ‘elite controllers’ of HIV infection is less common. These are ART-naïve individuals who spontaneously suppress viremia to undetectable levels. Approximately 40% of elite controllers express HLA-B*57 [5], an example being the original 1999 ‘Berlin patient’, in whom virologic control has been maintained for >15 years to date [6].

Mechanisms proposed to explain HLA-B*57-mediated immune control include immunodominant CD8+ T-cell-targeting of multiple conserved Gag epitopes from which mutational escape is detrimental to viral fitness, characteristics of the T-cell receptor on HLA-B*57-restricted CD8+ T cells, HLA-B*57-peptide binding affinity, and HLA-B*57 cross-talk with innate immune cells [7]. However, some HLA-B*57-positive elite controllers have no detectable Gag-specific responses without ex-vivo expansion [8,9]. Here, we studied one such elite controller, to determine whether the immunodominant CD8+ T-cell response in such cases mediates the most potent antiviral efficacy, as Gag-specific CD8+ T-cell responses typically have greater capacity to inhibit viral replication than non-Gag specificities [10,11].

An African-Caribbean female was recruited in the UK at 52 years of age in 2013. She had been diagnosed with HIV in 1991, an estimated 2 years after heterosexual transmission in Jamaica (and hence is referred to here as the ‘1991 Jamaica patient’). Our study was approved by the Oxford Research Ethics Committee and the patient provided written informed consent.

For more than 24 years, she has remained ART-naïve and aviremic with a healthy CD4+ T-cell count (median 1237 cells/μl) (Fig. (Fig.1a).1a). Despite being HLA-B*57 : 03-positive, she demonstrated only two HIV-specific CD8+ T-cell responses detectable by ELISPOT assay, neither greater than 60 spot forming units (SFC)/million peripheral blood mononuclear cell (PBMC) and none detectable by tetramer staining (Fig. (Fig.1b1b and c). This is in contrast to the ‘1999 Berlin patient’, who had a dominant HLA-B*57-restricted Nef-HW9 response of 3000 SFC/million PBMC [6] (Fig. (Fig.1b).1b). One of the two significant ELISPOT responses in the 1991 Jamaica patient was also against this same Nef-HW9 epitope (Fig. (Fig.1b).1b). However, via peptide stimulation of memory T-cell responses [8], we identified five HLA-B*57-restricted responses (Fig. (Fig.1c),1c), three of which we tested for their ability to inhibit HIV replication. Bulk CD8+ T cells demonstrated weak ex-vivo ability to suppress viral replication (Fig. (Fig.1d1d and e), fitting the profile of a subset of HLA-B*57-positive elite controllers [12]. Of the three expanded HLA-B*57-restricted CD8+ T-cell specificities tested, Gag-TW10-specific CD8+ T cells were significantly the most potent in suppressing HIV replication, followed by Nef-KF9 and then Nef-HW9 (Fig. (Fig.1d1d and e).

Fig. 1
Clinical profile and anti-HIV suppressive activity of the 1991 Jamaica patient.

The study of this HLA-B*57-positive individual confirms that, in spite of HIV-specific responses being low frequency or undetectable by tetramer staining or ELISPOT assay, strong responses could be ‘recalled’ from memory, as previously reported [8]. Among these, Gag-TW10-specific CD8+ T cells were more potent at inhibiting viral replication than Nef-KF9-specific cells, despite the latter being a stronger response in ELISPOT assays. These data support previous findings in subjects chronically infected with HIV [13] indicating that subdominant responses may be more efficacious in terms of control of viremia. The findings here are extended also to the case of an HLA-B*57-positive elite controller. Although, like the 1999 Berlin patient, this is a single case report, the data are consistent with the hypothesis that HLA-B*57-mediated Gag-specific targeting by CD8+ T cells confers benefit to the host in HIV infection [7,14] and that vaccine induction of broad Gag-specific CD8+ T-cell responses would tend to increase immune control in HIV infection [15].

Acknowledgements

The authors would like to thank the 1991 Jamaica patient for her participation in our study. The following reagent was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: CD3.4 Bi-specific Monoclonal Antibody (Cat#12278) from Drs Johnson Wong and Galit Alter.

Funding: This work was supported by NIHR and OUCAGS to PCM; by the National Institutes of Health [R01AI46995 to PJRG]; and by the Clarendon Foundation to EML.

Conflicts of interest

There are no conflicts of interest.

References

1. Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S, Lee TH, et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases . Ann Intern Med 2014; 161:319–327. [PMC free article] [PubMed]
2. Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, et al. Posttreatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study . PLoS Pathog 2013; 9:e1003211. [PMC free article] [PubMed]
3. Frange P, Faye A, Avettand-Fenoel V, Bellaton E, Deschamps D, Angin M, et al. HIV-1 virological remission lasting more than 12 years after interruption of early antiretroviral therapy in a perinatally infected teenager enrolled in the French Pediatric Cohort ANRS EPF-CO10. A case report . Lancet HIV 2015; [In press]. [PubMed]
4. Luzuriaga K, Gay H, Ziemniak C, Sanborn KB, Somasundaran M, Rainwater-Lovett K, et al. Viremic relapse after HIV-1 remission in a perinatally infected child . N Engl J Med 2015; 372:786–788. [PMC free article] [PubMed]
5. Pereyra F, Addo MM, Kaufmann DE, Liu Y, Miura T, Rathod A, et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy . J Infect Dis 2008; 197:563–571. [PubMed]
6. Jessen H, Allen TM, Streeck H. How a single patient influenced HIV research: 15-year follow-up . N Engl J Med 2014; 370:682–683. [PMC free article] [PubMed]
7. Goulder PJ, Walker BD. HIV and HLA class I: an evolving relationship . Immunity 2012; 37:426–440. [PMC free article] [PubMed]
8. Ndhlovu ZM, Proudfoot J, Cesa K, Alvino DM, McMullen A, Vine S, et al. Elite controllers with low to absent effector CD8+ T cell responses maintain highly functional, broadly directed central memory responses . J Virol 2012; 86:6959–6969. [PMC free article] [PubMed]
9. Ndhlovu ZM, Stampouloglou E, Cesa K, Mavrothalassitis O, Alvino DM, Li JZ, et al. The breadth of expandable memory CD8+ T cells inversely correlates with residual viral loads in HIV elite controllers . J Virol 2015; 89:10735–10747. [PMC free article] [PubMed]
10. Payne RP, Kloverpris H, Sacha JB, Brumme Z, Brumme C, Buus S, et al. Efficacious early antiviral activity of HIV Gag- and Pol-specific HLA-B 2705-restricted CD8+ T cells . J Virol 2010; 84:10543–10557. [PMC free article] [PubMed]
11. Chen H, Ndhlovu ZM, Liu D, Porter LC, Fang JW, Darko S, et al. TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection . Nat Immunol 2012; 13:691–700. [PMC free article] [PubMed]
12. Lecuroux C, Saez-Cirion A, Girault I, Versmisse P, Boufassa F, Avettand-Fenoel V, et al. Both HLA-B*57 and plasma HIV RNA levels contribute to the HIV-specific CD8+ T cell response in HIV controllers . J Virol 2014; 88:176–187. [PMC free article] [PubMed]
13. Frahm N, Kiepiela P, Adams S, Linde CH, Hewitt HS, Sango K, et al. Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes . Nat Immunol 2006; 7:173–178. [PubMed]
14. Kiepiela P, Ngumbela K, Thobakgale C, Ramduth D, Honeyborne I, Moodley E, et al. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load . Nature Med 2007; 13:46–53. [PubMed]
15. Janes H, Friedrich DP, Krambrink A, Smith RJ, Kallas EG, Horton H, et al. Vaccine-induced Gag-specific T cells are associated with reduced viremia after HIV-1 infection . J Infect Dis 2013; 208:1231–1239. [PMC free article] [PubMed]

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