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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
For Immunopathol Dis Therap. Author manuscript; available in PMC 2017 March 23.
Published in final edited form as:
For Immunopathol Dis Therap. 2015; 6(1-2): 67–77.
doi:  10.1615/ForumImmunDisTher.2016014160
PMCID: PMC5363401
NIHMSID: NIHMS847080

Programming T cell Killers for an HIV Cure: Teach the New Dogs New Tricks and Let the Sleeping Dogs Lie

Abstract

Despite the success of combination antiretroviral therapy (cART), a latent viral reservoir persists in HIV-1-infected persons. Unfortunately, endogenous cytotoxic T lymphocytes (CTLs) are unable to control viral rebound when patients are removed from cART. A “kick and kill” strategy has been proposed to eradicate this reservoir, whereby infected T cells are induced to express viral proteins via latency-inducing drugs followed by their elimination by CTLs. It has yet to be determined if stimulation of existing HIV-1-specific CTL will be sufficient, or if new CTLs should be primed from naïve T cells. In this review, we propose that dendritic cells (DCs), the most potent antigen presenting cells, act as dog trainers and can induce T cells (the dogs) to do magnificent tricks. We propose the hypothesis that an HIV-1 cure will require targeting of naïve T cells and will necessitate “teaching new dogs new tricks” while avoiding activation of potentially dysfunctional endogenous memory CTLs (letting the sleeping dogs lie).

Keywords: CTL, dendritic cells, HIV-1, immunotherapy

I. INTRODUCTION

Combination antiretroviral therapy (cART) has greatly reduced the morbidity and mortality associated with chronic HIV-1 infection. While on cART, subjects experience partial CD4+ T cell recovery and decreases in AIDS-defining opportunistic infections, and many maintain plasma viremia at levels undetectable by standard assays (<50 copies/ml).1 Despite this, viral reservoirs persist in the gut-associated lymphoid tissues and other lymphatics and blood.24 Importantly, the frequency of anti-HIV-1 CD4+ and CD8+ T cells decreases, presumably due to low antigenic stimulation consequent to the lower viral load.57 Thus, partial immune reconstitution is achieved during cART, but the functionality of the reconstituted immune system is limited.8 When subjects are removed from cART, due to drug toxicity or treatment noncompliance, there is an associated rebound in HIV-1 load and resumption of disease progression.4,9

T cell immunity is the most important parameter in controlling virus infection in the absence of cART and is paramount in controlling virus infection in concert with cART.1013 Hence, to effectively control HIV-1 replication and ultimately cure HIV-1 infection, a “shock” or “kick and kill” approach has been proposed.14 In this model, latently infected CD4+ T cells are induced (the “shock”) to produce viral protein antigens, together with a potent immunotherapy that induces cytotoxic T lymphocytes (CTLs) specific for the patient’s own, unique (autologous) virus (the “kill”). We use the analogy in this commentary of these T cells being immune “police dogs” that need to be trained to do unique and spectacular tricks.

II. THE PROFESSIONAL DOG TRAINERS—MYELOID DENDRITIC CELLS (DCS)

We and others propose that the afferent arm of the killer response can be induced by autologous dendritic cells (DCs),1519 the most potent antigen-presenting cells (APCs), which are capable of enhancing the breadth, magnitude, and polyfunctionality of the efferent or effector arm of the immune response, i.e., HIV-1-specific CTL responses.2024 Critical features of this approach and the rationale behind using DCs as an HIV immunotherapy has been described elsewhere. 15 A key issue in this approach is how these DCs are educated to result in the greatest breadth and magnitude of anti-HIV-1 T cell reactivity after they are given as an immunotherapy. During cART, myeloid DCs obtained from blood monocytes and matured with mixtures of different cytokines and T cell co-stimulatory molecules retain their capacity to process and present antigen25,26 and stimulate HIV-1-specific IFN-γ production in CD8+ (Refs. 21, 27, 28) and CD4+ T cells.29 In particular, we have shown that DCs generated from subjects on cART have the capacity to secrete high levels of IL-12p70 if treated with the combination of CD40L and IFN-γ, or the αDC1 maturation cocktail that is being used in cancer immunotherapy trials.21,30,31 This supports the functional integrity of DCs in HIV-1-infected persons on cART, and underscores their usefulness in immunotherapy. Other critical factors in this afferent arm of the DC immunotherapy model are the type/dose of HIV-1 antigen, dose of DCs, route of inoculation, and other immunological parameters as previously discussed.15

III. TEACHING THE NEW DOGS NEW TRICKS

A major consideration in the immunotherapy approach we propose is which subset or subsets of T cells should be the target of activation by HIV-1 antigen-loaded DCs to achieve an optimal antiviral response. We propose that the key objective of a DC-based immunotherapy to treat HIV-1 infection should be to specifically target naïve T cell precursors in order to prime CTLs de novo (teach the new dogs new tricks), and avoid or even inhibit activation of the existing, dysfunctional memory T cell population (let the sleeping dogs lie), as their presence prior to cART32,33 already supports the notion that they are incapable of controlling the virus. This is problematic, however, as studies have revealed decreases in the prevalence and function of naïve T cells following HIV-1 infection compared to uninfected controls.3437

Abnormalities in T cell receptor (TCR) diversity and function, including responsiveness to neo-antigens, have also been reported in chronic HIV-1 infection and are reviewed elsewhere.38 It has been suggested that the pool of naïve T cells present in long-term, HIV-1 chronically infected subjects on cART may not have a sufficient TCR repertoire or functional capacity to respond to primary stimulation against autologous HIV-1,3437 or that viral escape has specifically evaded potential recognition by this new repertoire of naïve T cells.3941 Moreover, alterations in T cell homeostasis during chronic, untreated HIV-1 infection largely impact the naïve subset and partially result from decreases in thymic output.36,37,42 Under cART, however, there is a progressive restoration of naïve CD4+ T cells that results in normalization of their frequency in subjects who began treatment with higher baseline CD4+ T cell counts (>200 cells/μl).43,44 Subjects who began treatment with <200 CD4+ T cells/μl experienced partial restoration in CD4+ T cell numbers but not normalization of the naïve CD4+ T cell compartment, suggesting delayed initiation of cART may adversely affect immune reconstitution even in the absence of viral burden.43

To develop an effective CTL-mediated immunotherapy that would allow the reduction or cessation of cART in chronically infected individuals, it is essential to evaluate the effects of untreated HIV-1 infection on the naïve CD8+ T cell compartment. Progressive HIV-1 infection is accompanied by decreases in the naïve CD8+ T cell subset despite increases in total CD8+ T cells.45 Cossarizza et al. assessed CD4+ and CD8+ v-beta TCR repertoires in acutely and chronically infected subjects pre- and post-cART. Although the naïve CD4+ compartment was only restored in subjects receiving cART in acute infection, the naïve CD8+ compartment was restored with cART irrespective of when treatment began.46 These findings suggest naïve CD8+ T cells in subjects on cART possess the breadth and specificity required to respond to an array of diverse HIV-1 antigens.

Perturbations in the normal distribution of TCRs within the naïve T cell repertoire of untreated HIV-1 infected persons have been noted.47 These alterations lead to TCR clones being both more or less prevalent in HIV-1-infected subjects compared to healthy, uninfected age-matched donors.40,48 Baum et al. showed that while HIV-1-infected persons exhibited a tenfold decrease in TCR repertoire diversity in the blood, the diversity of purified T cell populations was comparable between HIV-1-infected and HIV-uninfected subjects.49 They therefore postulate that changes in TCR repertoire diversity are the result of changes in T cell subpopulations and not the direct result of specific clonal deletion or expansion within the naïve compartment. These findings further underscore the potential efficacy of an immunotherapy aimed to stimulate primary anti-HIV-1 CTL responses from naïve CD8+ T cell precursors.

While changes in the frequency of naïve T cells may play a role in the generation of an effective immune response, their function in response to neo-antigen is of equal importance. Lange et al. evaluated antibody concentrations, lymphocyte proliferation, and delayed-type hypersensitivity responses following tetanus toxoid, diphtheria-toxoid, and key hole limpet hemocyanin immunization and showed that delayed initiation of cART predicted an impaired response to vaccination, despite partial restoration of CD4+ T cell numbers.50 Gelinck et al. reported significantly lower concentrations of antirabies IgG and IgM following rabies vaccination in HIV-1 infected subjects compared to uninfected donors.51 While both of these studies demonstrated an impaired capacity to generate primary immune responses against neo-antigens, they also focused solely on Th2-driven antibody responses.

In an immunotherapy, however, the goal is to induce a CD8+ T cell–mediated response via potent HLA class I-restricted antigenic stimulation. Because of this, results from vaccines that aim to induce antibody-mediated immune responses in HIV-1-infected patients should be interpreted with caution when applying them to analyses of potential CTL-mediated immunotherapy efficacy. Additionally, these studies compare HIV-1-infected subjects on cART to uninfected donors, which is difficult when assessing naïve T cell function in response to primary stimulation without accounting for a variety of factors, including HLA type, individual differences in autologous APCs, age, comorbidities, duration of infection, etc. A more pertinent approach would be to confine the studies to the analysis of the individual HIV-1-infected subjects to determine if the proposed immunotherapy generates responses of efficacy greater than that generated through natural infection. Although the de novo response generated in an HIV-1-infected person on cART may not be equivalent to that which is generated in an uninfected person, it may be sufficient for viral clearance.

In the absence of immune dysfunction and during suppressive cART, it is plausible that an effective CD8+ T cell response could be generated from naïve precursors if induced by a potent antigenic stimulation, possibly in the form of an antigen-loaded DCs. These APCs may be able to overcome any deficiencies that exist in the naïve CD8+ T cell compartment and could provide the potent stimulus needed to induce an HIV-1-specific CTL response.

IV. TEACHING THE OLD DOGS NEW TRICKS

HIV-1-specific CTLs are effective at imposing immunological pressure in acute infection, as shown by their induction of a large turnover and mutation rate in the virus population.5254 Their failure to control virus in chronic infection, however, is hypothesized to be due to several factors. Regulatory T cells have been shown to suppress HIV-1-specific T cell responses following DC immunotherapy in subjects on cART,55 and have been implicated in HIV-1 pathogenesis and disease progression, the details of which have been reviewed elsewhere.56,57

Prolonged antigenic stimulation in chronic HIV-1 infection also results in T cell exhaustion with concomitant upregulation of checkpoint markers, such as programmed cell death 1 (PD-1), CTLA-4, TIM3, and others.5860 Programmed cell death 1 (PD-1) expression on HIV-1-specific T cells is associated with multiple parameters of T cell dysfunction, including impaired proliferative capacity and reduced cytokine secretion.6164 Interestingly, PD-1 upregulation is not associated with CD8+ T cell exhaustion in long-term nonprogressors,61 suggesting a mechanism by which CTLs could initially control virus in typical HIV-1 progression but fail to do so in the chronic stages of infection, potentially due to the upregulation of immunological checkpoint markers. Because of these observations, PD-1 has been proposed as a target in HIV-1 immunotherapy.65 Indeed, Youngblood et al. demonstrated an epigenetic program for PD-1 expression by CD8+ T cells following prolonged exposure to HIV-1,66 suggesting immunotherapies targeting PD-1 may be of variable efficacy depending on the time of cART administration relative to infection.

To overcome this dysfunction in memory T cells, DCs could “recondition” or “reprogram” the endogenous memory T cells such that they effectively recognize and eliminate infected targets. Wesa et al. showed that type-1 polarized DCs can revitalize defective CD4+ T cell responses specific for melanoma- associated antigens.67 Polarized DCs shifted the T cell response from one that predominantly secretes IL-5 to one predominantly secreting the type-1-associated cytokine, IFN-γ. Indeed, much of what we have learned regarding HIV-1 immunotherapy was pioneered in the cancer field, and perhaps memory T cell reconditioning could translate into HIV-1 immunotherapy as well. Recently, Deng et al. reported CTL elimination of CD4+ T cells infected with latent HIV-1 on peptide stimulation,68 thereby suggesting that boosting the endogenous memory response is sufficient to induce targeting of the HIV-1 reservoir. While these findings support the function of recall HIV-1-specific CTLs, the longevity and efficacy of such a response in chronically infected patients on cART has yet to be evaluated. It is possible that prolonged antigenic stimulation throughout years of untreated infection generated a pool of memory CTLs with short-lived effector capacity. Despite this, reconditioning or “boosting” memory CD8+ T cells is an attractive approach, as memory T cells are much more frequent and have a higher percentage of antigen-specific cells that require less co-stimulation. In contrast, these cells also have a higher likelihood of possessing an exhausted phenotype, and while they may be specific for the immunotherapy antigen, they may also perpetuate an environment of exhaustion and immune dysfunction.

V. SHOULD WE LET THE SLEEPING DOGS LIE?

A more recent and less explored consideration is the effect of existing HIV-1-specific memory T cells on the efficacy of a DC immunotherapy that aims to induce primary CTL responses from naïve precursors. Despite their failure to control virus during treatment interruption, HIV-1-specific CD8+ T cells persist in the blood of subjects on ART. While only a small fraction of PBMC and purified CD8+ T cells from these subjects secrete IFN-γ in response to HIV-1 peptide antigens, DCs loaded with these same antigens reveal broad and robust T cell responses.22,33,69 Additionally, peptide-loaded DCs enhance the percent of T cells that secrete multiple type 1 cytokines, including IL-2, IFN-γ, TNFα, MIPip-1β, and CD107a, and stimulate proliferation of T cells in response to MHC class I-restricted HIV-1 peptide epitopes.20,22,33 As the assays used in these studies range from 6 h 18 h, it is highly unlikely that DCs are inducing primary responses, but are rather revealing T cell responses that were undetectable with standard assay procedures. These findings show that HIV-1-specific T cells persist during ART and are capable of secreting high levels of type 1 cytokines in response to HIV-1 antigens, yet are not effective at eliminating infected cells. These studies also suggest that these quiescent memory cells (aka “sleeping dogs”) can be awoken with the proper stimulus.

Of particular interest to us is the fact that the activity of highly avid HIV-1 antigen specific CTLs has been shown to be maintained throughout chronic stages of infection without any apparent impact on viral evolution.32,7072 However, these responses can be shown to diminish once the subjects undergo cART, suggesting that these CTLs actively respond to autologous virus.8 Similarly, the successful establishment of CTL epitope variants arising during the acute stages of SIV infection has been shown to occur while in the presence of preexisting variant reactive CTLs.73 Related to these findings, in longitudinal studies designed to determine the impact of CTL responses on viral evolution and the frequency of epitope variants, our group also found evidence that antigen specific activity of CTL responders, naturally generated in the acute phase of HIV-1 infection against epitope sequences presented during early infection, can be maintained throughout infection against antigenic variants established at later time points.32,74 We found that these early arising CTL responders would secrete cytokines when challenged with autologous HIV-1 epitope variants that had evolved well beyond the time of T cell sampling. However, cytotoxicity mediated by these “cross-reactive” CTLs against autologous CD4+ T cell and immature DC targets was specific for the founder epitopes, while minimal killing was observed in those targets expressing the antigenic variants, suggesting that these CTLs may be “all bark and no bite.” This uncoupling of the T cell helper and killing functions, and the selective induction of the CTL cytokine production by the late-evolving variants, was found to create an inflammatory environment suitable for promoting DC maturation, chemotactic activity, and enhanced HIV-1 trans infection of CD4+ T cells, thus supporting the concept that we should let the sleeping dogs lie.

These findings have implications in the design of prophylactic and therapeutic vaccines and suggest that a form of “original antigen sin” may exist in the context of HIV-1. The presence of memory T cells specific for HIV-1 antigens may not only be ineffective at eliminating infected cells, but could potentially enhance viral spread on encountering a similar, yet different, antigen. Indeed, the STEP vaccine trial, which utilized an Ad5 vector containing the Gag, Pol, and Nef proteins, noted slight increases in the rate of HIV-1 infection among vaccine recipients. 75,76 Despite this, T cell responses were detected in ~80% of vaccinated individuals.77 Follow-up studies in vaccine recipients noted the expansion of CCR5-expressing, memory CD4+ T cells that were susceptible to HIV-1 infection.78,79 It is possible that among other compounding factors, memory T cells specific for the vaccine proteins actually enhanced infection when the patients encountered heterologous HIV-1. Although speculative in the context of HIV-1 vaccination, there is evidence of this in other disease models.80

VI. CONCLUSIONS

While several studies have noted deficiencies in naïve T cells from HIV-1-infected persons on cART, this could be overcome by using potent APCs and appropriate antigenic stimuli. Perhaps the function of naïve T cells in these patients is less than those seen in HIV-negative persons, but maybe the response induced via a potent APC is still sufficient to eliminate infected cells. While HIV-1-specific memory T cells persist in subjects on ART, they are largely dysfunctional and may provide a barrier to successful CTL induction. A model outlining this hypothesis is shown in Fig. 1 and the immunological characteristics that favor targeting naïve T cells in a DC immunotherapy are described in Table 1. It may be of interest to develop methods of specifically targeting naïve T cells while minimizing memory T cell activation in immunotherapies. We therefore propose that an effective HIV-1 immunotherapy for persons on ART should teach the new dogs new tricks, but let the sleeping dogs lie.

FIG. 1
Proposed outcome of DC immunotherapy targeting naïve and memory CD8+ T cells. DC priming of naïve CD8+ T cells will result in primary HIV-1-specific CTLs that are capable of producing multiple type-1 immune mediators and can effectively ...
TABLE 1
Immunologic characteristics that favor targeting naïve T cells in a DC immunotherapy for HIV-1-infected subjects on cART

Acknowledgments

The authors were supported in part by NIH Grants No. T32 AI065380, No. U01 AI35041, No. U01 AI068636, and No. R37 AI41870.

ABBREVIATIONS

APC
antigen-presenting cell
cART
combination antiretroviral therapy
CD
cluster of differentiation
CTL
cytotoxic T cell
DC
dendritic cell
HIV-1
human immunodeficiency virus type-1
IFN-g
interferon-gamma
IL
interleukin
PD-1
programmed cell death-1
TCR
T cell receptor

References

1. Battegay M, Nuesch R, Hirschel B, Kaufmann GR. Immunological recovery and antiretroviral therapy in HIV-1 infection. Lancet Infect Dis. 2006;6(5):280–7. [PubMed]
2. Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G, Hallahan CW, Kottilil S, Moir S, Mican JM, Mullins JI, Ward DJ, Kovacs JA, Mannon PJ, Fauci AS. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis. 2008;197(5):714–20. [PubMed]
3. Haggerty CM, Pitt E, Siliciano RF. The latent reservoir for HIV-1 in resting CD4+ T cells and other viral reservoirs during chronic infection: insights from treatment and treatment-interruption trials. Curr Opin HIV AIDS. 2006;1(1):62–8. [PubMed]
4. Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C, Quinn TC, Chaisson RE, Rosenberg E, Walker B, Gange S, Gallant J, Siliciano RF. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5(5):512–7. [PubMed]
5. Pitcher CJ, Quittner C, Peterson DM, Connors M, Koup RA, Maino VC, Picker LJ. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med. 1999;5(5):518–25. [PubMed]
6. Mollet L, Li TS, Samri A, Tournay C, Tubiana R, Calvez V, Debré P, Katlama C, Autran B. Dynamics of HIV-specific CD8+ T lymphocytes with changes in viral load. The RESTIM and COMET Study Groups. J Immunol. 2000;165(3):1692–704. [PubMed]
7. Rinaldo CR, Jr, Huang XL, Fan Z, Margolick JB, Borowski L, Hoji A, Kalinyak C, McMahon DK, Riddler SA, Hildebrand WH, Day RB, Mellors JW. Anti-human immunodeficiency virus type 1 (HIV-1) CD8(+) T-lymphocyte reactivity during combination antiretroviral therapy in HIV-1-infected patients with advanced immunodeficiency. J Virol. 2000;74(9):4127–38. [PMC free article] [PubMed]
8. Gaardbo JC, Hartling HJ, Gerstoft J, Nielsen SD. Incomplete immune recovery in HIV infection: mechanisms, relevance for clinical care, and possible solutions. Clin Dev Immunol. 2012;2012:670957. [PMC free article] [PubMed]
9. Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, Gallant J, Markowitz M, Ho DD, Richman DD, Siliciano RF. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278(5341):1295–300. [PubMed]
10. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol. 1994;68(9):6103–10. [PMC free article] [PubMed]
11. Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, Farthing C, Ho DD. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994;68(7):4650–5. [PMC free article] [PubMed]
12. Pantaleo G, Demarest JF, Soudeyns H, Graziosi C, Denis F, Adelsberger JW, Borrow P, Saag MS, Shaw GM, Sekaly RP, Fauci AS. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature. 1994;370(6489):463–7. [PubMed]
13. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science. 1999;283(5403):857–60. [PubMed]
14. Deeks SG. HIV: Shock and kill. Nature. 2012;487(7408):439–40. [PubMed]
15. Rinaldo CR. Dendritic cell-based human immunodeficiency virus vaccine. J Intern Med. 2009;265(1):138–58. [PMC free article] [PubMed]
16. Oshiro TM, de Almeida A, da Silva Duarte AJ. Dendritic cell immunotherapy for HIV infection: from theory to reality. Immunotherapy. 2009;1(6):1039–51. [PubMed]
17. Van Gulck E, Van Tendeloo VF, Berneman ZN, Vanham G. Role of dendritic cells in HIV-immunotherapy. Curr HIV Res. 2010;8(4):310–22. [PubMed]
18. Vanham G, Van Gulck E. Can immunotherapy be useful as a “functional cure” for infection with Human Immunodeficiency Virus-1? Retrovirology. 2012;9:72. [PMC free article] [PubMed]
19. Garcia F, Leon A, Gatell JM, Plana M, Gallart T. Therapeutic vaccines against HIV infection. Hum Vaccine Immunother. 2012;8(5):569–81. [PubMed]
20. Huang XL, Fan Z, Borowski L, Rinaldo CR. Multiple T cell responses to human immunodeficiency virus type 1 are enhanced by dendritic cells. Clin Vaccine Immunol. 2009;16(10):1504–16. [PMC free article] [PubMed]
21. Huang XL, Fan Z, Borowski L, Rinaldo CR. Maturation of dendritic cells for enhanced activation of anti-HIV-1 CD8(+) T cell immunity. J Leukoc Biol. 2008;83(6):1530–40. [PubMed]
22. Huang XL, Fan Z, Borowski L, Mailliard RB, Rolland M, Mullins JI, Day RD, Rinaldo CR. Dendritic cells reveal a broad range of MHC class I epitopes for HIV-1 in persons with suppressed viral load on antiretroviral therapy. PloS One. 2010;5(9):e12936. [PMC free article] [PubMed]
23. Colleton BA, Huang XL, Melhem NM, Fan Z, Borowski L, Rappocciolo G, Rinaldo CR. Primary human immunodeficiency virus type 1-specific CD8+ T-cell responses induced by myeloid dendritic cells. Journal of Virology. 2009;83(12):6288–99. [PMC free article] [PubMed]
24. Lubong Sabado R, Kavanagh DG, Kaufmann DE, Fru K, Babcock E, Rosenberg E, Walker B, Lifson J, Bhardwaj N, Larsson M. In vitro priming recapitulates in vivo HIV-1 specific T cell responses, revealing rapid loss of virus reactive CD4 T cells in acute HIV-1 infection. PloS One. 2009;4(1):e4256. [PMC free article] [PubMed]
25. Connolly N, Riddler S, Stanson J, Gooding W, Rinaldo CR, Ferrone S, Whiteside TL. Levels of antigen processing machinery components in dendritic cells generated for vaccination of HIV-1+ subjects. AIDS. 2007;21(13):1683–92. [PubMed]
26. Sapp M, Engelmayer J, Larsson M, Granelli-Piperno A, Steinman R, Bhardwaj N. Dendritic cells generated from blood monocytes of HIV-1 patients are not infected and act as competent antigen presenting cells eliciting potent T cell responses. Immunol Lett. 1999;66(1–3):121–8. [PubMed]
27. Huang XL, Fan Z, Colleton BA, Buchli R, Li H, Hildebrand WH, Rinaldo CR., Jr Processing and presentation of exogenous HLA class I peptides by dendritic cells from human immunodeficiency virus type 1-infected persons. J Virol. 2005;79(5):3052–62. [PMC free article] [PubMed]
28. Fan Z, Huang XL, Zheng L, Wilson C, Borowski L, Liebmann J, Gupta P, Margolick J, Rinaldo C. Cultured blood dendritic cells retain HIV-1 antigen-presenting capacity for memory CTL during progressive HIV-1 infection. J Immunol. 1997;159(10):4973–82. [PubMed]
29. Newton PJ, Weller IV, Williams IG, Miller RF, Copas A, Tedder RS, Katz DR, Chain BM. Monocyte derived dendritic cells from HIV-1 infected individuals partially reconstitute CD4 T-cell responses. AIDS. 2006;20(2):171–80. [PubMed]
30. Fan Z, Huang XL, Kalinski P, Young S, Rinaldo CR., Jr Dendritic cell function during chronic hepatitis C virus and human immunodeficiency virus type 1 infection. Clin Vaccine Immunol. 2007;14(9):1127–37. [PMC free article] [PubMed]
31. Mailliard RB, Wankowicz-Kalinska A, Cai Q, Wesa A, Hilkens CM, Kapsenberg ML, Kirkwood JM, Storkus WJ, Kalinski P. alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity. Cancer Res. 2004;64(17):5934–7. [PubMed]
32. Melhem NM, Smith KN, Huang XL, Colleton BA, Jiang W, Mailliard RB, Mullins JI, Rinaldo CR. The impact of viral evolution and frequency of variant epitopes on primary and memory human immunodeficiency virus type 1-specific CD8(+) T cell responses. Virology. 2014;450–451:34–48. [PMC free article] [PubMed]
33. Smith KN, Mailliard RB, Larsen BB, Wong K, Gupta P, Mullins JI, Rinaldo CR. Dendritic cells restore CD8+ T cell reactivity to autologous HIV-1. J Virol. 2014;88(17):9976–90. [PMC free article] [PubMed]
34. Zhang L, Lewin SR, Markowitz M, Lin HH, Skulsky E, Karanicolas R, He Y, Jin X, Tuttleton S, Vesanen M, Spiegel H, Kost R, van Lunzen J, Stellbrink HJ, Wolinsky S, Borkowsky W, Palumbo P, Kostrikis LG, Ho DD. Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy. J Exp Med. 1999;190(5):725–32. [PMC free article] [PubMed]
35. Hazenberg MD, Otto SA, Cohen Stuart JW, Verschuren MC, Borleffs JC, Boucher CA, Coutinho RA, Lange JM, Rinke de Wit TF, Tsegaye A, van Dongen JJ, Hamann D, de Boer RJ, Miedema F. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat Med. 2000;6(9):1036–42. [PubMed]
36. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998;396(6712):690–5. [PubMed]
37. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debré P, Leibowitch J. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science. 1997;277(5322):112–6. [PubMed]
38. Khoury G, Rajasuriar R, Cameron PU, Lewin SR. The role of naive T-cells in HIV-1 pathogenesis: an emerging key player. Clin Immunol. 2011;141(3):253–67. [PubMed]
39. Malhotra U, Huntsberry C, Holte S, Lee J, Corey L, McElrath MJ. CD4+ T cell receptor repertoire perturbations in HIV-1 infection: association with plasma viremia and disease progression. Clin Immunol. 2006;119(1):95–102. [PubMed]
40. Gorochov G, Neumann AU, Kereveur A, Parizot C, Li T, Katlama C, Karmochkine M, Raguin G, Autran B, Debré P. Perturbation of CD4+ and CD8+ T cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nat Med. 1998;4(2):215–21. [PubMed]
41. Pahwa S, Chitnis V, Mitchell RM, Fernandez S, Chandrasekharan A, Wilson CM, Douglas SD. CD4+ and CD8+ T cell receptor repertoire perturbations with normal levels of T cell receptor excision circles in HIV-infected, therapy-naive adolescents. AIDS Res Hum Retroviruses. 2003;19(6):487–95. [PubMed]
42. Zhang ZQ, Notermans DW, Sedgewick G, Cavert W, Wietgrefe S, Zupancic M, Gebhard K, Henry K, Boies L, Chen Z, Jenkins M, Mills R, McDade H, Goodwin C, Schuwirth CM, Danner SA, Haase AT. Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection. Proc Natl Acad Sci U S A. 1998;95(3):1154–9. [PubMed]
43. Vrisekoop N, van Gent R, de Boer AB, Otto SA, Borleffs JC, Steingrover R, Prins JM, Kuijpers TW, Wolfs TF, Geelen SP, Vulto I, Lansdorp P, Tesselaar K, Borghans JA, Miedema F. Restoration of the CD4 T cell compartment after long-term highly active antiretroviral therapy without phenotypical signs of accelerated immunological aging. J Immunol. 2008;181(2):1573–81. [PubMed]
44. Yin L, Kou ZC, Rodriguez C, Hou W, Goodenow MM, Sleasman JW. Antiretroviral therapy restores diversity in the T-cell receptor Vbeta repertoire of CD4 T-cell T cell subpopulations among human immunodeficiency virus type 1-infected children and adolescents. Clin Vaccine Immunol. 2009;16(9):1293–301. [PMC free article] [PubMed]
45. Roederer M, Dubs JG, Anderson MT, Raju PA, Herzenberg LA. CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest. 1995;95(5):2061–6. [PMC free article] [PubMed]
46. Cossarizza A, Poccia F, Agrati C, D’Offizi G, Bugarini R, Pinti M, Borghi V, Mussini C, Esposito R, Ippolito G, Narciso P. Highly active antiretroviral therapy restores CD4+ Vbeta T-cell repertoire in patients with primary acute HIV infection but not in treatment-naive HIV+ patients with severe chronic infection. J Acquir Immune Defic Syndr. 2004;35(3):213–22. [PubMed]
47. Connors M, Kovacs JA, Krevat S, Gea-Banacloche JC, Sneller MC, Flanigan M, Metcalf JA, Walker RE, Falloon J, Baseler M, Feuerstein I, Masur H, Lane HC. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med. 1997;3(5):533–40. [PubMed]
48. Gea-Banacloche JC, Weiskopf EE, Hallahan C, Lopez Bernaldo de Quiros JC, Flanigan M, Mican JM, Falloon J, Baseler M, Stevens R, Lane HC, Connors M. Progression of human immunodeficiency virus disease is associated with increasing disruptions within the CD4+ T cell receptor repertoire. J Infect Dis. 1998;177(3):579–85. [PubMed]
49. Baum PD, Young JJ, Schmidt D, Zhang Q, Hoh R, Busch M, Martin J, Deeks S, McCune JM. Blood T-cell receptor diversity decreases during the course of HIV infection, but the potential for a diverse repertoire persists. Blood. 2012;119(15):3469–77. [PubMed]
50. Lange CG, Lederman MM, Medvik K, Asaad R, Wild M, Kalayjian R, Valdez H. Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. AIDS. 2003;17(14):2015–23. [PubMed]
51. Gelinck LB, Jol-van der Zijde CM, Jansen-Hoogendijk AM, Brinkman DM, van Dissel JT, van Tol MJ, Kroon FP. Restoration of the antibody response upon rabies vaccination in HIV-infected patients treated with HAART. AIDS. 2009;23(18):2451–8. [PubMed]
52. Streeck H, Jolin JS, Qi Y, Yassine-Diab B, Johnson RC, Kwon DS, Addo MM, Brumme C, Routy JP, Little S, Jessen HK, Kelleher AD, Hecht FM, Sekaly RP, Rosenberg ES, Walker BD, Carrington M, Altfeld M. Human immunodeficiency virus type 1-specific CD8+ T-cell responses during primary infection are major determinants of the viral set point and loss of CD4+ T cells. J Virol. 2009;83(15):7641–8. [PMC free article] [PubMed]
53. Vanderford TH, Bleckwehl C, Engram JC, Dunham RM, Klatt NR, Feinberg MB, Garber DA, Betts MR, Silvestri G. Viral CTL escape mutants are generated in lymph nodes and subsequently become fixed in plasma and rectal mucosa during acute SIV infection of macaques. PLoS Pathog. 2011;7(5):e1002048. [PMC free article] [PubMed]
54. Dong T, Zhang Y, Xu KY, Yan H, James I, Peng Y, Blais ME, Gaudieri S, Chen X, Lun W, Wu H, Qu WY, Rostron T, Li N, Mao Y, Mallal S, Xu X, McMichael A, John M, Rowland-Jones SL. Extensive HLA-driven viral diversity following a narrow-source HIV-1 outbreak in rural China. Blood. 2011;118(1):98–106. [PubMed]
55. Macatangay BJ, Szajnik ME, Whiteside TL, Riddler SA, Rinaldo CR. Regulatory T cell suppression of Gag-specific CD8 T cell polyfunctional response after therapeutic vaccination of HIV-1-infected patients on ART. PloS One. 2010;5(3):e9852. [PMC free article] [PubMed]
56. Chevalier MF, Weiss L. The split personality of regulatory T cells in HIV infection. Blood. 2013 Jan 3;121(1):29–37. Epub 2012/10/09. eng. [PubMed]
57. Macatangay BJ, Rinaldo CR. Regulatory T cells in HIV immunotherapy. HIV Ther. 2010;4(6):639–47. [PMC free article] [PubMed]
58. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–45. [PubMed]
59. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–7. [PubMed]
60. Larsson M, Shankar EM, Che KF, Saeidi A, Ellegard R, Barathan M, Velu V, Kamarulzaman A. Molecular signatures of T-cell inhibition in HIV-1 infection. Retrovirology. 2013;10:31. [PMC free article] [PubMed]
61. Zhang JY, Zhang Z, Wang X, Fu JL, Yao J, Jiao Y, Chen L, Zhang H, Wei J, Jin L, Shi M, Gao GF, Wu H, Wang FS. PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors. Blood. 2007;109(11):4671–8. [PubMed]
62. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350–4. [PubMed]
63. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, Boulassel MR, Delwart E, Sepulveda H, Balderas RS, Routy JP, Haddad EK, Sekaly RP. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006;12(10):1198–202. [PubMed]
64. Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, Precopio ML, Schacker T, Roederer M, Douek DC, Koup RA. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med. 2006;203(10):2281–92. [PMC free article] [PubMed]
65. Macatangay BJ, Rinaldo CR. PD-1 blockade: A promising immunotherapy for HIV? Cellscience. 2009;5(4):61–5. [PMC free article] [PubMed]
66. Youngblood B, Noto A, Porichis F, Akondy RS, Ndhlovu ZM, Austin JW, Bordi R, Procopio FA, Miura T, Allen TM, Sidney J, Sette A, Walker BD, Ahmed R, Boss JM, Sékaly RP, Kaufmann DE. Cutting edge: prolonged exposure to HIV reinforces a poised epigenetic program for PD-1 expression in virus-specific CD8 T cells. J Immunol. 2013;191(2):540–4. [PMC free article] [PubMed]
67. Wesa A, Kalinski P, Kirkwood JM, Tatsumi T, Storkus WJ. Polarized type-1 dendritic cells (DC1) producing high levels of IL-12 family members rescue patient TH1-type antimelanoma CD4+ T cell responses in vitro. J Immunother. 2007;30(1):75–82. [PubMed]
68. Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Ghiaur G, Lai J, McHugh HL, Hao H, Zhang H, Margolick JB, Gurer C, Murphy AJ, Valenzuela DM, Yancopoulos GD, Deeks SG, Strowig T, Kumar P, Siliciano JD, Salzberg SL, Flavell RA, Shan L, Siliciano RF. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015;517(7534):381–5. [PMC free article] [PubMed]
69. Huang X, Fan Z, Zheng L, Rinaldo CR., Jr Stimulation of anti-HIV-1 cytotoxic T lymphocytes by dendritic cells. Methods Mol Med. 2001;64:441–53. [PubMed]
70. Draenert R, Verrill CL, Tang Y, Allen TM, Wurcel AG, Boczanowski M, Lechner A, Kim AY, Suscovich T, Brown NV, Addo MM, Walker BD. Persistent recognition of autologous virus by high-avidity CD8 T cells in chronic, progressive human immunodeficiency virus type 1 infection. J Virol. 2004;78(2):630–41. [PMC free article] [PubMed]
71. Hay CM, Ruhl DJ, Basgoz NO, Wilson CC, Billingsley JM, DePasquale MP, D’Aquila RT, Wolinsky SM, Crawford JM, Montefiori DC, Walker BD. Lack of viral escape and defective in vivo activation of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes in rapidly progressive infection. J Virol. 1999;73(7):5509–19. [PMC free article] [PubMed]
72. Iversen AK, Stewart-Jones G, Learn GH, Christie N, Sylvester-Hviid C, Armitage AE, Kaul R, Beattie T, Lee JK, Li Y, Chotiyarnwong P, Dong T, Xu X, Luscher MA, MacDonald K, Ullum H, Klarlund-Pedersen B, Skinhøj P, Fugger L, Buus S, Mullins JI, Jones EY, van der Merwe PA, McMichael AJ. Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope. Nat Immunol. 2006;7(2):179–89. [PubMed]
73. Cale EM, Hraber P, Giorgi EE, Fischer W, Bhattacharya T, Leitner T, Yeh WW, Gleasner C, Green LD, Han CS, Korber B, Letvin NL. Epitope-specific CD8+ T lymphocytes cross-recognize mutant simian immunodeficiency virus (SIV) sequences but fail to contain very early evolution and eventual fixation of epitope escape mutations during SIV infection. J Virol. 2011;85(8):3746–57. [PMC free article] [PubMed]
74. Mailliard RB, Smith KN, Fecek RJ, Rappocciolo G, Nascimento EJ, Marques ET, Watkins SC, Mullins JI, Rinaldo CR. Selective induction of CTL helper rather than killer activity by natural epitope variants promotes dendritic cell-mediated HIV-1 dissemination. J Immunol. 2013;191(5):2570–80. [PMC free article] [PubMed]
75. Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D, Gilbert PB, Lama JR, Marmor M, Del Rio C, McElrath MJ, Casimiro DR, Gottesdiener KM, Chodakewitz JA, Corey L, Robertson MN. Step Study Protocol Team. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008;372(9653):1881–93. [PMC free article] [PubMed]
76. Sekaly RP. The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development? J Exp Med. 2008;205(1):7–12. [PMC free article] [PubMed]
77. Priddy FH, Brown D, Kublin J, Monahan K, Wright DP, Lalezari J, Lalezari J, Santiago S, Marmor M, Lally M, Novak RM, Brown SJ, Kulkarni P, Dubey SA, Kierstead LS, Casimiro DR, Mogg R, DiNubile MJ, Shiver JW, Leavitt RY, Robertson MN, Mehrotra DV, Quirk E. Merck V520-016 Study Group. Safety and immunogenicity of a replication-incompetent adenovirus type 5 HIV-1 clade B gag/pol/nef vaccine in healthy adults. Clin Infect Dis. 2008;46(11):1769–81. [PubMed]
78. Benlahrech A, Harris J, Meiser A, Papagatsias T, Hornig J, Hayes P, Lieber A, Athanasopoulos T, Bachy V, Csomor E, Daniels R, Fisher K, Gotch F, Seymour L, Logan K, Barbagallo R, Klavinskis L, Dickson G, Patterson S. Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1. Proc Natl Acad Sci U S A. 2009;106(47):19940–5. [PubMed]
79. Chakupurakal G, Onion D, Cobbold M, Mautner V, Moss PA. Adenovirus vector-specific T cells demonstrate a unique memory phenotype with high proliferative potential and coexpression of CCR5 and integrin alpha4beta7. AIDS. 2010;24(2):205–10. [PubMed]
80. Klenerman P, Zinkernagel RM. Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature. 1998;394(6692):482–5. [PubMed]
81. Cockerham LR, Jain V, Sinclair E, Glidden DV, Hartogenesis W, Hatano H, Hunt PW, Martin JN, Pilcher CD, Sekaly R, McCune JM, Hecht FM, Deeks SG. Programmed death-1 expression on CD4(+) and CD8(+) T cells in treated and untreated HIV disease. AIDS. 2014;28(12):1749–58. [PMC free article] [PubMed]
82. Kloverpris HN, McGregor R, McLaren JE, Ladell K, Stryhn A, Koofhethile C, Brener J, Chen F, Riddell L, Graziano L, Klenerman P, Leslie A, Buus S, Price DA, Goulder P. Programmed death-1 expression on HIV-1-specific CD8+ T cells is shaped by epitope specificity, T-cell receptor clonotype usage and antigen load. AIDS. 2014;28(14):2007–21. [PMC free article] [PubMed]
83. Youngblood B, Oestreich KJ, Ha SJ, Duraiswamy J, Akondy RS, West EE, Wei Z, Lu P, Austin JW, Riley JL, Boss JM, Ahmed R. Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8(+) T cells. Immunity. 2011;35(3):400–12. [PMC free article] [PubMed]
84. Youngblood B, Wherry EJ, Ahmed R. Acquired transcriptional programming in functional and exhausted virus-specific CD8 T cells. Curr Opin HIV AIDS. 2012;7(1):50–7. [PMC free article] [PubMed]
85. Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW, Miura T, Palmer S, Brockman M, Rathod A, Piechocka-Trocha A, Baker B, Zhu B, Le Gall S, Waring MT, Ahern R, Moss K, Kelleher AD, Coffin JM, Freeman GJ, Rosenberg ES, Walker BD. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat Immunol. 2007;8(11):1246–54. [PubMed]
86. Vigano S, Banga R, Bellanger F, Pellaton C, Farina A, Comte D, Harari A, Perreau M. CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression. PLoS Pathogens. 2014;10(9):e1004380. [PMC free article] [PubMed]
87. Peretz Y, He Z, Shi Y, Yassine-Diab B, Goulet JP, Bordi R, Filali-Mouhim A, Loubert JB, El-Far M, Dupuy FP, Boulassel MR, Tremblay C, Routy JP, Bernard N, Balderas R, Haddad EK, Sékaly RP. CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction. PLoS Pathogens. 2012;8(8):e1002840. [PMC free article] [PubMed]
88. Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, Wong JC, Satkunarajah M, Schweneker M, Chapman JM, Gyenes G, Vali B, Hyrcza MD, Yue FY, Kovacs C, Sassi A, Loutfy M, Halpenny R, Persad D, Spotts G, Hecht FM, Chun TW, McCune JM, Kaul R, Rini JM, Nixon DF, Ostrowski MA. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med. 2008;205(12):2763–79. [PMC free article] [PubMed]
89. Legrand FA, Nixon DF, Loo CP, Ono E, Chapman JM, Miyamoto M, Diaz RS, Santos AM, Succi RC, Abadi J, Rosenberg MG, de Moraes-Pinto MI, Kallas EG. Strong HIV-1-specific T cell responses in HIV-1-exposed uninfected infants and neonates revealed after regulatory T cell removal. PloS One. 2006;1:e102. [PMC free article] [PubMed]
90. Aandahl EM, Michaelsson J, Moretto WJ, Hecht FM, Nixon DF. Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens. J Virol. 2004;78(5):2454–9. [PMC free article] [PubMed]
91. Kinter AL, Hennessey M, Bell A, Kern S, Lin Y, Daucher M, Planta M, McGlaughlin M, Jackson R, Ziegler SF, Fauci AS. CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med. 2004;200(3):331–43. [PMC free article] [PubMed]
92. Weiss L, Donkova-Petrini V, Caccavelli L, Balbo M, Carbonneil C, Levy Y. Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood. 2004;104(10):3249–56. [PubMed]
93. Wang X, Zhang Z, Zhang S, Fu J, Yao J, Jiao Y, Wu H, Wang FS. B7-H1 up-regulation impairs myeloid DC and correlates with disease progression in chronic HIV-1 infection. Eur J Immunol. 2008;38(11):3226–36. [PubMed]