Daniel Kaufmann Kaufmann Lab

Principal Investigator: Daniel E. Kaufmann, M.D., Assistant Professor
Lab staff: 1 senior research scientist, 1 post-doctoral fellow, 1 visiting postdoctoral fellow, 1 student, 1 research technician
Contact: phone 617.726.8630 / dkaufmann@partners.org

 


Dr Kaufmann is a physician scientist whose research focuses on causes of T cell impairment in HIV infection, with a special interest in active mechanisms of immune dysfunction that can be reversed by manipulation of inhibitory pathways.

A major goal of the research in Dr Kaufmann’s laboratory is to understand the mechanisms of T cell exhaustion during HIV infection.  In the large majority of HIV-infected individuals, HIV-specific CD4 and CD8 T cells are easily detectable by standard laboratory assays.  Yet, these responses fail to control virus replication and in the absence of antiviral therapy, the large majority of infected subjects experience progressive immune suppression and progress toward AIDS.  A critical question is thus to determine whether this immune dysfunction is irreversible or under the control of active mechanisms that can be manipulated to restore effective immunity.  Our previous work has demonstrated that T cell exhaustion is indeed – at least in part - under the control of inhibitory pathways, and that a significant component of virus-specific CD4 and CD8 T cell exhaustion can be reversed by blockade of specific molecules like PD-1, CTLA-4 and IL-10.  Therapeutic manipulation of these inhibitory networks has considerable potential for treatment of both chronic infections and cancer, and they can also be targeted to enhance the efficacy of prophylactic and therapeutic vaccines.

Some areas of special current interest for the laboratory include inhibitory receptors, the role of transcription factors and inflammatory pathways in the regulation of T cell function.  In addition, we are examining the impact of activated HIV-specific T cells on antigen-presenting cell phenotype and function, and the dynamics of immunological synapses built by infection- and vaccine-induced HIV-specific T cells.  We are studying responses in both peripheral blood and lymphoid tissues of individuals at different stages of HIV infection, including the rare individuals capable of controlling viral replication in the absence of therapy.  We use a variety of approaches of cellular biology, molecular immunology and advanced cell imaging to pinpoint critical molecular events that regulate effective and inefficient antiviral responses.  Additionally, we are involved in the first Phase I clinical trial to determine the safety, pharmacokinetics and efficacy of blockade of PD-1 with a monoclonal anti-PD-1 antibody in order to reduce the latent HIV reservoir.  This ACTG protocol is currently under review by the NIH and the FDA.

Present Areas of Investigation:
Analysis of the role of the B7/CD28 family of co-signaling molecules, in particular PD-1 and CTLA-4, in HIV-specific CD4 and CD8 T cell dysfunction.
Study that the role that the B7/CD28 family of co-signaling molecules plays in the gut-associated lymphoid tissue (GALT) compared to peripheral blood.
Investigation of mechanisms of antigen-presenting cell dysfunction, with a focus on monocytic/myeloid cell subsets endowed with suppressive activity.
Analysis of the qualitative differences between T cell responses in progressive HIV infection and T cell responses in subjects who control viral load in the absence of therapy (“elite controllers”) with regard to inhibitory pathways.
Important Accomplishments:
Demonstration of the involvement of the PD-1 pathway in HIV-specific T cell exhaustion.
Analysis of the selective involvement of the CTLA-4 pathway in HIV-specific CD4 T cell dysfunction.
Characterization of the role of the IL-10 pathway in HIV-specific T cell impairment.
Detailed comprehensive analysis of HIV-specific CD4 T cell responses at the single peptide level.
Demonstration of dissociated CD4- viral load responses in HIV-infected individuals who remain viremic on antiviral therapy (HAART) and of their link to viral fitness.
Selected Recent Publications:
Original manuscripts:
1.

Douglas S. Kwon DS, Angin M, Hongo T, Law KM, Streeck H, Porichis F, Pavlik DF, Tighe DP, Kavanagh DG, Addo MM, Kaufmann DE.  CD4+ CD25+ Regulatory T cells Impair HIV-Specific CD4 T Cell Responses by Upregulating IL-10 Production in Monocytes. (submitted for publication).
2.

Porichis F, Kwon DS,Zupkosky J, Tighe DP, McMullen A, Brockman MA, Pavlik DF, Rodriguez-Garcia M, Pereyra F, Freeman GJ, Kavanagh DG, Kaufmann DE. Responsiveness of HIV-specific CD4 T cells to PD-1 blockade. Blood. 2011 Jul 28;118(4):965-74. PMID: 21652684. PMCID: PMC3148173. PubMed
3.

Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q, Julg B, Jesneck JL, Brosnahan K, Imam S, Russell K, Toth I, Piechocka-Trocha A, Dolfi D, Angelosanto J, Crawford A, Shin H, Kwon DS, Zupkosky J, Francisco L, Freeman GJ, Wherry EJ, Kaufmann DE, Walker BD, Ebert B, Haining WN. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.  Nat Med. 2010 Oct;16(10):1147-51. PMID: 20890291. PubMed
4.

Brockman MA*, Kwon DS*, Tighe DP, Pavlik DF, Rosato PC, Sela J, Porichis F, Le Gall S, Waring MT, Moss K, Jessen H, Pereyra F, Kavanagh DG, Walker BD, Kaufmann DE.IL-10 is up-regulated in multiple cell types during viremicHIV infection and reversibly inhibits virus-specific T cells. Blood. 2009 Jul 9;114(2):346-56. PMID: 19365081.  PMCID: PMC2714209.(*first co-authors). PubMed
5.

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 Nov;8(11):1246-54.  PMID: 17906628. (*first co-authors). PubMed
6.

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 Sep 21;443(7109):350-4.  PMID: 16921384.(*first co-authors). PubMed
Review Articles
1.

Porichis F and Kaufmann DE. Role of PD-1 in HIV Pathogenesis and as Target for Therapy.Current HIV/AIDS Reports. (in press).
2.

Thèze J, Chakrabarti LA, Vingert B, Porichis F, Kaufmann DE. HIV controllers: a multifactorial phenotype of spontaneous viral suppression. ClinImmunol. 2011 Oct;141(1):15-30. PMID: 21865089.  PMCID: PMC3183253. PubMed
3.

Porichis F, Kaufmann DE. HIV-specific CD4 T cells and immune control of viral replication. CurrOpin HIV AIDS. 2011 May;6(3):174-80.  PMID: 21502921. PubMed
4.

Kwon DS, Kaufmann DE.Protective and detrimental roles of IL-10 in HIV pathogenesis.Eur Cytokine Netw. 2010 Sep;21(3):208-14. PMID: 20732847 PubMed
5.

Kaufmann DE, Walker BD.PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J Immunol. 2009 May 15;182(10):5891-7. PMID: 19414738. PubMed