H. Clifford Lane, M.D.

Immunopathogenesis Section

H. Clifford Lane, M.D.

Deputy Director for Clinical Research and Special Projects, NIAID
Director, Division of Clinical Research, NIAID
Clinical Director, NIAID
Acting Chief, Laboratory of Immunoregulation
Chief, Clinical and Molecular Retrovirology Section, LIR, DIR, NIAID
Acting Chief, Immunopathogenesis Section, LIR, DIR, NIAID

Contact: For contact information, search the NIH Enterprise Directory.

Specialty(s): Diagnostic Laboratory Immunology, Infectious Disease, Internal Medicine
Provides direct clinical care to patients at NIH Clinical Center

H. Clifford Lane, M.D.

Major Areas of Research

  • Role of HIV envelope signaling in viral replication and immune dysfunction
  • Novel approaches to the inhibition of HIV binding and entry into CD4+ T cells

Program Description

The Immunopathogenesis Section investigates the cellular and molecular mechanisms underlying the immune dysfunction caused by HIV infection. Several major projects ongoing in the section are described below.

Role of HIV envelope-target cell interactions in the pathogenesis of HIV infection (Lead Investigators: James Arthos, Ph.D., and Claudia Cicala, Ph.D.)

The primary aim of this project is to better understand the role of the HIV envelope protein in HIV pathogenesis. To that end, we have focused on the complex interplay between the viral envelope and several of the known cell surface receptors to which it binds (CD4, CCR5, CXCR4, integrin α4β7). Understanding the complexities and significance of the signaling processes that gp120 mediates will enhance our understanding of HIV-1 pathogenesis and may facilitate the discovery of new strategies for the treatment and prevention of HIV-1 disease. The finding that gp120 engages integrin α4β7, the gut-homing receptor, opens up many new and potentially important questions. Because α4β7 mediates leukocyte homing to gut-associated lymphoid tissue (GALT), which is a principal site of HIV replication during the acute phase of infection, we explored the role of α4β7-expressing CD4+ T cells in HIV transmission. We previously determined that human α4β7high CD4+ T cells are highly susceptible in vitro to productive infection by HIV, in part because α4β7high CD4+ T cells are enriched with metabolically active cells. We then tested this hypothesis in a non-human primate in vivo model of HIV/SIV infection and determined that an antibody specific for α4β7 prevented transmission in a rhesus macaque model of mucosal transmission. In addition, we have investigated the interaction between HIV and α4β7 on primary B cells. We have learned that some of the defects associated with HIV disease result from direct interactions between gp120 and receptors on B cells. These findings have relevance to our understanding of early HIV transmission and viral dissemination, particularly in GALT, providing new avenues of investigation regarding the potential role of α4β7+ as a therapeutic target against HIV infection.

Major Findings

  • HIV-1 envelope binds to, and signals through α4β7 integrin, the gut mucosal homing receptor for peripheral T cells.
  • The HIV envelope protein gp120 binds to a conformationally active form of α4β7 on CD4+ T cells. This binding is independent of the binding of envelope to the CD4 molecule. Because the function of α4β7 is intimately linked to GALT, where HIV replicates at high levels especially in acute/early infection, the specific affinity observed suggests that envelope-α α4β7 interactions play an important role in HIV pathogenesis.
  • α4β7high CD4+ T cells are more susceptible to productive infection by HIV than are α4β7low/neg CD4+ T cells, in part because this cellular subset is enriched with metabolically active cells.
  • Removal of N-linked glycosylation sites in HIV envelopes results in large increases in the specific affinity of gp120 for α4β7. Several envelopes derived from viruses isolated shortly after transmission react with α4β7 to a substantially higher level than do the great majority of envelopes derived from viruses isolated in the chronic phase of infection. These results suggest that mucosal transmission may frequently involve a relative requirement for the productive infection of α4β7+ CD4+ T cells.
  • Targeting α4β7 significantly reduces intravaginal mucosal transmission and subsequent tissue dissemination of SIV in a non-human primate model of HIV/AIDS. This supports our hypothesis that α4β7+/CD4+ T cells can play an important role in mucosal transmission of HIV.

Biography

Education

M.D., 1976, University of Michigan

Dr. Lane received his M.D. from the University of Michigan in 1976. He then completed an internship and residency at the University of Michigan Hospital, Ann Arbor. In 1979, Dr. Lane came to the National Institutes of Health as a clinical associate in the Laboratory of Immunoregulation (LIR). In 1985, he was appointed deputy clinical director of NIAID; in 1989, he became the chief of the Clinical and Molecular Retrovirology Section of LIR, a position he still holds. In 1991, Dr. Lane became clinical director of NIAID and, in 2006, became NIAID Deputy Director for Clinical Research and Special Projects and Director of the Division of Clinical Research.

Selected Publications

Fauci AS, Marston HD. Ending the HIV-AIDS Pandemic--Follow the Science. N Engl J Med. 2015 Dec 3;373(23):2197-9.

Fauci AS, Marston HD. Toward an HIV vaccine: A scientific journey. Science. 2015 Jul 24;349(6246):386-7.

Chun TW, Moir S, Fauci AS. HIV reservoirs as obstacles and opportunities for an HIV cure. Nat Immunol. 2015 Jun;16(6):584-9.

Kardava L, Moir S, Shah N, Wang W, Ho J, Wilson R, Buckner CM, Santich BH, Kim LJY, Spurlin EE, Nelson AK, Wheatley AK, Harvey CJ, McDermott AB, Wucherpfennig KW, Chun TW, Tsang JS, Li Y, Fauci AS. Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals. J Clin Invest. 2014 Aug;124(8):3352-63.

Byrareddy SN, Kallam B, Arthos J, Cicala C, Nawaz F, Hiatt J, Kersh EN, McNicholl JM, Hanson D, Reimann KA, Brameier M, Walter L, Rogers K, Mayne AE, Dunbar P, Villinger T, Little D, Parslow TG, Santangelo PJ, Villinger F, Fauci AS, Ansari AA.Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection. Nat Med. 2014 Dec;20(12):1397-400.

Jelicic K, Cimbro R, Nawaz F, Huang da W, Zheng X, Yang J, Lempicki RA, Pascuccio M, Van Ryk D, Schwing C, Hiatt J, Okwara N, Wei D, Roby G, David A, Hwang IY, Kehrl JH, Arthos J, Cicala C, Fauci AS. The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-β1 production and FcRL4 expression. Nat Immunol. 2013 Dec;14(12):1256-65.

Visit PubMed for a complete publication listing.

Patents

Arthos J, Good D, Cicala C, Fauci AS, inventors; The United States of America, as represented by the Secretary, Department of Health and Human Services, assignee. Use of antagonists of the interaction between HIV GP120 and A4B7 integrin. United States patent US 9,193,790. 2015 Nov 24.

Arthos J, Cicala C, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Fusion protein including of CD4. United States patent US 7,368,114. 2008 May 6.

Scala G, Chen X, Cohen OJ, Fauci AS, inventors; The United States of America as represented by the Secretary of the Department of Health and Human Services, assignee. HIV related peptides. United States patent US 6,911,527. 2005 Jun 28.

Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 6,548,055. 2003 Apr 15.

Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 6,190,656. 2001 Feb 20.

Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 5,696,079. 1997 Dec 9.

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