Opinion
Pathogen-specific T cell depletion and reactivation of opportunistic pathogens in HIV infection

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During HIV infection, it is unclear why different opportunistic pathogens cause disease at different CD4 T cell count thresholds. Early work has shown that CD4 T cell depletion is influenced both by cellular activation status and expression of viral entry receptors. More recently, functional characteristics of the CD4 T cells, such as cytokine and chemokine production, have also been shown to influence cellular susceptibility to HIV. Here, we examine how functional differences in pathogen-specific CD4 T cells could lead to their differential loss during HIV infection. This may have implications for when different opportunistic infections occur, and a better understanding of the mechanisms for functional imprinting of antigen-specific T cells may lead to improvements in design of vaccines against HIV and opportunistic pathogens.

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HIV-induced CD4 T cell depletion increases susceptibility to opportunistic pathogens

Untreated HIV infection leads to AIDS, a disease characterised by immune suppression and a loss of immune-mediated control against diverse opportunistic pathogens. Immune suppression in AIDS results from the progressive loss of CD4 T cells brought on by persistent HIV replication. Although the pathogenic mechanisms underlying CD4 T cell loss by HIV have been widely debated, a simple rule still applies: the lower the number of CD4 T cells, the higher the risk of opportunistic infections.

Viral entry receptors and CD4 T cell depletion

HIV entry into T cells is dependent on expression of the primary HIV receptor CD4 and one of two chemokine receptors: CCR5 or CXCR4 7, 8. HIV transmission occurs almost exclusively with CCR5-tropic HIV strains [9]. Historically, CCR5-tropic strains have been referred to as M-tropic, because of their potential to infect both macrophages and primary T cells. CXCR4-tropic strains typically appear late during the course of HIV disease progression, are more cytopathic and have historically been

Integrin α4β7 in transmission and early dissemination of HIV

High integrin α4β7 expression defines a subset of memory CD4 T cells within genital mucosa, the rectum and the gut associated lymphoid tissue (GALT). The integrin α4β7 has recently been described as a cellular receptor for HIV on CD4 T cells 30, 31. It contributes to efficient entry of HIV into the cell by capturing virions in close spatial proximity to the viral entry receptors CD4 and CCR5 32, 33. Many cells in this population also express the viral co-receptor CCR5 and are in the active

T cell activation status and HIV infection

T cell activation and proliferation contribute to productive HIV infection of memory CD4 T cells 35, 36, 37, 38. Expression of HLA-DR and CD25 [interleukin (IL)-2 receptor α chain] on CD4 T cells within lymphoid tissue explants defines the main target CD4 T cell population for productive HIV infection [35]. Indeed, the IL-2 signalling pathway, which is essential for clonal expansion after antigen-specific T cell stimulation, promotes HIV replication 6, 36. Other cytokines that promote T cell

CD4 T cell specificity and HIV-induced depletion

Both MTB and CMV typically cause latent or controlled infection in immunocompetent individuals but can reactivate and cause disease during periods of immunosuppression, and both infections appear to be controlled predominantly by pathogen-specific CD4 T cells 1, 3, 43, 44. Despite these similarities, the CD4 T cell thresholds at which these infections cause opportunistic disease are very different: active tuberculosis (TB) disease is often the first severe opportunistic infection affecting HIV+

Antigen stimulation history affects CD4 T cell phenotype and function

Antigen exposure can influence CD4 T cell phenotype and function, and thus potentially affects susceptibility to HIV. In situations in which antigen is cleared, for example, after tetanus toxoid vaccination, the antigen-specific CD4 T cells predominantly express a less differentiated, central memory phenotype, and produce IL-2 upon restimulation. Infections with low, but persistent antigen levels, such as latent/recurrent CMV or non-progressing HIV infections, are associated with more

APCs contribute to HIV infection of CD4 T cells

Conjugates of APCs (including DCs) and T cells are the predominant sites for HIV replication in vivo [62]. Infected DCs preferentially transmit HIV to responding antigen-specific CD4 T cells [63]; a process that would contribute to efficient infection and subsequent depletion of newly emerging antigen-specific CD4 T cell populations during the expansion phase [53]. Not only are DCs crucial for the transfer of HIV to responding CD4 T cells, but the co-stimulatory molecules and

Depletion of CD4 Th17 cells contributes to impaired mucosal barrier function of the gut

Profound depletion of GALT memory CD4 T cells during HIV infection 12, 67 results in impaired mucosal immunity and systemic immune activation, which are hallmarks of pathogenic immunodeficiency virus infection [27]. Memory Th17 cells are found in high frequency in GALT [68] and their depletion plays a central role in the translocation of microbes and their products into the blood stream, promoting systemic immune activation 27, 69. The extent of immune activation is an important predictor of

Depletion of pathogen-specific CD4 T cells might promote development of virus-associated malignancies in HIV infection

Loss of control of some viral pathogens can lead to cancer rather than disseminated infection. Cancers and lymphoproliferative disorders occurring in patients with HIV infection are often closely linked to oncogenic viruses, such as the gamma herpes viruses Epstein–Barr virus (EBV) and Kaposi sarcoma virus (KSV), or human papilloma virus (HPV) 74, 75, 76, 77. Perhaps most thoroughly studied are malignancies associated with HIV-induced immunosuppression that are caused by EBV coinfection, which

Concluding remarks

Not all pathogen-specific CD4 T cells are created equal and this may have implications for opportunistic infection during HIV infection. Emerging data suggests that specific characteristics of CD4 T cells, including their phenotype, function and location, can have a direct influence on their likelihood of being infected and depleted by HIV. The susceptibility of MTB- and CMV-specific CD4 T cells to HIV infection has been linked to specific characteristics of these cells 5, 6, and differential

Acknowledgements

The authors thank Joseph Casazza, Pratip Chattopadhyay, Joe Jarvis and Costas Petrovas for useful discussions. The illustrated data has kindly been provided by Joseph Casazza from the Vaccine Research Center, National Institutes of Health, Bethesda, MD, USA. We also thank Jennifer Ring for the illustration of Figure 2.

References (92)

  • V. Cecchinato

    Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques

    Mucosal Immunol.

    (2008)
  • S.G. Deeks

    Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load

    Blood

    (2004)
  • A. Carbone

    HIV-associated lymphomas and gamma-herpesviruses

    Blood

    (2009)
  • E. Piriou

    Loss of EBNA1-specific memory CD4+ and CD8+ T cells in HIV-infected patients progressing to AIDS-related non-Hodgkin lymphoma

    Blood

    (2005)
  • R. Cheynier

    HIV and T cell expansion in splenic white pulps is accompanied by infiltration of HIV-specific cytotoxic T lymphocytes

    Cell

    (1994)
  • N.R. Klatt

    SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination

    Blood

    (2011)
  • N.D. McKenzie

    Women with HIV are more commonly infected with non-16 and -18 high-risk HPV types

    Gynecol. Oncol.

    (2010)
  • C. Bronke

    Dynamics of cytomegalovirus (CMV)-specific T cells in HIV-1-infected individuals progressing to AIDS with CMV end-organ disease

    J. Infect. Dis.

    (2005)
  • K.V. Komanduri

    Loss of cytomegalovirus-specific CD4+ T cell responses in human immunodeficiency virus type 1-infected patients with high CD4+ T cell counts and recurrent retinitis

    J. Infect. Dis.

    (2001)
  • K.V. Komanduri

    Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1

    Nat. Med.

    (1998)
  • B. Autran

    Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease

    Science

    (1997)
  • J.P. Casazza

    Autocrine production of beta-chemokines protects CMV-Specific CD4 T cells from HIV infection

    PLoS Pathog.

    (2009)
  • C. Geldmacher

    Preferential infection and depletion of Mycobacterium tuberculosis-specific CD4 T cells after HIV-1 infection

    J. Exp. Med.

    (2010)
  • T. Dragic

    HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5

    Nature

    (1996)
  • Y. Huang

    The role of a mutant CCR5 allele in HIV-1 transmission and disease progression

    Nat. Med.

    (1996)
  • J.P. Moore

    The CCR5 and CXCR4 coreceptors – central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection

    AIDS Res. Hum. Retroviruses

    (2004)
  • J.A. Levy

    HIV pathogenesis: 25 years of progress and persistent challenges

    AIDS

    (2009)
  • L.J. Picker

    Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection

    J. Exp. Med.

    (2004)
  • J.M. Brenchley

    CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract

    J. Exp. Med.

    (2004)
  • S. Qin

    The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions

    J. Clin. Invest.

    (1998)
  • Y. Nishimura

    Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses

    Proc. Natl. Acad. Sci. U.S.A.

    (2004)
  • C.S. Ma

    Early commitment of naïve human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12

    Immunol. Cell Biol.

    (2009)
  • M. Bermejo

    Activation of blood T lymphocytes down-regulates CXCR4 expression and interferes with propagation of X4 HIV strains

    Eur. J. Immunol.

    (1998)
  • P. Jourdan

    Cytokines and cell surface molecules independently induce CXCR4 expression on CD4+ CCR7+ human memory T cells

    J. Immunol.

    (2000)
  • A. Ganesan

    Immunologic and virologic events in early HIV infection predict subsequent rate of progression

    J. Infect. Dis.

    (2010)
  • S. Mehandru

    Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract

    J. Exp. Med.

    (2004)
  • Q. Li

    Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells

    Nature

    (2005)
  • J.J. Mattapallil

    Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection

    Nature

    (2005)
  • G.H. Holm et al.

    Distinct mechanisms of CD4+ and CD8+ T-cell activation and bystander apoptosis induced by human immunodeficiency virus type 1 virions

    J. Virol.

    (2005)
  • K.N. Brown

    Rapid influx and death of plasmacytoid dendritic cells in lymph nodes mediate depletion in acute simian immunodeficiency virus infection

    PLoS Pathog.

    (2009)
  • G. Hutter

    Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation

    N. Engl. J. Med.

    (2009)
  • R.M. Ribeiro

    Naive and memory cell turnover as drivers of CCR5-to-CXCR4 tropism switch in human immunodeficiency virus type 1: implications for therapy

    J. Virol.

    (2006)
  • R.A. Hawkins

    Expression of mucosal homing receptor alpha4beta7 is associated with enhanced migration to the Chlamydia-infected murine genital mucosa in vivo

    Infect. Immun.

    (2000)
  • N. Wagner

    Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue

    Nature

    (1996)
  • J. Arthos

    HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells

    Nat. Immunol.

    (2008)
  • C. Cicala

    The integrin alpha4beta7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1

    Proc. Natl. Acad. Sci. U.S.A.

    (2009)
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