Trends in Immunology
OpinionPathogen-specific T cell depletion and reactivation of opportunistic pathogens in HIV infection
Section snippets
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.
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