I wrote recently about a review by Beth Jamieson and Tammy Rickabaugh describing the parallel effects of HIV infection and aging on the pool of naïve T cells in humans. Three recent papers address different aspects of naïve T cell loss, including the first study to document a decrease in this population in people with chronic hepatitis C infection.
In PLoS One, Beth Jamieson’s group reports on a study of naïve CD4 T cell levels in younger (20-32 years) and older (39-58 years) individuals with untreated HIV infection, compared to age-matched HIV-negative controls. The researchers use a cell surface marker named CD31 to discriminate between naïve CD4 T cells that have recently been produced by the thymus (CD31+) and those that have proliferated in the circulation (CD31-). Consistent with previous studies, HIV infection had a strong effect on naïve CD4 T cell levels that was additive to that seen in aging; the absolute number of CD31+ naïve CD4 T cells in the younger individuals mirrored those measured in HIV-negative controls who were 17-28 years older. While both HIV infection and aging were associated with declines in CD31+ naïve CD4 T cell numbers, loss of CD31- naïve CD4 T cells was only observed HIV infection; in this case the effect was independent of aging as the absolute loss was similar in both the younger and older HIV-positive participants. In a separate longitudinal analysis of the effects of antiretroviral therapy, CD31+ naïve CD4 T cells achieved levels comparable to age-matched controls after two years of treatment. However, CD31- naïve CD4 T cell levels remained significantly reduced.
The researchers also evaluate telomere lengths in both naïve CD4 T cell subsets, finding them to be reduced both as a result of HIV infection and aging; as was seen for CD31+ naïve CD4 T cell numbers, the effects were additive. Jamieson and colleagues conclude by suggesting that their results likely explain why disease progression occurs more rapidly among HIV-positive individuals over the age of 50, because this older population already has reduced numbers of naïve CD4 T cells, making the impact of HIV infection more severe. They also note that incomplete recovery of naïve CD4 T cells may play a role in increasing the risk of aging-associated diseases in people with HIV.
One commonly cited causative mechanism of naïve T cell depletion in HIV is the persistent activation of these cells, which leads to their differentiation into memory cells. Another contributing factor is lymphoid tissue fibrosis (a type of scarring damage associated with immune activation & inflammation). Naïve T cells continually recirculate through lymphoid tissue and depend on signals received in that environment for their survival. A recent study by Ming Zeng and colleagues delves into this link between lymphoid tissue fibrosis and naïve T cell loss in both SIV and HIV infection.
The researchers find that fibroblastic reticular cells (FRC)--which form the pathways along which T cells travel in lymph nodes--are the major source of IL-7, a cytokine essential for naïve T cell survival. Fibrotic damage (measured by the accumulation of collagen) is shown to disrupt the FRC network and therefore impede the ability of T cells to access IL-7, causing an increase in T cell apoptosis. Both naïve CD4 and CD8 T cells are affected. Additional studies reveal that the loss of T cells in turn exacerbates the damage to FRCs by reducing the production of a cytokine called lymphotoxin-β, which is vital for maintaining FRC networks. The results suggest that there is a vicious cycle in which fibrosis damages FRCs, which causes T cell loss, which then further exacerbates FRC loss.
Continuing their investigative work, Zeng et al look for a source of collagen and find that production of the cytokine TGF-beta by regulatory T cells is increased in HIV, and TGF-beta induces collagen production by fibroblasts. In lab experiments, the antifibrotic drug pirfenidone blocks TGF-beta signaling and reduces collagen production, leading the researchers to conclude that this drug may deserve consideration as an adjunctive therapy for promoting immune reconstitution in HIV.
Lastly, a study published in the March 1st issue of the Journal of Infectious Diseases demonstrates that another persistent chronic infection, hepatitis C, can accelerate naïve CD4 T cell loss. The authors conclude that their findings provide an explanation for the reduced response to vaccinations observed in people with chronic HCV.
PLoS One. 2011 Jan 26;6(1):e16459.
Rickabaugh TM, Kilpatrick RD, Hultin LE, Hultin PM, Hausner MA, Sugar CA, Althoff KN, Margolick JB, Rinaldo CR, Detels R, Phair J, Effros RB, Jamieson BD.
Department of Medicine, UCLA AIDS Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Abstract
HIV-1-infected adults over the age of 50 years progress to AIDS more rapidly than adults in their twenties or thirties. In addition, HIV-1-infected individuals receiving antiretroviral therapy (ART) present with clinical diseases, such as various cancers and liver disease, more commonly seen in older uninfected adults. These observations suggest that HIV-1 infection in older persons can have detrimental immunological effects that are not completely reversed by ART. As naïve T-cells are critically important in responses to neoantigens, we first analyzed two subsets (CD45RA(+)CD31(+) and CD45RA(+)CD31(-)) within the naïve CD4(+) T-cell compartment in young (20-32 years old) and older (39-58 years old), ART-naïve, HIV-1 seropositive individuals within 1-3 years of infection and in age-matched seronegative controls. HIV-1 infection in the young cohort was associated with lower absolute numbers of, and shorter telomere lengths within, both CD45RA(+)CD31(+)CD4(+) and CD45RA(+)CD31(-)CD4(+) T-cell subsets in comparison to age-matched seronegative controls, changes that resembled seronegative individuals who were decades older. Longitudinal analysis provided evidence of thymic emigration and reconstitution of CD45RA(+)CD31(+)CD4(+) T-cells two years post-ART, but minimal reconstitution of the CD45RA(+)CD31(-)CD4(+) subset, which could impair de novo immune responses. For both ART-naïve and ART-treated HIV-1-infected adults, a renewable pool of thymic emigrants is necessary to maintain CD4(+) T-cell homeostasis. Overall, these results offer a partial explanation both for the faster disease progression of older adults and the observation that viral responders to ART present with clinical diseases associated with older adults.
J Clin Invest. doi:10.1172/JCI45157.
Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections
Ming Zeng1, Anthony J. Smith1, Stephen W. Wietgrefe1, Peter J. Southern1, Timothy W. Schacker2, Cavan S. Reilly3, Jacob D. Estes4, Gregory F. Burton5, Guido Silvestri6, Jeffrey D. Lifson4, John V. Carlis7 and Ashley T. Haase1
1Department of Microbiology and
2Department of Medicine, Medical School, University of Minnesota, Minneapolis, Minnesota, USA.
3Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
4AIDS and Cancer Virus Program, Science Applications International Corporation–Frederick Inc., National Cancer Institute, Frederick, Maryland, USA.
5Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA.
6Yerkes National Primate Research Center, and Emory University, Atlanta, Georgia, USA.
7Department of Computer Science and Engineering, Institute of Technology, University of Minnesota, Minneapolis, Minnesota, USA.
Authorship note: Ming Zeng and Anthony J. Smith contributed equally to this work.
The hallmark of HIV-1 and SIV infections is CD4+ T cell depletion. Both direct cell killing and indirect mechanisms related to immune activation have been suggested to cause the depletion of T cells. We have now identified a mechanism by which immune activation-induced fibrosis of lymphoid tissues leads to depletion of naive T cells in HIV-1 infected patients and SIV-infected rhesus macaques. The T regulatory cell response to immune activation increased procollagen production and subsequent deposition as fibrils via the TGF-β1 signaling pathway and chitinase 3-like-1 activity in fibroblasts in lymphoid tissues from patients infected with HIV-1. Collagen deposition restricted T cell access to the survival factor IL-7 on the fibroblastic reticular cell (FRC) network, resulting in apoptosis and depletion of T cells, which, in turn, removed a major source of lymphotoxin-β, a survival factor for FRCs during SIV infection in rhesus macaques. The resulting loss of FRCs and the loss of IL-7 produced by FRCs may thus perpetuate a vicious cycle of depletion of T cells and the FRC network. Because this process is cumulative, early treatment and antifibrotic therapies may offer approaches to moderate T cell depletion and improve immune reconstitution during HIV-1 infection.
J Infect Dis. 2011 Mar;203(5):635-45. Epub 2011 Jan 10.
Yonkers NL, Sieg S, Rodriguez B, Anthony DD.
Department of Pathology.
Abstract
Background. Chronic hepatitis C virus (HCV) infection is characterized by reduced numbers of functional HCV-specific T cells. In addition, chronically HCV-infected individuals have reduced response to vaccine. Alterations in naive CD4 T cell phenotype or function may contribute to these immune impairments. Methods. Using flow cytometric analysis and enzyme-linked immunospot assay, we examined peripheral naive CD4 T cell phenotype and function in chronically HCV-infected patients and control subjects. Results. We observed significantly lower absolute cell numbers of naive CD4 T cells in HCV-infected patients, localized to the CD127(+)CD25(low/-) and CD31(+) (RTE) subsets. Moreover, we found greater percentages of naive cells expressing CD25 and KI67 in HCV-infected patients, consistent with immune activation, further supported by higher plasma sCD27 levels. Functional analysis revealed an intact interferon-γ response to allogeneic B cell stimulus. However, after direct TCR stimulation, naive CD4 T cells from HCV-infected patients had altered up-regulation of KI67 and CD25 and less CD27 expression. The latter was associated with elevated baseline activation state. In addition, naive CD4 T cells from HCV-infected patients were more susceptible to cell death. Conclusions. These numerical and functional defects may contribute to inadequate formation of virus and neoantigen-specific T cell responses during chronic HCV infection.
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