/SUP> T-cell Count

Courtesy of Timothy Shacker COLLAGEN COUNTS: (A) A modified trichrome stain on lymphatic tissue from an HIV- patient. Stained tissue from an HIV+ patient (B) shows a relatively intact peripheral CD4+ count with collagen at 2.2%, compared with a patient with advanced HIV-1 (C) with collagen at 18.6%. (J Clin Invest, 10:1133-9, 2002) Because HIV preferentially targets CD4+ T cells, their numbers, along with other metrics like HIV RNA levels, traditionally are used to indicate the infection's severity. Moreover, clinicians use these numbers to predict the efficacy of future immunological reconstitution treatment in first-time patients undergoing antiretroviral therapy. But a recent finding shows that highly active antiretroviral therapy (HAART) failed to markedly increase the peripheral CD4+ count in 25% of patients, despite sometimes being able to reduce HIV RNA in the blood to undetectable levels. This finding has brought into question the utility of these factors as recovery predictors.1 "There must be factors beyond suppression of viral replication," says Timothy Schacker, associate professor of medicine, University of Minnesota. Schacker and his colleagues contend that the amount of lymph node fibrosis prior to HAART initiation is perhaps a better indicator of a patient's ability to recover peripheral CD4+ T cells following HAART.1 The damage to the lymph nodes, where nearly all HIV replication takes place in the activated CD4+ cells that reside there, has already occurred before therapy has even started. An ever-expanding body of work--much of it undertaken by the once-lone voice of the National Institutes of Health's Steven Shaw2,3--is showing the importance of lymph node architecture in providing a suitable microenvironment for the immune processes. Here, T cells interact with B cells, antigen-presenting cells, stroma, and each other, as well as receive soluble messages through cytokines and other growth factors. So, if the structure is compromised, the lymph nodes' ability to support a viable immune system may be severely compromised as well. PERPETUAL INFLAMMATION Schacker and colleagues examined the T-cell zones of lymph nodes from treatment-naïve patients at various stages of HIV infection, from presymptomatic to full-blown AIDS. The number of CD4+ T cells found there did not correlate with either peripheral CD4+ cells or with detectable amounts of viral RNA in the plasma. But the nodes had considerably more collagen deposition than HIV-negative controls. The collagen showed an inverse relationship to the nodal CD4+ T-cell population; the number of CD4+ cells decreased as the amount of fibrosis increased. Similarly, the potential for immunological reconstitution as measured by the peripheral CD4+ T-cell count after therapy showed an inverse relationship with the amount of nodal collagen deposition. The investigators speculate that lymph nodes are likely damaged because of perpetual inflammation. "In the long struggle between immune defenses and HIV-1 that partially controls replication, the immune system is maintained in a state of chronic activation," they write. The model is not unprecedented. "The situation is analogous to what happens to the liver in a chronic hepatitis infection," says Schacker. In such cases, ongoing viral replication leads to chronic inflammation and fibrosis, eventually replacing functional hepatic tissue with collagen; the end result is cirrhosis. "While it is unclear exactly what mechanism is operating here," notes Jerome Zack, professor of microbiology, immunology, and molecular genetics, University of California, Los Angeles, "damage to lymph node structure could have several consequences for the immune response, including the inability of the lymph nodes with large amounts of collagen to physically house T cells, or to alter positioning of T cells such that proper activation, growth or chemotactic signals are not received." Jason Cyster, assistant professor of microbiology, UC-San Francisco, calls the work "tantalizing" and explains that "excessive deposition of collagen and other extracellular matrix components within the T zone might be expected to disrupt T-cell interactions with dendritic cells or local production of IL-7 [the T-cell survival factor interleukin 7]." Schacker's data suggest that "damage and disruption to the lymphatic tissue microenvironment ... results in the impaired recruitment, retention, and proliferation of CD4+ cells." They expect that the most significant impact would be on naïve CD4+ T cells, which are known to require greater external signaling to proliferate and remain viable than do activated or memory cells. Schacker says this hypothesis is currently being investigated by flow-cytometric and other studies to phenotype T cells taken from patients' lymph nodes. For his part, Cyster wants to see whether the frequencies of other cell types, such as dendritic or stromal cells, are diminished in the patient samples, or whether IL-7 mRNA levels have been affected. Presuming that chronic inflammation is responsible for damaging the lymph node architecture, Schacker's team also wants to test whether adjoining anti-inflammatory therapy with HAART would lessen, prevent, or even reverse some of the fibrosis, perhaps leading to an improved immunological recovery. Shaw finds the new research quite satisfactory. "[We are] delighted that our work has built a conceptual framework upon which this work has built." Josh P. Roberts (tcwriter@msn.com) is a freelance writer in Minneapolis, Minn. References 1. T. Schacker et al., "Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis," J Clin Invest, 110:1133-9, October 2002. 2. A.O. Anderson, S. Shaw, "T cell adhesion to endothelium: the FRC conduit system and other anatomic and molecular features which facilitate the adhesion cascade in lymph node," Semin Immunol, 5:271-82, 1993. 3. J.E. Gretz et al., "Cords, channels, corridors and conduits: Critical architectural elements facilitating cell interactions in the lymph node cortex." Immunol Rev, 156:11-24, 1997.

/SUP> T-cell Count

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Courtesy of Timothy Shacker

	COLLAGEN COUNTS: (A) A modified trichrome stain on lymphatic tissue from an HIV- patient. Stained tissue from an HIV+ patient (B) shows a relatively intact peripheral CD4⁺ count with collagen at 2.2%, compared with a patient with advanced HIV-1 (C) with collagen at 18.6%. (J Clin Invest, 10:1133-9, 2002)