Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis

Abstract

Lymphatic tissues (LTs) are structurally organized to promote interaction between antigens, chemokines, growth factors, and lymphocytes to generate an immunologic response and maintain normal-sized populations of CD4(+) and CD8(+) T cells. Inflammation and tissue remodeling that accompany local innate and adaptive immune responses to HIV-1 replication cause damage to the LT architecture. As a result, normal populations of CD4(+) and CD8(+) T cells cannot be supported and antigen-lymphocyte interactions are impaired. This conclusion is supported herein following LT sampling before and during anti-HIV therapy in persons with acute, chronic, and late-stage HIV-1 infection. Among seven individuals treated with anti-retroviral therapy (ART) and four individuals deferring therapy we found evidence of significant paracortical T cell zone damage associated with deposition of collagen, the extent of which was inversely correlated with both the size of the LT CD4(+) T cell population and the change in peripheral CD4(+) T cell count with anti-HIV therapy. The HIV-1-associated inflammatory changes and scarring in LT both limit the ability of the tissue to support and reestablish normal-sized populations of CD4(+) T cells and suggest a novel mechanism of T cell depletion that may explain the failure of ART to significantly increase CD4(+) T cell populations in some HIV-1-infected persons.

Figure 1

Histologic changes in B cell follicles and TZ characteristic of HIV-1 infection. (a) Section of lymph node from an HIV-negative patient. There is one B cell follicle that is normal in size and shape (black arrow). The TZ is normal in size with a normal population of cells (white arrow). (b) Section of a lymph node from an HIV-1–infected patient with presymptomatic HIV-1 infection. The follicles are hyperplastic and disorganized (black arrow), and the TZ is small and somewhat depleted of cells (white arrow). (c) Lymph node section from a patient with AIDS. The follicular space is disorganized and without structure (black arrow), and the TZ is unrecognizable with few cells (white arrow). All images are at a magnification of ×4.

Figure 2

Comparison of peripheral versus LT CD4⁺ T cell population at baseline shows no significant relationship.

Figure 3

Quantitative analysis of collagen deposition in the TZ in HIV-1–infected persons. Tissues were stained with a modified trichrome stain using the Masson method to identify collagen fibers as blue. (a) HIV-negative patient. Collagen makes up 0.23% of the tissue section. (b) Patient 1407. Section shows collagen deposition (stained blue) in the wall of the high endothelial venule. Percent area collagen was calculated to be 2.2%. (c) Patient 1327, the patient with AIDS. In contrast to b, this section shows significant deposition of collagen in the TZ. Percent area collagen was calculated to be 18.6%. A total of 18 images from each tissue sample, imported through the Photoshop program (Adobe, Version 6.0), are displayed (magnification, ×40). (d) The transformed Photoshop image from c. All shades of blue representing collagen in c were averaged and displayed in black; non-collagen area was removed. This image was imported into the MetaMorph imaging program and the percent area in black was calculated.

Figure 4

Relationship between the percentage of LT occupied by collagen and two parameters: baseline LT CD4⁺ T cell population and change in peripheral CD4⁺ T cell count after 6 months. (a) Size of the baseline LT CD4⁺ T cell population is compared with the percent area of the TZ occupied by collagen. There is a significant correlation between these values (R² = 0.72, P < 0.0001, Spearman rank correlation). (b) Change in the peripheral CD4⁺ T cell population after 6 months of HAART is compared with the percent area of the TZ occupied by collagen. There is significant correlation between these measurements (R² = 0.91, P < 0.001).