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Active Infection by Variant A of Human Herpesvirus Six Causes Destruction of Lymphoid Tissues in HIV Infected Individuals 

Konstance Kehl Knox, Ph.D. and Donald R. Carrigan Ph.D.
Institute for Viral Pathogenesis, 10437 Innovation Drive, Milwaukee, Wisconsin
Presented at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy
Toronto, Canada; September 18, 2000

Abstract

Background

The pathogenesis of AIDS centers upon the progressive destruction of the lymphoid tissues of patients infected with HIV.  Mechanisms of this lymphoid tissue involution are poorly understood, but direct tissue destruction by HIV is unlikely to be involved.  Previous work by our laboratory has demonstrated that the A variant of human herpesvirus six (HHV-6A) reactivates to productive infection in the lymph nodes of virtually every HIV infected individual when their absolute CD4+ lymphocyte counts are greater than 300 per mm3


Methods

Lymph node biopsies from 12 patients with progressive HIV disease and from 4 individuals with nonprogressive HIV disease were immunohistochemically stained with a monoclonal antibody specific for a structural glycoprotein of HHV-6A.  


Results

All 16 lymph node biopsies examined contained cells actively infected with HHV-6A.  However, the densities of the HHV-6A infections in the lymph nodes of patients with nonprogressive HIV disease were significantly (p < 0.02) lower than in lymph nodes from patients with progressive HIV disease.  Further, a significant (p < 0.035) inverse correlation was found between the absolute CD4+ lymphocyte counts of the patients and the density of the HHV-6A infection in their lymph nodes.  Finally, the densities of HHV-6A infections were significantly (p < 0.016) higher in lymph node areas undergoing active lymphocyte depletion than in areas free of destructive pathological changes.  


Conclusion

HHV-6A is the cause of the lymphoid tissue destruction that occurs in patients infected with HIV, probably through a synergistic interaction between it and HIV.  Nonprogressive HIV disease is associated with low level, and apparently well controlled, HHV-6A infection.  It can be postulated that early intervention with effective antiviral agents, such as ganciclovir, may slow or even stop the HHV-6 mediated destruction of lymphoid tissues in HIV infected individuals.  


Introduction

Tissue involution with lymphocyte depletion and histiocytosis are the major histopathological correlates of the destruction of lymphoid tissues in HIV infected.
The basic cause of these pathological processes remains unclear, but direct effects by HIV are unlikely to underlie these pathologies.
Previous work from our laboratory has shown that:
We have now extended these studies by exploring the relationships between HHV-6A infection of the lymph nodes of HIV infected individuals and the histopathological changes present in the tissues.

Methods

Patient Tissues

Immunohistochemical Staining (IHC)

Histopathological and quantitative virological analyses of lymph node biopsies

Control Tissues

Lymph nodes from 4 HIV negative normal individuals and from 3 lymph nodes from HIV negative patients with follicular hyperplasia served as control materials.

Results

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Figure 1. Histopathological grading system used for evaluation of lymph node biopsies. Panels A - D show tissue sections stained with hematoxylin/eosin that respectively exemplify lymphocyte depletion scores of 1: less than 10% depletion; score 2: 10% to 50% depletion; score 3: 50% to 75% depletion; and score 4: greater than 75% depletion. Arrowheads indicate infiltrating histiocytes and fibrosis. 

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Figure 2. Association between type of HIV disease and density of HHV-6A infection in the patients' lymph nodes. Long horizontal lines indicate mean value. Short horizontal lines denote the 95% confidence intervals (p < 0.02 by two-tailed Mann-Whitney Test). 

Histopathological Correlates of HHV-6A Infections 

Only low levels of HHV-6A infection were found in lymph node areas with either low or no depletion of lymphocytes and in areas with essentially complete replacement of the lymphoid tissue by histiocytes and fibroblasts (Figure 3).  In contrast, very high densities of HHV-6A infected cells were present in lymph node areas undergoing active lymphocyte depletion [Figure 4].  The differences between the HHV-6A infected cell densities of lymph node areas with lymphocyte depletion scores of 1 or 4 and those of areas with lymphocyte depletion scores of 2 or 3 were significant (p < 0.016 by Kruskal-Wallis Nonparametric ANOVA test).  
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Figure 3.  Comparison of HHV-6A infected cell density and lymphocyte depletion scores for the entire data set for lymph node biopsies from HIV infected patients.  Long horizontal bars indicate the mean values.  Short horizontal bars indicate the 95% confidence intervals for the HHV-6A infected cell densities for each lymphocyte depletion score. Differences between the infected cell densities for the lymphocyte depletion scores was significant (p < 0.016).  

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Figure 4. IHC staining of a section of lymph node from an HIV infected patient for cells actively infected with HHV-6A.  Panel A: Low magnification view showing a large area of active lymphocyte depletion in the upper right side of the tissue section.  Arrowheads indicate the intact periphery of a follicle undergoing follicular lysis (upper right of follicle). Panel B: Higher magnification view of the area of follicular lysis shown in panel A.  Some of the cells actively infected with HHV-6A are indicated by arrowheads.

Conclusions

Lymph nodes from nonprogressive HIV disease patients contained significantly lower densities of HHV-6A infected cells compared with progressive HIV disease patients.
These results have implications concerning other established aspects of the pathogenesis of HIV-1 disease:
Thus we propose that HHV-6A and HIV become locked in a synergistic cycle such as the one illustrated in Figure 5.  The ultimate result of this cycle is the progressive destruction of lymphoid tissues in patients infected with HIV.

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