AIDSWEEKLY Plus, Monday, 1 September 1997
Daniel J. DeNoon, Senior Editor
New data argue against the popular idea that HIV causes AIDS by directly killing off T cells.
A study of tonsil biopsies from people at various stages of HIV disease show that depletion of CD4(+) T cells occurs when viral load reaches a threshold level in lymphoid tissue.
"At a threshold level when only about 1:100 tonsillar CD4(+) T cells are infected, and only approximately 3:10,000 tonsillar T cells are active virus producers, the balance between tonsillar CD4 cells lost and replaced is disturbed and the level of tonsillar CD4(+) T cells starts to fall," reported Bard Rosok of the Center for Research in Virology, Bergen, Norway, and colleagues. "A direct cytopathic effect by HIV-1 on individual infected cells alone seems insufficient to explain this loss of CD4(+) T cells."
Rosok et al. reported their findings in the Proceedings of the National Academy of Sciences ("Correlates of Latent and Productive HIV Type-1 Infection in Tonsillar CD4(+) T Cells," PNAS, 1997;94:9332-6).
The researchers obtained tonsillar biopsies from 13 people with HIV infection (median age, 34 years) with CD4 counts ranging from 2 to 1,500 cells/(micro)L and with plasma viremia ranging from 2.6 to 5.9 log[10] HIV RNA copies/mL.
They found that when fewer than one in 100 tonsillar CD4(+) T cells contained replication-competent provirus, tonsillar CD4(+) T-cell levels were the same in subjects as in uninfected, healthy individuals. HIV viremia in subjects' tonsils correlated with their levels of plasma viremia, although tonsil viremia was some 40 times higher.
Interestingly, only 3 percent of the HIV infected T cells produced virus.
"Death of all or most of the virus-producing CD4(+) tonsillar T cells seems insufficient to account for the degree of apoptosis observed among tonsillar T cells, and insufficient as an explanation for the eventual depletion of CD4(+) T cells in lymphoid tissues as long as the repopulation system for lymphocytes is functioning normally," Rosok et al. wrote. "The exact mechanisms leading to the loss of CD4 cells in lymphoid tissue thus remain elusive."
The findings lend support to the model of HIV pathogenesis put forward by Michael Ascher, chief of the Viral and Rickettsial Disease Laboratory of the California Department of Health Sciences, Berkeley, at the recent SPIRAT/NCDDG-HIV conference sponsored by the National Institute of Allergy and Infectious Diseases (see AIDS Weekly Plus, July 7, 1997).
In Ascher's model, HIV emits or elicits activation signals that alter the setpoint of T-cell homeostasis so that the immune system believes there are too many CD4(+) lymphocytes. Thus, homeostatic mechanisms delete what are perceived to be excess CD4 cells even though these cells are, in reality, desperately needed.
The model has troubling implications for rebuilding the immune system in the era of highly active antiretroviral therapy (HAART).
Virologic implications are that even a very small residual amount of HIV - or HIV DNA integrated into the host genome - might prevent the resetting of T-cell homeostasis to normal levels.
There are several immunologic implications:
* Clonal regulation - the law of which, Ascher said, is zero population growth - could prevent T-cell expansion.
* The surviving T-cell repertoire may contain only specificities irrelevant for normal immune surveillance.
* The shrunken T-cell environment may be seen as normal by the immune system, in which case homeostatic mechanisms would prevent expansion.
* The infrastructure of the immune system (e.g., antigen- presenting cells or lymph nodes) may be too badly damaged for immune reconstitution.
* The population of naive T cells may be depleted after the long struggle with HIV.
"The model predicts that even if all HIV is killed, the [T-cell] repertoire is limited," Ascher said. "With a new source of cells, the repertoire may be increased but the level of homeostasis is not much changed."
The challenge of immune reconstitution, he concluded, is to better understand - and one day learn to adjust - the mechanism of homeostasis.
Financial support for the Rosok et al. study was provided by the Norwegian Research Council.
The corresponding author for this study is Bard Rosok, Department of Microbiology and Immunology, Center for Research in Virology, N-5020 Bergen, Norway.
970901
AW970901
Copyright © 1997 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.
Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588 http://www.newsfile.com
AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 1997. This material is designed to support, not replace, the relationship that exists between you and your doctor.
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1990, 2000. AEGiS & the Sisters of Saint Elizabeth of Hungary. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of ÆGIS, or the party credited as the provider of the content.