The Body Covers: The 36th Annual Meeting of the Infectious Diseases Society of America
Abstract S94: Host Factors in the Pathogenesis of HIV Disease
November 15, 1998
Dr. Fauci discussed basic principles of HIV eradication theory and listed the limitations of current therapeutic options. In particular, he described the importance of latently infected CD4 lymphocytes that have replication competent proviral DNA that had a half-life of approximately 104 days; calculations for eradication of HIV within this pool of cells may then require up to 11 years for eradication. The current limitations of therapy make eradication unlikely over this time period given problems with imperfect adherence, adverse long term consequences of therapy and that not all patients' plasma HIV RNA is suppressed with current options and with multi-drug resistant mutations. Dr. Fauci outlined current limitations of HAART in that newer and more sensitive techniques of isolating replication competent proviral DNA had been able to detect its presence even in patients whose plasma HIV-1 RNA had been suppressed for over two years. To address the issue of facilitating eradication of replication competent DNA in latently infected cells, he suggested a "purge" approach to activate viral replication in the setting of HAART to enhance depletion of latently infected CD4 lymphocytes. Chemokines associated with inducing viral replication of latently infected CD4 lymphocytes in vitro include the use of IL-2, IL-6, or TNF-alpha. Data from the recent study of HAART use with (N=12) and without (N=14) IL-2 were reviewed. Intermittent IL-2 administration was either IV or SQ at doses ranging from 3-18 million U per day over 5 days every 8-12 weeks. Patients had plasma viral RNA suppressed to less than 50 copies/mL for ~ 20 months on HAART and 14 received IL-2 for ~39 months. Baseline CD4 count for the HAART only group was ~500 lymphocytes/mL and was ~800 lymphocytes/mL for the HAART plus IL-2. All twelve patients on HAART only had replication competent proviral DNA. Among the 14 receiving HAART plus IL-2, six were without recovery of replication competent virus. Using a more robust technique probing 100-300 million cells, three of the six individuals had replication competent virus recovered. Among these three, one patient had completed analysis of a lymph node biopsy that demonstrated non-reactive, normal architecture. Analysis of 50 million cells from the node demonstrated that no replication competent virus could be isolated.
These data provide the first demonstration that replication competent virus can be eradicated from large quantities of evaluated latent CD4 lymphocytes. While these data are extremely optimistic for potentially decreasing the time to eradication for an infected cell population with a long half-life, several important caveats remain. The demonstration of no replication competent virus from the lymph node biopsy does not indicate that other lymphatic beds are devoid of virus. Secondly, the durability of this treatment is, as yet, unknown. Further information should be forthcoming as the two other patients' lymph node biopsy results become available.
Authored by: A. Fauci
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