Modeling the Effects of Vaccination on Chronically Infected HIV-Positive Patients *Laura E. Jones and †Alan S. Perelson *Ecology and Evolutionary Biology, Cornell University, Ithaca, New York; and †Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, U.S.A. Abstract: T-cell activation plays a critical role in the initiation and propagation of HIV-1 infection and yet transient activation of the immune system is a normal response to immunization. While it is now considered wise to vaccinate HIV-1–positive pa- tients, it is crucial to anticipate any lasting effects of vaccination on plasma HIV-1 RNA levels and on infected T-cell populations. We extend a simple dynamic model of HIV infection to include T-cell activation by vaccination. We show that the model can reproduce many but not all of the features of the post-tetanus immunization rise in viral load observed and reported on by Stanley et al. in 1966 (N Engl J Med, 334:1222– 1230). Amplitudes and approximate timing of postimmunization peak viral loads were matched in 10 of 12 cases; in patients with double postimmunization peaks of nearly equal amplitude the later peaks were matched. Furthermore, our simulations suggest that productively infected cell populations track postvaccination increases in plasma viral load, rising and falling in concert over a period of about 4 weeks, whereas chronically infected cells peak later and remain elevated over baseline levels for up to 6 weeks postvaccination. Key Words: Viral dynamics—Mathematical models— Tetanus vaccination. T-cell activation plays a critical role in HIV infection and progression to AIDS (1–4). In vitro studies have demonstrated the importance of cell activation in estab- lishing productive HIV infection. For example, reverse transcription within resting cells may be incomplete and integration of proviral DNA may not occur, resulting in abortive infection (5,6). In contrast, activated peripheral blood mononuclear cells are readily infected in culture (5–7). The course of HIV infection in vivo appears to be influenced by cell activation. High levels of activated peripheral T cells are a predictor of early progression to AIDS (8,9), and chronic immune activation resulting from frequent and repeated parasitic infection has been suggested as the probable cause of the increased rate of HIV progression to AIDS and the greater susceptibility to infection observed in sub-Saharan Africa compared with the developed countries (10–12). Transient activation of the immune system occurs dur- ing infections and is a normal response to immunization. Such activation can affect the course of HIV infection. Numerous studies have examined the consequences of vaccinating both untreated (2,13–18) and treated HIV- infected individuals (18–21). Stanley et al. (2) found that giving a booster dose of tetanus toxoid resulted in tran- sient increases in plasma viremia in all 13 HIV-infected subjects studied. Staprans et al. (13) found that influenza vaccination led to transient increases of plasma HIV-1 RNA, and that patients with higher CD4 T-cell counts had larger and more rapid increases in viral load. The large immunization-related increases in virus reported by Staprans et al. (13) suggest that the observed viral rep- lication may be correlated with activation of both anti- gen-specific T-cells and other non-specific T-cell popu- lations, which, once activated, then become targets for infection (3). In a double-blind placebo-controlled study of the effects of influenza vaccination on HIV-infected This work was performed under the auspices of the U.S. Department of Energy and was supported by NIH grants AI28433 and RR06555. Address correspondence and reprint requests to Alan S. Perelson, Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, Los Alamos, NM 87545, USA; e-mail: asp@lanl. gov Manuscript received February 28, 2002; accepted September 10, 2002. JAIDS Journal of Acquired Immune Deficiency Syndromes 31:369–377 © 2002 Lippincott Williams & Wilkins, Inc., Philadelphia 369