Influence of Peak Viral Load on the Extent of CD4 + T-Cell Depletion in Simian HIV Infection Miles P. Davenport, MD, PhD,* Lei Zhang, MSc,* John W. Shiver, PhD,† Danilo R. Casmiro, PhD,† Ruy M. Ribeiro, PhD,‡ and Alan S. Perelson, PhD‡ Summary: Simian HIV (SHIV) infection of macaques with CXCR4 tropic viruses results in early and profound CD4 + T-cell depletion in the first few weeks of infection. Analyzing data from a large study of vaccination and SHIV-89.6P challenge, we observe a strong correlation between peak viral load and the extent of CD4 + T-cell depletion in acute infection, consistent with a simple kinetic model of viral infection of CD4 + T cells. We have modeled the dynamics of the interaction of virus and CD4 + T cells over time to investigate the rate of CD4 + T-cell infection and death. This analysis indicates that up to 80% of CD4 + T cells are infected at peak viremia and that the proportion of CD4 + T cells destroyed is correlated with the peak viral load. The simple relation between viral load and CD4 + T-cell de- pletion allows prediction of the level of viral control required to pre- vent CD4 + T-cell depletion in acute SHIV infection. Whether such a simple relation also holds for HIV or simian immunodeficiency virus infections remains to be determined, particularly in the gut and other anatomic sites in which most early T-cell depletion occurs. Key Words: vaccine, pathogenesis, viral load, virus-cell interaction, CD4-positive T lymphocytes, mathematic models (J Acquir Immune Defic Syndr 2006;41:259Y265) T he natural history of HIV infection is characterized by a moderate loss of CD4 + T cells in peripheral blood during acute infection, followed by a slow long-term decline in CD4 + T-cell numbers and progression to AIDS in most cases. Recent evidence suggests that the CD4 + T-cell loss observed in peripheral blood may underestimate the scale of CD4 + T-cell depletion in other organs, particularly the gastrointestinal tract. 1Y3 In addition, there is increasing evi- dence that the early loss of CD4 + T-cell function is a major contributor to the long-term impairment of CD8 + T-cell function. 4Y6 Therefore, it seems likely that the loss of CD4 + T cells in acute HIV infection is likely more profound than previously thought and may play an important role in de- termining the long-term loss of immune control of HIV. Several monkey models of HIV infection have been developed and used for testing different approaches to im- munoprophylaxis and therapy for HIV. These viruses dif- fer with respect to their pathogenicity, tropism for cellular coreceptors, and susceptibility to antibody neutralization. CXCR4 tropic simian HIV (SHIV), such as SHIV89.6P, 7,8 SHIV89.6PD, 9 and SHIVmn229, 10 are used for vaccine studies because of the extremely rapid course of disease, characterized by early and profound depletion of CD4 + T cells during acute infection. Several different interventions, in- cluding immunization with DNA or viral vectors, 7,8 passive antibody treatment, 9,11 transient antiretroviral therapy, 12 and even low-dose challenge, 12 have been shown to lead to long- term viral control in such models. Importantly, in the case of passive antibody treatment 9,11 and transient antiretroviral therapy, 12 a short-term intervention in acute infection seems to Bprogram^ the course of chronic infection even after the intervention has ceased. This occurs presumably through preservation of host CD4 + T cells in acute infection, leading to maintenance of immune responsiveness to virus. 4,13 The rapid and profound loss of CD4 + T cells in acute SHIV infection provides a model to examine the kinetics of CD4 + T-cell depletion in vivo. We used mathematic mod- eling to analyze early CD4 + T-cell and viral load data from a study of 35 macaques vaccinated with a variety of regimens and challenged intravenously with SHIV89.6P. We found that even across these multiple vaccination regimens, the kinetics of CD4 + depletion in acute infection are consistent with simple models of CD4 + T-cell infection and death 14,15 and provide important insights into the effects of vaccina- tion. Understanding the relation between viral load and CD4 + T-cell infection and death allows prediction of the level of viral control required to prevent CD4 + T-cell de- pletion and should assist in the evaluation of vaccination and therapy regimens in early infection. METHODS Vaccination Challenge Studies Thirty-five macaques were vaccinated with a variety of regimens, consisting of SIV gag containing plasmid DNA BASIC SCIENCE J Acquir Immune Defic Syndr & Volume 41, Number 3, March 2006 259 Received for publication September 23, 2005; accepted November 28, 2005. From the *Department of Haematology, Prince of Wales Hospital and Centre for Vascular Research, University of New South Wales, Kensington, New South Wales, Australia; †Merck Research Laboratories, West Point, PA; and ‡Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM. Supported by the James S. McDonnell Foundation 21st Century Research Award/Studying Complex Systems and National Health and Medical Research Council (NHMRC) project grant 350841 (M. P. Davenport), and National Institutes of Health grants AI28433 and RR06555 (A.S. Perelson) and RR18754 (R. M. Ribeiro). M. P. Davenport is supported by a Sylvia and Charles Viertel Charitable Foundation Senior Medical Research Fellowship. Portions of this work were done under the auspices of the US Department of Energy under contract W-7405-ENG-36. Reprints: Alan S. Perelson, MS-K710, T-10 Los Alamos National Labora- tory, Los Alamos, NM 87545 (e-mail: asp@lanl.gov). Copyright * 2006 by Lippincott Williams & Wilkins Copyr ight © Lippincott Williams & Wilkins. Unauthor iz ed reproduction of this article is prohibited.