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39 Early Antiretroviral Treatment Facilitates CD8+ Lymphocyte-Mediated Control of Pathogenic SIV Infection and Resistance to Homologous and Heterologous Rechallenge
J. D. Lifson*1, J. L. Rossio1, M. Piatak, Jr.1, B. M. Flynn2, B. Fisher2, R. C. Desrosiers3, V. M. Hirsch4, K. Reimann5, J. Schmitz5, J. Ghrayeb6, N. Bischofberger7, D. Wodarz8, and M. A. Nowak8
1AVP, SAIC Frederick, NCI at Frederick, MD, USA; 2ASB/NCI, Bethesda, MD, USA; 3HMS/NERPRC, Southborough, MA, USA;4LMM/NIAID, Bethesda, MD, USA; 5HMS/BIMC, Boston, MA, USA; 6Centocor, Malvern, PA, USA; 7Gilead Sci., Foster City, CA, USA; and 8IAS, Princeton, NJ, USA
Background: To test the hypothesis that suboptimal antiviral immune responses in the face of overwhelming infection cytopathic for CD4+ T cells underlie the inability of most AIDS virus-infected hosts to effectively control the infection, we used transient early antiretroviral treatment to suppress viral replication during primary SIV infection, with the intent of facilitating development of sustained effective host control.
Methods: Rhesus macaques were inoculated I.V. with 100 MID(50) of SIVsmE660 and received 28 days of Tenofovir treatment, beginning 1 day p.i. Viral load, anti-SIV immune responses, and resistance to homologous (SIVsmE660) and hetereologous (SIVmac239) rechallenge were monitored.
Results: Unlike untreated controls, a majority of treated animals developed anti-SIV cellular immune responses, contained SIV (plasma SIV RNA < 100 copies/ml) after drug discontinuation, and resisted SIVsmE660 rechallenge, but not heterologous SIVmac239 rechallenge, 10 weeks p.i. (6 weeks post-drug discontinuation). Emergence of viremia after mAb-mediated depletion of CD8+ lymphocytes 10 weeks p.i. confirmed persisting, controlled infection. Treated animals also resisted homologous rechallenge and a subsequent heterologous rechallenge more than 1 year after initial infection, becoming coinfected with SIVmac239 and SIVsmE660 but with controlled viremia (SIV RNA from <100 to ~104 copies/mL, depending on the animal, vs. 106 to 108 for controls). Rapid transient increases of plasma SIV RNA of up to 5 logs after in vivo mAb depletion demonstrated a role for CD8+ cells in controlling infection.
Conclusions: Viral suppression during primary infection allowed development of host responses capable of impressive control of infection with 2 pathogenic heterologous SIVs, at least partly CD8 mediated. Understanding the basis of this control may provide insights relevant to the development of effective vaccines.
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