The Clinical Benefits of Tenofovir for Simian Immunodeficiency Virus???Infected Macaques Are Larger Than Predicted by its Effects on Standard Viral and Immunologic Parameters

Abstract

Previous studies have demonstrated that tenofovir (9-[2-(phosphonomethoxy)propyl]adenine; PMPA) treatment is usually very effective in suppressing viremia in macaques infected with simian immunodeficiency virus (SIV). The present study focuses on a subset of infant macaques that were chronically infected with highly virulent SIVmac251, and for which prolonged tenofovir treatment failed to significantly suppress viral RNA levels in plasma despite the presence of tenofovirsusceptible virus at the onset of therapy. While untreated animals with similarly high viremia developed fatal immunodeficiency within 3-6 months, these tenofovir-treated animals had significantly improved survival (up to 3.5 years). This clinical benefit occurred even in animals for which tenofovir had little or no effect on CD4 and CD8 lymphocyte counts and antibody responses to SIV and test antigens. Thus, the clinical benefits of tenofovir were larger than predicted by plasma viral RNA levels and other routine laboratory parameters.

Evaluation of Passively Transferred, Nonneutralizing Antibody-Dependent Cellular Cytotoxicity-Mediating IgG in Protection of Neonatal Rhesus Macaques against Oral SIVmac251 Challenge

“…In this regard, CD4 T cell counts declined somewhat by wk 2 postchallenge but not to exceedingly low levels (Fig. 1, C and D), which is consistent with previous studies on SIV mac251 -infected infant macaques (21,31). No difference in CD4 count was observed between neonates that received immune IgG or control IgG.…”

“…In macaques, as in humans, the proportion of NK cells increases with age. Neonatal macaques have ϳ3.5% NK cells in peripheral blood (31) in contrast to ϳ13% in adults (40). The mean percentage of NK cells in the neonates at challenge was as expected, low (3.5%), and declined following SIV infection instead of exhibiting the expected age-dependent increase (Fig.…”

“…ϩ T cell counts compared with adults (21,30,31). Thus, this phenotype partly explains the high viral burdens because more target cells are available for viral infection.…”

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

“…75 SIV exposure followed by PEP may activate immune responses to protect against subsequent infection with heterologous SIV challenge virus. 17,76 Transient early treatment with tenofovir in macaques infected with SIV [76][77][78][79][80][81] and SHIV 82 has been associated with the stimulation of SIV-or SHIVspecific CD4 þ and CD8 þ T cell responses and resistance to rechallenge with heterologous virus more than 1 year following the initial challenge. [83][84][85] A possible interpretation of these results is that drug treatment suppressed viral replication in the infected animals sufficiently to allow development of effective immune responses that controlled or eliminated SIV.…”

Structured Treatment Interruptions with Tenofovir Monotherapy for Simian Immunodeficiency Virus-Infected Newborn Macaques

“…Eight animals received structured treatment interruptions (as described below), while three animals were untreated contemporary control animals. Those three animals had high viremia and a rapid disease course (AIDS at 11, 14, and 15 weeks of age) indistinguishable from that of 19 historical untreated newborn animals infected orally with a previous lot number of this SIVmac251 stock (8/95) and described previously (59,62,65,68,71). Accordingly, the data from studies of these 22 untreated animals were pooled for the analysis of comparison with the drug-treated animals.…”