Prophylactic and Therapeutic Benefits of Short-Term 9-[2-( R )-(Phosphonomethoxy)Propyl]Adenine (PMPA) Administration to Newborn Macaques following Oral Inoculation with Simian Immunodeficiency Virus with Reduced Susceptibility to PMPA

Abstract

Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of humanpediatric AIDS to study pathogenesis and to develop intervention strategies aimed at preventing infection or delaying disease progression. In previous studies, we demonstrated that 9-[2-(R)-(phosphonomethoxy)propyl] adenine (PMPA; tenofovir) was highly effective in protecting newborn macaques against infection with virulent wild-type (i.e., drug-susceptible) SIVmac251. In the present study, we determined how reduced drug susceptibility of the virus inoculum affects the chemoprophylactic success. SIVmac055 is a virulent isolate that has a fivefold-reduced in vitro susceptibility to PMPA, associated with a K65R mutation and additional amino acid changes (N69T, R82K, A158S, S211N) in reverse transcriptase (RT). Eight newborn macaques were inoculated orally with SIVmac055. The three untreated control animals became SIVmac055 infected; these animals had persistently high viremia and developed fatal immunodeficiency within 3 months. Five animals were treated once daily with PMPA (at 30 mg/kg of body weight) for 4 weeks, starting 24 h prior to oral SIVmac055 inoculation. Two of the five PMPA-treated animals had no evidence of infection. The other three PMPA-treated infant macaques became infected but had a delayed viremia, enhanced antiviral antibody responses, and a slower disease course (AIDS in 5 to 15 months). No reversion to wild-type susceptibility or loss of the K65R mutation was detected in virus isolates from any of the PMPA-treated or untreated SIVmac055-infected animals. Several additional amino acid changes developed in RT, but they were not exclusively associated with PMPA therapy. The results of this study suggest that prophylactic administration of PMPA to human newborns and to adults following exposure to human immunodeficiency virus will still be beneficial even in the presence of viral variants with reduced susceptibility to PMPA.

HIV, transmitted drug resistance, and the paradox of preexposure prophylaxis

“…Lower acute viremias in the other four macaques may have diminished their risk of acquiring resistance. These data suggest selection of resistance during PrEP may be less frequent than during treatment of established infections (17)(18)(19). The macaque studies also provide qualitative information on how drug resistance emerges, and how reversion to wild-type may occur.…”

“…The macaque studies have shown that PrEP can be highly effective in preventing infection; for example, the risk of SHIV infection in macaques receiving daily PrEP with FTC or Truvada was 3.8-and 7.8-fold, respectively, lower than in untreated macaques (17). However, macaques exposed to an SIV isolate carrying the TDF resistance mutation (K65R) were not protected by TDF, which suggests PrEP may be less effective against ARV-resistant viruses (19). Substantial reductions in viremia and blunted acute viremias (up to 2log 10 reduction) have been observed in a patient failing Truvada and in macaques failing PrEP with FTC, Truvada, or a CCR5 inhibitor (17,18,(20)(21)(22).…”

“…The assumptions made to construct the PrEP intervention model, and the parameter ranges used to characterize PrEP (17)(18)(19)(20) and a phase II study of PrEP in humans (3). The macaque studies have shown that PrEP can be highly effective in preventing infection; for example, the risk of SHIV infection in macaques receiving daily PrEP with FTC or Truvada was 3.8-and 7.8-fold, respectively, lower than in untreated macaques (17).…”

CD8+-Cell-Mediated Suppression of Virulent Simian Immunodeficiency Virus during Tenofovir Treatment

“…K65R SIV mutants also accumulate other mutations in RT, which are believed to be compensatory and improve replication fitness in vivo (80,81). These K65R SIV mutants, when inoculated in infant or juvenile macaques in the absence of tenofovir treatment, were found to replicate to high levels and be as virulent as wild-type virus with similar time to disease without reversion to the wild type (46,81,89). Persistent suppression of virulent K65R SIV mutants has only been observed in tenofovir-treated animals.…”

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

“…Similarly to observations in our previous studies (60,61,69,71,72), the detection of K65R in virus isolates coincided with or was followed by the development of other mutations in RT (such as K64R, N69S, I118V, and S211N), which are thought to be compensatory mutations (as they do not further decrease the in vitro phenotypic susceptibility). The development of these additional RT mutations (the time of first detection, specific mutations, or number of mutations) did not have any obvious correlation with the viral RNA set point of the STI animals (Fig.…”