Susceptibilities of Simian Immunodeficiency Virus to Protease Inhibitors

Abstract

We used a focal infectivity assay with HeLa H1-JC.37 cells to directly compare susceptibilities of simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) to protease inhibitors. SIVmac239 was inhibited by indinavir, saquinavir, and ritonavir, with 50% effective concentrations (means ؎ standard deviations) of 39 ؎ 8, 55 ؎ 3, and 13 ؎ 5 nM, respectively. The corresponding values for inhibition of HIV-1 were 66 ؎ 4, 47 ؎ 10, and 25 ؎ 14 nM, respectively.

Suppression of Virus Load by Highly Active Antiretroviral Therapy in Rhesus Macaques Infected with a Recombinant Simian Immunodeficiency Virus Containing Reverse Transcriptase from Human Immunodeficiency Virus Type 1

“…SIV infection of rhesus macaques has provided an important animal model for studies of AIDS pathogenesis, but its use in studies of AIDS therapy has been mostly limited to studies of nucleoside analog inhibitors of RT (31,(34)(35)(36); reviewed in reference 11). SIV is similar to HIV-1 in its susceptibility to several of the protease inhibitors used in AIDS therapy (12), but there is little data on the efficacy of PIs in SIV-infected macaques. Unlike HIV-1 and RT-SHIV, SIV is not inhibited by NNRTIs.…”

“…Stocks of RT-SHIV and SIVmac239 were prepared from the appropriate 5Ј-and 3Ј-half clones, as described previously (12,16). The 5Ј-half clone of the RT-SHIV containing the RT-encoding region from HIV-1 HXBc2 (32) was provided by Joseph Sodroski, Harvard Medical School, Boston, Mass.…”

“…Simian immunodeficiency virus (SIV) infection of rhesus macaques has proven to be a useful animal model for studies of AIDS pathogenesis, but its usefulness as a model for HAART has been limited by the inability of commonly used NNRTIs to inhibit SIV replication. However, a chimera of SIV (RT-SHIV) in which the reverse transcriptase (RT) from SIVmac239 was replaced with the RT from an HIV-1 clone (HXBc2) is infectious for rhesus macaques (32) and susceptible to several nucleoside and nonnucleoside reverse transcriptase inhibitors (1, 2), including efavirenz (16), and to PIs (12). We report here the use of the RT-SHIV/rhesus macaque model to evaluate a HAART combination consisting of efavirenz (Sustiva), lamivudine [(Ϫ)-␤-2Ј-deoxy-3Ј-thiacytidine], and tenofovir {9-[2-(phosphonomethoxy)propyl]adenine} (PMPA) (36).…”

Simian Immunodeficiency Virus SIVagm Dynamics in African Green Monkeys

“…Moreover, other ARV classes, such as nonnucleoside RT inhibitors, are not suitable for studies like these because SIVs are intrinsically resistant to these drugs (78). Similarly, SIVs reportedly have variable susceptibilities to protease inhibitors (14). Conversely, NRTIs are drugs of choice for these types of studies because they are potent enough to induce significant and rapid reduction in viral replication (28,74) and also because they do not affect preformed virus or the ability of previously infected cells to continue to produce new virions (11), thus allowing a reliable quantification of the in vivo turnover of infected cells and providing indirect information on what cell type(s) supports virus replication in this nonpathogenic model of infection.…”

Enhanced Antiretroviral Therapy in Rhesus Macaques Improves RT-SHIV Viral Decay Kinetics

“…One rhesus macaque model uses a virus consisting of the backbone of the pathogenic molecular clone SIV mac239 with the HIV-1 RT from clone HXBc2 (RT-SHIV) (21). RT-SHIV is sensitive to several nucleoside RT inhibitors (NRTIs), protease inhibitors (PIs), and NNRTIs (22)(23)(24). Studies in RT-SHIV-infected macaques support the relevance of this animal model for identifying potential reservoirs of latency/persistence during HAART.…”