Characterization of Simian Immunodeficiency Virus (SIV) That Induces SIV Encephalitis in Rhesus Macaques with High Frequency: Role of TRIM5 and Major Histocompatibility Complex Genotypes and Early Entry to the Brain

Abstract

Although nonhuman primate models of neuro-AIDS have made tremendous contributions to our understanding of disease progression in the central nervous system (CNS) of human immunodeficiency virus type 1 (HIV-1)-infected individuals, each model holds advantages and limitations. In this study, in vivo passage of SIVsmE543 was conducted to obtain a viral isolate that can induce neuropathology in rhesus macaques. After a series of four in vivo passages in rhesus macaques, we have successfully isolated SIVsm804E. SIVsm804E shows efficient replication in peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) in vitro and induces neuro-AIDS in high frequencies in vivo. Analysis of the acute phase of infection revealed that SIVsm804E establishes infection in the CNS during the early phase of the infection, which was not observed in the animals infected with the parental SIVsmE543-3. Comprehensive analysis of disease progression in the animals used in the study suggested that host major histocompatibility complex class I (MHC-I) and TRIM5␣ genotypes influence the disease progression in the CNS. Taken together, our findings show that we have successfully isolated a new strain of simian immunodeficiency virus (SIV) that is capable of establishing infection in the CNS at early stage of infection and causes neuropathology in infected rhesus macaques at a high frequency (83%) using a single inoculum, when animals with restrictive MHC-I or TRIM5␣ genotypes are excluded. SIVsm804E has the potential to augment some of the limitations of existing nonhuman primate neuro-AIDS models. IMPORTANCE Human immunodeficiency virus (HIV) is associated with a high frequency of neurologic complications due to infection of the central nervous system (CNS). Although the use of antiviral treatment has reduced the incidence of severe complications, milder disease of the CNS continues to be a significant problem. Animal models to study development of neurologic disease are needed. This article describes the development of a novel virus isolate that induces neurologic disease in a high proportion of rhesus macaques infected without the need for prior immunomodulation as is required for some other models.

Enhanced antagonism of BST-2 by a neurovirulent SIV envelope

“…This result indicates that introduction of 4 amino acid substitutions in the cytoplasmic tail of gp41 did not attenuate the viral replication in vivo and did not increase the plasma viral RNA load. All animals showed peak viremia in the CSF at 2 weeks after infection, regardless of potential neurovirulence of the virus with which they were infected, consistent with our previous observation (15). Peak CSF viral RNA loads of the group inoculated with SIVsmE543#154 were variable (9 × 10 2 to 3 × 10 5 copies/ml) compared with group inoculated with SIVsmE543-3 (1 × 10 4 to 5 × 10 5 copies/ml), but this variation did not influence the CSF viral RNA load in the chronic phase of infection ( Figure 9B).…”

“…SIVmac239 showed robust replication in PBMCs with delayed peak viral replication compared with SIVsmE543 variants. In contrast, while SIVsm804E showed robust replication in MDM, SIVsmE543-3 showed low levels of replication, consistent with our previous report (15). As expected, SIVmac239 showed no measurable replication in MDM.…”

“…Although a number of other mutations emerged in SIVsm804E after the final passage, frequencies of mutations I805T, I828R, T829A, and V878I are comparable with that of SIVsm783Br (Figure 8). Acquisition of these 4 mutations correlates well with the in vivo neuropathogenicity (15), suggesting that these mutations play an important role in disease progression in the CNS.…”

“…This is further supported by the fact that most HIV-1 isolates from the CNS from subjects with neurocognitive disorders are macrophage tropic (22). Indeed, the main difference between SIVsmE543-3 and SIVsm804E is that the latter virus replicates more efficiently in monocyte-derived macrophages (MDMs) (15). Since macrophage tropism is strongly influenced by the number of glycosylation sites on the envelope (Env) glycoprotein, mostly within gp120 (23), it was hypothesized that mutations found in nef and LTR of SIVsm804E would have minimal impact on SIVsmE543-3 replication in MDMs.…”

“…Although it may not directly reflect the disease progression in HIV-1-infected individuals, nonhuman primate models enable access to CNS samples at all stages of disease progression, something that cannot be done with human patients for ethical reasons. Our group has recently reported on the isolation of a neurovirulent strain of simian immunodeficiency virus (SIV) African primate lentivirus (sm), SIVsm804E, that induced neuropathology in 83% of infected rhesus macaques when animals with restrictive MHC or TRIM alleles were eliminated from the cohort (14,15). This virus isolate was generated by sequential passage of the nonneurovirulent parental virus SIVsmE543-3 through rhesus macaques.…”