Simian Immunodeficiency Virus–Infected Macaques Treated with Highly Active Antiretroviral Therapy Have Reduced Central Nervous System Viral Replication and Inflammation but Persistence of Viral DNA

Abstract

Background In the era of highly active antiretroviral therapy (HAART) the prevalence of HIV-associated CNS disease has increased despite suppression of plasma viremia. Methods Using an SIV model system where all animals develop AIDS and 90% develop CNS disease by three months postinoculation (p.i.), pigtailed macaques were treated with a regimen of tenofovir disoproxil fumarate, saquinavir, atazanavir, and an integrase inhibitor starting at 12 days and euthanized at ∼175 days p.i. Results Plasma and CSF viral loads declined rapidly after initiating HAART. Brain viral RNA was undetectable at necropsy but viral DNA levels were not different from untreated SIV-infected macaques. CNS inflammation was significantly reduced, with decreased brain expression of MHC Class II and GFAP and reduced CSF CCL2 and IL-6. Brain from treated macaques had significantly lower levels of IFNβ, the Type I IFN-inducible gene myxovirus (influenza) resistance A (MxA), and indolamine 2,3-dioxygenase (IDO) mRNA suggesting suppressed immune hyperactivation, and fewer CD4+ and CD8+ T cells, suggesting reduced trafficking of T cells from peripheral blood. Brain levels of CD68 protein and TNFα and IFNγ RNA, while reduced, were not significantly lower, indicating continued CNS inflammation. Conclusions These data, generated in a rigorous, high viral load, SIV/macaque model showed benefits of HAART therapy on CNS virus replication and inflammation but no change in the levels of viral DNA and continued CNS inflammation in some individuals.

Detection of Simian Immunodeficiency Virus in Semen, Urethra, and Male Reproductive Organs during Efficient Highly Active Antiretroviral Therapy

“…In line with our findings, the persistence of vDNA in the absence of vRNA detection was found in the testis, prostate, and seminal vesicles from juvenile rhesus macaques infected with reverse transcriptase simian-human immunodeficiency virus (SHIV) treated by HAART for 26 weeks (52). A similar differential effect of HAART on vDNA and vRNA levels has been reported in the brain, a well-established HIV/SIV reservoir (67). The lack of HAART impact on vDNA suggests the presence of long-lived cells containing very low vRNA copies, such as latently infected memory T cells (which may be reactivated over time to produce virus and prevent full eradication in the MGT), macrophages producing low level of SIV RNA, or cells harboring defective vDNA.…”

“…The initiation of HAART quickly and drastically decreased viremia. All the treated animals went down to a PVL measurement of Յ100 copies/ml at weeks 3 to 8 after the initiation of HAART (threshold indicative of efficient HAART [52,[65][66][67][68][69], delineated in gray on the graph in Fig. 1B).…”

Replication-Competent Simian Immunodeficiency Virus (SIV) Gag Escape Mutations Archived in Latent Reservoirs during Antiretroviral Treatment of SIV-Infected Macaques

“…With this drug regimen, the number of long-term latently infected resting CD4 ϩ cells in the blood and lymphoid tissues of SIV-infected macaques is comparable to that of HIV-infected patients on HAART, providing an excellent model to study latent HIV/SIV reservoirs, including the CNS. Although viral replication in the brain was dramatically reduced by HAART in this model, viral DNA levels in the brain were unchanged compared to untreated SIV-infected macaques, thus demonstrating that the brain also is a significant viral reservoir (39).…”

“…Our previous studies of the SIV/macaque model have demonstrated that as early as 4 days p.i., a latent reservoir has been established in the brain and the amount of proviral SIV DNA in the CNS reservoir remains stable throughout infection regardless of HAART (1,36,39). However, the presence of the SIV Gag K165R escape mutations in the CNS reservoir suggests that there may be FIG.…”

Use of Animal Models for Anti-HIV Drug Development

“…Lymphoid and gastrointestinal tissues showed the highest level of viral DNA in virally suppressed animals, suggesting that they consist of the majority of the viral reservoir. In a model of neuropathogenic AIDS, although viremia in plasma and cerebral spinal fluid was significantly reduced by therapy, levels of viral DNA in the brains of these animals were not significantly different than the untreated controls, suggesting that virally infected cells in the central nervous system can contribute to the reservoir (Zink et al, 2010).…”