A simian immunodeficiency virus macaque model of highly active antiretroviral treatment: viral latency in the periphery and the central nervous system

Abstract

Purpose of review: Here, simian immunodeficiency virus (SIV) macaque models are examined for their strengths in identifying in-vivo sites of HIV latency and persistent virus replication during highly active antiretroviral treatment (HAART). The best characterized HIV reservoir in HAART-treated persons is resting CD4 T cells in blood, although residual virus also comes from other reservoirs. Nonhuman primate/SIV models of HAART have been developed to characterize potential HIV reservoirs, particularly the central nervous system (CNS) and stem cells in bone marrow, known and potential reservoirs of latent virus that are difficult to study in humans.

Recent findings: Few SIV macaque models of HAART have examined plasma and cerebrospinal fluid virus decay, the number of resting CD4 T cells harboring replication-competent latent SIV, HAART-treatment effect on the CNS, or residual viral replication or viral DNA levels in that tissue. Using a consistent, accelerated SIV macaque model, we characterized peripheral viral reservoirs, including those in the CNS, among HAART-treated macaques. The SIV model reproduces latency in memory CD4 T cells throughout the body and indicates that the CNS contains a stable SIV DNA reservoir.

Summary: An SIV macaque model of HAART recapitulating viral latency, particularly in the CNS, is required to study therapeutic approaches for a functional HIV cure.

Figure 1. Virus replication and decay in SIV-infected macaques treated with HAART

(A) Viral RNA levels in plasma increase rapidly during the first 7 to 10 days after virus inoculation, decline by approximately 1 log, then increase again and remain at 10⁷ to 10⁸ for the remainder of the infection period. Viral RNA levels in CSF increase during acute infection, decline by several logs during the next 2 weeks, then increase again only in macaques that will develop moderate to severe encephalitis. CD4+ cell counts in peripheral blood decline during acute infection, recover briefly, then begin to decline again during the asymptomatic stage of infection. (B) Viral RNA levels in plasma and CSF increase rapidly during the first 7 to 10 days prior to HAART treatment, which was initiated at 12 days p.i. Within a few days after initiation of HAART, plasma and CSF viral load begin to decline. By approximately 60 days p.i., plasma and CSF viral load have declined to below the level of detection (~100 copy eq./mL) and viral loads remained low throughout the remainder of the experiment. (B & C) The decline in plasma and CSF viral RNA occurred in two phases–an initial short-term rapid decline followed by a longer term slower decline similar to the two-phase decline seen in the plasma of HIV-infected individuals on HAART. At 80 days p.i., there were 8 to 10 latently infected resting CD4+ T cells per million resting CD4+ T cells in the blood. These numbers declined gradually to approximately one latently infected resting CD4+ T cells per million by 175 days p.i. p.i. = post-inoculation; CSF = cerebrospinal fluid

Figure 2. Viral, inflammatory, and immune parameters in the accelerated, consistent SIV/macaque model of HIV-associated neurological disease

(A) CSF:Plasma CCL2 ratio, an estimate of the gradient of CCL2 in the brain as compared to the periphery, rose acutely, but declined significantly after initiation of HAART therapy. Macrophage surface markers MHC Class II and CD68, astrocyte marker GFAP, and immune markers IFNβ RNA and Mx RNA all were expressed at very low levels in brain at necropsy as compared to untreated macaques (Figure 1). In addition, viral RNA in brain was undetectable at necropsy. (B) CCL2 production in the CNS, expressed as the ratio of CCL2 in CSF:plasma rises during acute infection, declines by day 21 p.i., then increases again in macaques that will develop moderate to severe encephalitis. Markers of macrophage infiltration and activation (CD68 and MHC class II) are elevated in brain tissue during acute and terminal infection. In contrast, activation of astrocytes as measured by expression of GFAP in brain tissue increases gradually throughout infection. p.i. = post-inoculation