Effects of chronic HIV-1 Tat exposure in the CNS: heightened vulnerability of males versus females to changes in cell numbers, synaptic integrity, and behavior

Abstract

HIV-associated damage to the central nervous system results in cognitive and motor deficits. Anti-retroviral therapies reduce the severity of symptoms, yet the proportion of patients affected has remained the same or increased. Although approximately half of HIV-infected patients worldwide are women, the question of whether biological sex influences outcomes of HIV infection has received little attention. We explored this question for both behavioral and cellular/morphologic endpoints, using a transgenic mouse that inducibly expresses HIV-1 Tat in the brain. After 3 months of HIV-1 Tat exposure, both sexes showed similar reduced open field ambulation. Male Tat+ mice also showed reduced forelimb grip strength and enhanced anxiety in a light–dark box assay. Tat+ males did not improve over 12 weeks of repeated rotarod testing, indicating a motor memory deficit. Male mice also had more cellular deficits in the striatum. Neither sex showed a change in volume or total neuron numbers. Both had equally reduced oligodendroglial populations and equivalent microglial increases. However, astrogliosis and microglial nitrosative stress were higher in males. Dendrites on medium spiny neurons in male Tat+ mice had fewer spines, and levels of excitatory and inhibitory pre- and post-synaptic proteins were disrupted. Our results predict sex as a determinant of HIV effects in brain. Increased behavioral deficits in males correlated with glial activation and synaptic damage, both of which are implicated in cognitive/motor impairments in patients. Tat produced by residually infected cells despite antiretroviral therapy may be an important determinant of the synaptodendritic instability and behavioral deficits accompanying chronic infection.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-013-0676-6) contains supplementary material, which is available to authorized users.

Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice

“…Interestingly, Tat did not affect tolerance to the effects of morphine in the locomotor activity assay, suggesting that Tat does not interact with morphine's actions at supraspinal sites governing locomotor activity including the striatum. This was somewhat unexpected because prior studies have shown that Tat and morphine interactions have pronounced neuroinflammatory and neurodegenerative effects on the striatum (BruceKeller et al, 2008;Fitting et al, 2010aFitting et al, ,b, 2014Zou et al, 2011;Hauser et al, 2012), and prolonged Tat induction was found to disrupt locomotor activity (Hahn et al, 2015). Nevertheless, it has been noted that the effects of Tat on locomotor activity can vary depending on the duration of Tat induction using DOX Hahn et al, 2015).…”

“…Doxycycline (DOX)-inducible, brain-specific HIV-1 IIIB Tat 1-86 transgenic mice were developed on a C57BL/6J hybrid background as described in detail elsewhere Hahn et al, 2015). Tat expression, which is under the control of a tetracyclineresponsive promoter controlled by glial fibrillary acidic protein (GFAP) expression, was induced with a specially formulated chow containing 6 mg/g DOX (product TD.09282; Harlan, Indianapolis, IN).…”

“…All transgenic mice (∼4 months of age, ∼25 g, males) were genotyped to confirm the presence of tat and/or rtTA transgenes. In addition, nontransgenic C57BL/6 mice (∼4 months of age, ∼25 g, males) from Harlan Laboratories (Indianapolis, IN) were used to control for the potential effects of the foreign tat and/or rtTA transgenes, as well as any possible effects of the C57BL/6 hybrid background Hahn et al, 2015). The nontransgenic C57BL/6 mice will be referred to as C57 mice throughout this report.…”

Oligodendrocytes Are Targets of HIV-1 Tat: NMDA and AMPA Receptor-Mediated Effects on Survival and Development

“…2؉ ] i increases Tat disrupts Ca 2ϩ homeostasis in astroglia (El-Hage et al, 2005, 2008b, microglia (Sheng et al, 2000;Lokensgard et al, 2001), macrophages (Contreras et al, 2005), and neurons (Haughey and Mattson, 2002;Zhu et al, 2009 (Fig. 9A), indicating involvement of alternative molecular targets (see below).…”

“…HIV-1 transactivator of transcription (Tat) is a highly conserved HIV protein that can be detected in blood (Xiao et al, 2000), extracellular matrix (Urbinati et al, 2005a), and CSF in HIV ϩ individuals, even with cART (Johnson et al, 2013). In addition to its essential role in viral replication and efficient viral gene transcription, Tat has also been shown to be a toxic factor in the CNS that leads to glial inflammatory responses , 2008a and neuronal cell death (Zou et al, 2011;Rumbaugh et al, 2013).…”