Eradication of human immunodeficiency virus from brain reservoirs

Abstract

Isolated cases in which HIV infection was claimed to have been eradicated generated renewed interest in HIV reservoirs in the brain particularly since attempts to reproduce the findings using genetically engineered stem cells and immune or myeloablation have failed. A clear understanding of the cell types in which the virus resides in the brain, the mechanism of viral persistence, restricted replication and latency and the turnover rate of the infected cells is critical for us to develop ways to control or get rid of the virus in the brain. The brain has several unique features compared to other reservoirs. There are no resident T cells in the brain; the virus resides in macrophages and astrocytes where the viral infection is non-cytopathic. The virus evolves in the brain and since the turnover rate of these cells is low, the virus has the potential to reside in these cells for several decades and possibly for the life of the individual. This review discusses the HIV reservoirs in brain, issues related to eradication of the virus from sanctuaries in brain and current challenges faced by neuroscientists in finding a cure.

HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations

“…Despite regional differences in CNS vulnerability to HIV-1 (Nath 2015), few studies have examined why some brain regions and neuronal types are preferentially susceptible to the virus. A number of behavioral deficits, including attenuation of spatial learning and memory, which are common features of HAND, can be recapitulated by Tat exposure and may be attributed to cellular and functional deficits in the hippocampus (Li et al 2004; Fitting et al 2006; 2013).…”

Chemokine CCL2 enhances NMDA receptor-mediated excitatory postsynaptic current in rat hippocampal slices-a potential mechanism for HIV-1-associated neuropathy?

“…The severity of HAND can vary, from asymptomatic to mild neurocognitive impairment and in its most severe form, a debilitating dementia commonly called HIV-associated dementia or HAD (Antinori et al, 2007; Grant, 2008). Although the introduction of combination antiretroviral therapy (cART) has significantly decreased the incidence of HAD, the prevalence of less severe forms of HAND has been on the rise even in the cART era (Heaton et al, 2011; Alfahad and Nath, 2013; Nath, 2015; Watkins and Treisman, 2015). Nevertheless, the precise mechanisms for HAND pathogenesis are still not fully understood.…”

Platelet-activating factor attenuation of long-term potentiation in rat hippocampal slices via protein tyrosine kinase signaling

“…Although the advent of combined antiretroviral therapy (cART) has resulted in a dramatic decline in all forms of neurological complications of HIV-1 infection, it is becoming clear that cART cannot fully control HAND and the prevalence of HAND continues to rise due to sustained HIV-1-infection of mononuclear phagocytes (MP, brain macrophages and microglia), the emergence of resistant viral phenotypes, poor drug penetration of blood-brain barrier, drug toxicities and increase in patient lifespan [1, 30]. Nevertheless, the mechanisms underlying HAND pathogenesis, especially in the era of cART, are not fully understood.…”