Brain Inflammation is a Common Feature of HIV-Infected Patients without HIV Encephalitis or Productive Brain Infection

Abstract

HIV-associated neurocognitive disorders (HAND) describes different levels of neurocognitive impairment, which are a common complication of HIV infection. The most severe of these, HIV-associated dementia (HIV D), has decreased in incidence since the introduction of combination antiretroviral therapy (cART), while an increase in the less severe, minor neurocognitive disorder (MND), is now seen. The neuropathogenesis of HAND is not completely understood, however macrophages (MΦ)s/microglia are believed to play a prominent role in the development of the more severe HIV-D. Here, we report evidence of neuroinflammation in autopsy tissues from patients with HIV infection and varying degrees of neurocognitive impairment but without HIV encephalitis (HIVE). MΦ/microglial and astrocyte activation is less intense but similar to that seen in HIVE, one of the neuropathologies underlying HIV-D. MΦs and microglia appear to be activated, as determined by CD163, CD16 and HLA-DR expression, many having a rounded or ramified morphology with thickened processes, classically associated with activation. Astrocytes also show considerable morphological alterations consistent with an activated state and have increased expression of GFAP and vimentin, as compared to seronegative controls. Interestingly, in some areas, astrocyte activation appears to be limited to perivascular locations, suggesting events at the blood-brain barrier may influence astrocyte activity. In contrast to HIVE, productive HIV infection was not detectable by tyramide signal-amplified immunohistochemistry or in situ hybridization in the CNS of HIV infected persons without encephalitis. These findings suggest significant CNS inflammation, even in the absence of detectable virus production, is a common mechanism between the lesser and more severe HIV-associated neurodegenerative disease processes and supports the notion that MND and HIV-D are a continuum of the same disease process.

Evidence for cFMS signaling in HIV production by brain macrophages and microglia

“…Recently, we reported prominent neuroinflammation in brains of HIV infected subjects without encephalitis or productive infection that is similar but less severe than that seen in HIVE (Tavazzi et al, 2014). It is possible that the decrease in M-CSF we observe in SIV brain is due to increased secretion of the protein by astrocytes and/or microglia in response to chronic inflammation, even in the absence of gross pathological alterations or productive virus.…”

“…This supports the notion of a spatial relationship between the two cytokines (Wei et al, 2010), where IL-34 expression and function is limited to specific tissues (Wang et al, 2012) and M-CSF plays a larger role in the skeletal and hematopoietic systems. Accordingly, M-CSF, which is normally detected in plasma, may contribute to the increased frequency of circulating CD16 + CD163 + monocytes in viremic HIV infected subjects reported by ourselves and others (Allen et al, 1991, Locher et al, 1994, Thieblemont et al, 1995, Fischer-Smith et al, 2008b), as M-CSF increases the frequency of this subset in vitro , while IL-34 contributes more to microglial activation and CD16/CD163 expression in HIV brain (Fischer-Smith et al, 2001, Tavazzi et al, 2014). M-CSF may also support the significant accumulation of CD16 + /CD163 + MΦs from the peripheral blood in HIVE/SIVE brain that serves as the principle reservoir of productive virus in the CNS (Fischer-Smith et al, 2001, Fischer-Smith et al, 2008a).…”

Enigma of HIV-1 latent infection in astrocytes: an in-vitro study using protein kinase C agonist as a latency reversing agent

“…The presence of viral DNA ([20] but absence of viral RNA and p24 protein [24] in astrocytes in HIV-1-infected patients’ post-mortem brain tissues has been suggested as latent viral infection, but the significance of these findings is unknown. Thus, to investigate further the latent HIV-1 infection in primary astrocytes, a robust infection model of VSV-pseudotyped HIV-1 infected astrocytes was used ( Fig.…”

“…Molecular investigations of HIV-1-infected brain tissues from post-mortem cases have demonstrated that viral DNA in 3% to 19% of astrocytes is an unproductive infection [15-23]. Recently, immunohistochemical study of brain sections from individuals with HIV-associated neurocognitive disorders found that productive HIV-1 infection was undetectable [24]. Some studies, however, have shown that HIV-1 infection in astrocytes is moderately productive [12, 25-28].…”

Prevalência de alterações neurocognitivas associadas ao HIV em uma coorte aderente ao antirretroviral em um hospital geral na cidade de São Paulo

“…O HIV pode permanecer latente no SNC por muitos anos e sua presença pode levar a déficits sutis no funcionamento cognitivo, independente da supressão de HIV-RNA no sangue (18) . Esta independência da presença do vírus entre o plasma sanguíneo e o SNC pode ser resultado da má distribuição dos antirretrovirais no SNC.…”