Emergence of CD4 Independence Envelopes and Astrocyte Infection in R5 Simian-Human Immunodeficiency Virus Model of Encephalitis

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection in the central nervous system (CNS) is characterized by replication in macrophages or brain microglia that express low levels of the CD4 receptor and is the cause of HIV-associated dementia and related cognitive and motor disorders that affect 20 to 30% of treatment-naive patients with AIDS. Independent viral envelope evolution in the brain has been reported, with the need for robust replication in resident CD4 low cells, as well as CD4-negative cells, such as astrocytes, proposed as a major selective pressure. We previously reported giant-cell encephalitis in subtype B and C R5 simian-human immunodeficiency virus (SHIV)-infected macaques (SHIV-induced encephalitis [SHIVE]) that experienced very high chronic viral loads and progressed rapidly to AIDS, with varying degrees of macrophage or microglia infection and activation of these immune cells, as well as astrocytes, in the CNS. In this study, we characterized envelopes (Env) amplified from the brains of subtype B and C R5 SHIVE macaques. We obtained data in support of an association between severe neuropathological changes, robust macrophage and microglia infection, and evolution to CD4 independence. Moreover, the degree of Env CD4 independence appeared to correlate with the extent of astrocyte infection in vivo. These findings further our knowledge of the CNS viral population phenotypes that are associated with the severity of HIV/SHIV-induced neurological injury and improve our understanding of the mechanism of HIV-1 cellular tropism and persistence in the brain. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) infection of astrocytes in the brain has been suggested to be important in HIV persistence and neuropathogenesis but has not been definitively demonstrated in an animal model of HIV-induced encephalitis (HIVE).Here, we describe a new nonhuman primate (NHP) model of R5 simian-human immunodeficiency virus (SHIV)-induced encephalitis (SHIVE) with several classical HIVE features that include astrocyte infection. We further show an association between severe neuropathological changes, robust resident microglia infection, and evolution to CD4 independence of viruses in the central nervous system (CNS), with expansion to infection of truly CD4-negative cells in vivo. These findings support the use of the R5 SHIVE models to study the contribution of the HIV envelope and viral clades to neurovirulence and residual virus replication in the CNS, providing information that should guide efforts to eradicate HIV from the body.

Cell-to-cell contact facilitates HIV transmission from lymphocytes to astrocytes via CXCR4

“…This may be a key factor in HIV transmission from lymphocytes to astrocytes. These observations are also consistent with a recent study of SHIV-infected macaques showing the expansion of CD4 independent virus with infection of astrocytes [55]. …”

Envelope residue 375 substitutions in simian–human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques

“…SHIVs have been used to assess the protective effects of neutralizing or antibody-dependent cell-mediated cytotoxicity conferring antibodies (3)(4)(5)(6)(7), the elicitation of broadly neutralizing antibodies (bNAbs) (8)(9)(10)(11), the efficacy of broadly neutralizing monoclonal antibodies (mAbs) in preclinical trials with suppressive and curative intent (12,13), and virus-host interactions underlying virus transmission, immunodeficiency, and neurocognitive impairment (1,(14)(15)(16)(17)(18)(19)(20)(21)(22). Despite these varied and important applications of SHIVs to HIV/ AIDS research, it is widely recognized that most SHIVs developed thus far have significant shortcomings as a model system for HIV-1 infection of humans (reviewed in ref.…”

Neuropathogenesis of HIV: From Initial Neuroinvasion to HIV-Associated Neurocognitive Disorder (HAND)

“…However, as astrocytes lack CD4 receptors, the mechanism of entry into astrocytes has been a mystery. Now, evidence in a SIV model suggests that CNS compartmentalization may create selective pressures that allow the virus to enter cells independently of CD4 receptors, allowing the virus to enter astrocytes (51). Inhibition of a specific receptor decreased replication, and resulted in a decreased latent reservoir in the SIV model, suggesting the receptor might be important in the development of this particular CNS HIV reservoir.…”