Regulation of CC Chemokine Receptor 5 and CD4 Expression and Human Immunodeficiency Virus Type 1 Replication in Human Macrophages and Microglia by T Helper Type 2 Cytokines

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282

Complete envelope genes were amplified from autopsy brain tissue of five individuals who had died of AIDS and had neurological complications. Lymph node samples were included for two of the patients. Nineteen different envelope clones from the five patients had distinct V1V2 sequences. Thirteen of the envelopes were functional and conferred fusigenicity and infectivity for CD4 ؉ CCR5 ؉ cells. Infectivity and cell-cell fusion assays showed that most envelopes used both CCR5 and CCR3. One brain-derived envelope used a broad range of coreceptors, while three other brain envelopes from one individual were restricted to CCR5. However, there was no correlation between tissue of origin and coreceptor use. Envelopes showed two very distinct phenotypes depending on their capacity to infect macrophages and to exploit low levels of CD4 and/or CCR5 for infection. Envelopes that were highly fusigenic and tropic for macrophages were identified in brain tissue from four of the five patients. The enhanced macrophage tropism correlated with reduced sensitivity to inhibition by Q4120, a CD4-specific antibody, but not with sensitivity to the CCR5 inhibitor, TAK779. The highly macrophage-tropic envelopes were able to infect cells expressing low levels of CD4 and/or CCR5. Comparison with several wellcharacterized macrophage-tropic envelopes showed that the four identified patient envelopes were at the top limit of macrophage tropism. In contrast, all four lymph node-derived envelopes exhibited a non-macrophagetropic phenotype and required high levels of CD4 for infection. Our data support the presence of envelopes that are highly fusigenic and tropic for macrophages in the brains of patients with neurological complications. These envelopes are able to infect cells that express low levels of CD4 and/or CCR5 and may have adapted for replication in brain macrophages and microglia, which are known to express limited amounts of CD4.Human immunodeficiency virus type 1 (HIV-1) replication in the brain results in the development of severe neurological disorders known as AIDS dementia complex in about 30% of AIDS patients (29). The mechanisms that cause the loss of up to 40% of neurons (10) as well as result in dementia are unclear. In the rhesus macaque simian immunodeficiency virus (SIV) model, both neurotropic and neurovirulent SIV MAC variants have been described (11,22,38). It is therefore suspected that specific neurotropic and neurovirulent HIV-1 variants exist and are associated with dementia.CCR5-using HIV-1 strains are predominant in the brain (13), and CCR5 ϩ perivascular macrophages and microglia are the cell types most frequently infected (19,35,37,43,49,50). The role of other cell types resident in the brain is less clear. There is evidence that CD4Ϫ astrocytes become infected, particularly in pediatric AIDS cases (32,36,37,43). Astrocyte infection is relatively unproductive with early HIV mRNAs (e.g., for rev and nef) detectable, but no late mRNAs encoding the structural gag and env proteins needed to produce progeny virus par...

Section: Discussionmentioning

confidence: 59%

Biological Analysis of Human Immunodeficiency Virus Type 1 R5 Envelopes Amplified from Brain and Lymph Node Tissues of AIDS Patients with Neuropathology Reveals Two Distinct Tropism Phenotypes and Identifies Envelopes in the Brain That Confer an Enhanced Tropism and Fusigenicity for Macrophages

Peters

Bhattacharya

Hibbitts

et al. 2004

182

282

“…Variability in sCD4 neutralization and infection of macrophages suggests that the viruses in different brain regions of ET94 evolve with different CD4 requirements that may expand tropism. Indeed, microglia in the brain of ET94 were infected (Table 2) (57), and these CNS-resident cells expressed little or no CD4 (33)(34)(35). We therefore investigated the abilities of the Envs originating from different brain compartments and the CSF of ET94 to mediate entry independently of CD4.…”

Section: Characteristics Of R5 Shiv-infected Macaques With Encephalitismentioning

confidence: 99%

“…Emergence of highly macrophage-tropic viral strains that engage the CD4 and CCR5 receptors differently or have a lower CD4 dependence for entry has been reported in HIV and SIV infection of the brain (27)(28)(29)(30)(31)(32). The need for robust replication in macrophages and infection of CNS-resident cells, such as microglia and astrocytes, that express CCR5 but little or no CD4 (33)(34)(35), therefore, could be a major selective pressure for independent envelope evolution in the brain that contributes to neurological injury.…”

mentioning

confidence: 99%

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

Zhuang

Léda

Tsai

et al. 2014

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.

“…The expression of CXCL10, transforming growth factor ␤1 (TGF-␤1), interleukin 10 (IL-10), and other cytokines are increased in HIV-1-infected individuals (24,40,44,55). IL-10 and TGF-␤1 have been implicated in the up-regulation of CCR5 on human monocytes, monocytederived macrophages, and monocyte-derived dendritic cells (8,33,61,67,76). HIV-1-induced expression of IL-10 and IFN-␣ also leads to higher expression of major histocompatibility complex class I (MHC-I) on double positive (DP) thymocytes (39,46).…”

mentioning

confidence: 99%

R5 Human Immunodeficiency Virus Type 1 Infection of Fetal Thymic Organ Culture Induces Cytokine and CCR5 Expression

Choudhary¹,

Choudhary²,

Kimbrell

et al. 2005

Late-stage CCR5 tropic human immunodeficiency virus type 1 (HIV-1) isolates (R5 HIV-1) can deplete nearly all CD4؉ thymocytes from human thymus/liver grafts, despite the fact that fewer than 5% of these cells express CCR5. To resolve this paradox, we studied the replication and cytopathic effects (CPE) of late-stage R5 HIV-1 biological clones from two progressors and two long-term nonprogressors (LTNP) in fetal thymic organ culture (FTOC) with and without added cytokines. We found that R5 HIV-1 clones from progressors but not LTNP were cytopathic in untreated FTOC. Moreover, R5 HIV-1 clones from progressors replicated to higher levels than LTNP-derived R5 HIV-1 clones in this system. In contrast, when FTOC was maintained in the presence of interleukin 2 (IL-2), IL-4, and IL-7, both progressor and LTNP clones exhibited similar replication and CPE, which were equal to or greater than the levels achieved by progressor-derived R5 HIV-1 clones in untreated FTOC. This finding was likely due to IL-2-induced CCR5 expression on CD4 ؉ thymocytes in FTOC. R5 HIV-1 clones showed greater pathogenesis for CCR5؉ cells but also showed evidence of CPE on CCR5