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

Abstract

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...

Interaction with CD4 and Antibodies to CD4-Induced Epitopes of the Envelope gp120 from a Microglial Cell-Adapted Human Immunodeficiency Virus Type 1 Isolate

“…However, Peters et al recently published a study concluding that envelopes from primary brain isolates confer lower CD4 dependence and lower sensitivity to inhibition by anti-CD4 antibodies than envelopes derived from peripheral tissues of the same individuals (56). In addition, lower CCR5 and CD4 dependencies have been shown to represent a pathogenic viral phenotype contributing to the neurodegenerative manifestations of AIDS (25).…”

“…The inhibition curves showed a lower sensitivity for Bori-15, with statistically significant fourto sixfold-higher IC 50 values than Bori. Decreased sensitivity to inhibition of infection by anti-CD4 antibodies has been recently reported for brain-derived HIV envelopes by Peters et al (56). Additional studies will be required to dissect the role of the individual 8 amino acid changes between Bori and Bori-15 envelopes, especially the four substitutions located in the V1/V2 region, on gp120 conformation and/or flexibility.…”

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

“…The specific pressures that drive the tissue, as well as regional CNS env genetic divergence, remain unclear. 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.…”

Non-Macrophage-Tropic Human Immunodeficiency Virus Type 1 R5 Envelopes Predominate in Blood, Lymph Nodes, and Semen: Implications for Transmission and Pathogenesis

“…We reported that primary HIV-1 R5 isolates varied in their capacity to infect primary macrophage cultures by over 1,000-fold (33). We also first described a subset of HIV-1 R5 isolates that could infect CD4 ϩ T-cell lines via trace amounts of CCR5 (11), and we recently described HIV-1 R5 envelopes from brain tissues of individuals with neurological complications that were highly fusigenic and tropic for macrophages (27). These latter envelopes are able to exploit low amounts of CD4 and/or CCR5 for infection and contrast emphatically with envelopes from immune tissue (lymph node) that failed to confer macrophage infection and required higher amounts of CD4 for infection.…”