Genetic and Functional Analysis of Full-Length Human Immunodeficiency Virus Type 1 env Genes Derived from Brain and Blood of Patients with AIDS

Abstract

The genetic evolution of human immunodeficiency virus type 1 (HIV-1) in the brain is distinct from that in lymphoid tissues, indicating tissue-specific compartmentalization of the virus. Few primary HIV-1 envelope glycoproteins (Envs) from uncultured brain tissues have been biologically well characterized. In this study, we analyzed 37 full-length env genes from uncultured brain biopsy and blood samples from four patients with AIDS. Phylogenetic analysis of intrapatient sequence sets showed distinct clustering of brain relative to blood env sequences. However, no brain-specific signature sequence was identified. Furthermore, there was no significant difference in the number or positions of N-linked glycosylation sites between brain and blood env sequences. The patterns of coreceptor usage were heterogeneous, with no clear distinction between brain and blood env clones. Nine Envs used CCR5 as a coreceptor, one used CXCR4, and two used both CCR5 and CXCR4 in cell-to-cell fusion assays. Eight Envs could also use CCR3, CCR8, GPR15, STRL33, Apj, and/or GPR1, but these coreceptors did not play a major role in virus entry into microglia. Recognition of epitopes by the 2F5, T30, AG10H9, F105, 17b, and C11 monoclonal antibodies varied among env clones, reflecting genetic and conformational heterogeneity. Envs from two patients contained 28 to 32 N-glycosylation sites in gp120, compared to around 25 in lab strains and well-characterized primary isolates. These results suggest that HIV-1 Envs in brain cannot be distinguished from those in blood on the basis of coreceptor usage or the number or positions of N-glycosylation sites, indicating that other properties underlie neurotropism. The study also demonstrates characteristics of primary HIV-1 Envs from uncultured tissues and implies that Env variants that are glycosylated more extensively than lab strains and well-characterized primary isolates should be considered during development of vaccines and neutralizing antibodies.

Macrophage/Microglial Accumulation and Proliferating Cell Nuclear Antigen Expression in the Central Nervous System in Human Immunodeficiency Virus Encephalopathy

“…Although it has been demonstrated that HIV-1 envelope sequences in CNS are most closely related to sequences in peripheral blood and bone marrow, 38 it is possible that some MPs are infected as they enter the CNS. Furthermore, there is C, F, and I).…”

“…39 The relationship between the blood compartment and the CNS is further demonstrated by biological comparison with respect to the frequency of co-receptor utilization specificities. 38 It is possible that some of the differences that have been observed in comparison of brain sequence with other organs 40 may reflect differences in cell populations infected by HIV-1 in particular tissues (ie, the abundance of T cells in lymphoid tissue, but not brain) or, alternatively, mechanisms of immune selection as has been inferred from differences in T-cell epitopes in viruses isolated from different organs. 41 Further studies will be needed combining viral-genetic characterization with immunohistochemical analysis to characterize virus within individual cell populations in multiple organs.…”

HIV-1, chemokines and neurogenesis

“…Virtually all strains of HIV-1 interact with cells through the use of either CXCR4 or CCR5 receptors. Many viruses that replicate in the brain use CCR5 (i.e., are M-tropic), although it is now believed that CXCR4 (T-tropic) utilizing or dual specific viral strains may also occur (Ohagen et al, 2003). It is still unclear which viral tropism is more likely to produce brain disease.…”

Immunogenicity of Constrained Monoclonal Antibody A32-Human Immunodeficiency Virus (HIV) Env gp120 Complexes Compared to That of Recombinant HIV Type 1 gp120 Envelope Glycoproteins

“…Viruses BL01 and BR07 were provided by Dana Gabuzda of the Dana-Farber Cancer Institute. Both are chimeric infectious molecular clones of NL4-3 that contain the full-length env genes from primary HIV-1 isolates (20). After initial plasmid transfection of 293 cells, these viruses were expanded in PBMC as described above.…”