Short Communication: Unique HIV Type 1 V3 Region Sequences Derived from Six Different Regions of Brain: Region-Specific Evolution within Host-Determined Quasispecies

Abstract

HIV type 1 viral quasispecies were amplified by polymerase chain reaction (PCR) in the hypervariable V3 region of gp120 from six different regions of the brain (right and left frontal; right and left parietal; and right and left occipital) and from the peripheral blood mononuclear cells (PBMCs) of a patient who died of AIDS dementia complex (ADC). Cloning and sequencing of the entire V3 region suggested the presence of genetically unique sequences in different regions of the brain. In contrast, the blood-derived viral quasispecies carried homogeneous sequences that were characterized by a single octapeptide crest motif (HLGPGSAF), a motif important in viral fusion. The brain-derived viral strains showed extensive sequence heterogeneity and the presence of seven different octapeptide and four different tetrapeptide crest motifs (HIGPGRAF, RIGPGRAF, HIGPGSAI, HLGPGSAF, HIGPESAI, HLGPESAI, and YLRPGSAF). In addition, the brain-derived strains were also characterized by variable net V3 loop charge and hydrophilicity, along with distinct amino acid changes specific to different brain regions. Together, the sequence and phylogenetic analyses are unique in identifying the complexity of a viral quasispecies and its independent regional evolution within the brain compartment. Uniquely divergent viral strains were identified in the frontal regions and their presence was further supported by the presence of multinucleated giant cells (characteristic of HIV encephalopathy) predominantly in the left and right frontal regions. In summary, these analyses suggest that genetically different populations of HIV-1 may be present in different brain compartments and confirm that specific neurotropic variants may exist.

Phylodynamic Analysis of Human Immunodeficiency Virus Type 1 in Distinct Brain Compartments Provides a Model for the Neuropathogenesis of AIDS

“…Finally, we screened our data sets and 229 other V3 loop sequences isolated from brain-derived tissues available at the Los Alamos Database for crest motifs. Such motifs have previously been found in sequences isolated from brains of HAD patients (6). Only a minority of the available database sequences (HIGPGRAF, 8/229; RIGPGRAF, 0/229; HIGPG SAI, 0/229; HLGPGSAF, 0/229; HIGPESAI, 0/229; HLGPE a Different molecular-clock models were tested using the tree in Fig.…”

“…In particular, the finding of independently evolving HIV-1 subpopulations in the frontal lobe, basal ganglia, medial temporal lobe, and nonmedial temporal lobe suggests the ex-istence of restricted pathways for HIV-1 evolution within the CNS (6,29). Compartmentalization and independent evolution of primary and secondary drug resistance mutations to reverse transcriptase and protease inhibitors in diverse CNS regions of HIV-1 patients, with and without HAD, have also been shown (33).…”

Cell death in HIV dementia

“…98 Cloning and sequencing of the entire V3 region has provided evidence that genetically unique sequences exist in different brain regions. 99 Viral variation in different brain compartments may be the product of selection pressures that result from variable access to antiretroviral drugs; or compartmentalized viral evolution. The influence of brain-specific actively replicating viral reservoirs may be important for the development of dementia.…”

Macrophage Tropism of Human Immunodeficiency Virus Type 1 Isolates from Brain and Lymphoid Tissues Predicts Neurotropism Independent of Coreceptor Specificity

“…The genetic evolution of HIV-1 within the brain is distinct from that in lymphoid tissues and other organs (9,24,39,51,58,94,104,106). Specific sequences within Env, particularly the V3 region, are associated with brain infection (51,58,85,86,104,106).…”