In vivo compartmentalization of human immunodeficiency virus: evidence from the examination of pol sequences from autopsy tissues

Abstract

High rates of mutation and replication of human immunodeficiency virus (HIV) allow for the continuous generation of diverse genetic variants in vivo. Selective pressures within the microenvironments of different anatomic compartments result in the emergence of dominant quasispecies which can be distinguished by their envelope sequences. It is not known whether comparable tissue-specific selective pressures lead to the independent evolution of pol sequences within different tissue compartments, nor is it known how differing rates of virus turnover in tissues might affect the pace of such evolution. These issues are of importance for the formulation of a model for the emergence of drug resistance in vivo and for a general understanding of virus trafficking and virus turnover. Regions of the HIV type 1 reverse transcriptase (RT) which carry the majority of the known resistance codons to RT inhibitors (700 nucleotides from each clone) were cloned and sequenced directly from autopsied brain, spleen, and lymph node specimens from four subjects who had received zidovudine therapy. Clones from proviral DNA (143) and from viral cDNA (14) were analyzed. In three of four subjects, a discordance in distribution of resistance codons was noted. Moreover, brain-derived sequences appeared to be phylogenetically distinct from spleen-and lymph node-derived sequences even after exclusion of resistance codons from analysis. In each case, evidence for differential immune selective pressure, based on comparison of inferred amino acid sequences corresponding to known major histocompatibility complex class I cytotoxic T-lymphocyte epitopes, was found. These observations support the concept of anatomically distinct, independently evolving quasispecies (virodemes).

Viral Quasispecies Evolution

“…The mutation and recombination rates and frequencies, the virion production rate, and a short generation time all contribute to HIV-1 exhibiting quasispecies dynamics (references 145,369,385,407,478,511,552,588,589,639,655,674,675,735,800,804,844, and 852, among numerous other studies). The interpretation of the origin of HIV-1 heterogeneity and diversification of viral sequences is complicated by the compartmentalization of the infection, the presence of viral reservoirs (and therefore replicative and nonreplicative quasispecies memory), and reactivation of latent provirus (85,110,127,176,296,390,458,488,706,835,872). Retroviral sequences integrated into cellular DNA will be subjected to the relative evolutionary stasis typical of cellular genes (except in the case of potential integration at sites undergoing cellular hypermutational events).…”

Evolutionary analysis of the dynamics of viral infectious disease

“…Phylodynamic methods have detected and measured the compartmentalization of viral lineages into specific tissues during chronic infection, which creates within-host subpopulations (so-called virodemes), which are analogous to the location-specific clusters of infection seen at higher scales. Highly distinct strains of HIV are found in the brains of patients with neurological illness 85,86 , suggesting that virus movement across the blood-brain barrier is not common and might be unidirectional. Finer genetic structure is apparent even among viruses from different brain regions, which seem to evolve at different rates 87 .…”

The evolution of HIV: Inferences using phylogenetics

“…Some suggested sanctuaries include the central nervous system (CNS), gut-associated lymphoid tissue (GALT) and the genitourinary tract (Dahl et al, 2010). Evidence of compartmentalization of HIV sequences from different tissue types has been typically inferred from monophyletic assemblages of those sequences in phylogenetic trees (Wang et al, 2001;Wong et al, 1997). Even further sub-compartmentalization has been found in GALT tissue throughout the gastrointestinal tract (van Marle et al, 2007).…”