Comparative Study of Methods for Detecting Sequence Compartmentalization in Human Immunodeficiency Virus Type 1

Abstract

Human immunodeficiency virus (HIV) infects different organs and tissues. During these infection events, subpopulations of HIV type 1 (HIV-1) develop and, if viral trafficking is restricted between subpopulations, the viruses can follow independent evolutionary histories, i.e., become compartmentalized. This phenomenon is usually detected via comparative sequence analysis and has been reported for viruses isolated from the central nervous system (CNS) and the genital tract. Several approaches have been proposed to study the compartmentalization of HIV sequences, but to date, no rigorous comparison of the most commonly employed methods has been made. In this study, we systematically compared inferences made by six different methods for detecting compartmentalization based on three data sets: (i) a sample of 45 patients with sequences gathered from the CNS, (ii) sequences from the female genital tract of 18 patients, and (iii) a set of simulated sequences. We found that different methods often reached contradictory conclusions. Methods based on the topology of a phylogenetic tree derived from clonal sequences were generally more sensitive in detecting compartmentalization than those that relied solely upon pairwise genetic distances between sequences. However, as the branching structure in a phylogenetic tree is often uncertain, especially for short, low-diversity, or recombinant sequences, tree-based approaches may need to be modified to take phylogenetic uncertainty into account. Given the frequently discordant predictions of different methods and the strengths and weaknesses of each particular methodology, we recommend that a suite of several approaches be used for reliable inference of compartmentalized population structure.

The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

“…As shown in column 7 of Table 5, the F ST analysis showed statistically significant support for a genetic subdivision of sequences isolated before initiation and after several years of therapy in patients 2 and 6-8 (P ≤ 0.01) indicating a higher degree of structure than expected by chance for these patients. In addition, we detected evidence for compartmentalization in the nonrecombinant fragments for patient 1 (P = 0.02 and P = 0.04 for fragments 1 and 2, respectively), confirming that recombination can affect the power to detect compartmentalization (38). However, the corresponding AI values indicate that the extent of compartmentalization in all of these patients is low (Table S2, column 5).…”

“…AI statistical support was obtained using 1,000 bootstrap trees and 10 random relabelings per sample (only bootstrap values above 0.95 were considered significant). In addition, we used nucleotide distance-based methods that do rely on phylogenies, which are often poorly resolved for intrahost evolution (38). Particularly, we estimated F ST (55).…”

Analysis of Dominant HIV Quasispecies Suggests Independent Viral Evolution Within Spinal Granulomas Coinfected with Mycobacterium tuberculosis and HIV-1 Subtype C

“…29 In this study we investigated the impact of anatomic sequestration of HIV, within a tuberculous spinal, granuloma on viral evolution. Using phylogenetic reconstruction and computational measures of compartmentalization 30 we provide the first evidence to suggest divergent HIV evolution in spinal TB coinfected granulomas. These findings were supported by the fact that we noted no correlation between tissue and plasma viral load measurements, which suggests that viral variants in the tissue either accumulated slowly over time independent of plasma populations or are undergoing rapid tissue-specific expansion.…”

Cerebrospinal fluid analysis in the HIV infection and compartmentalization of HIV in the central nervous system

“…Compartments and reservoirs protect HIV from specific immune responses, ARV therapy, and biochemical changes, thereby providing an environment for pathogen-host interactions 36,37 . The CNS serves as an important reservoir for HIV 36,38,39 . Several constitutional characteristics specific to the CNS support the view that the CNS is an immunologically privileged site.…”

“…Despite the effective suppression of viremia with ARV therapy, HIV can still replicate in the CNS, with the development of resistant strains in the CNS in patients with acute and sub-acute neurological manifestations 38,39,54 . Disagreement between the HIV viral loads in the plasma and CSF is defined by detectable levels of HIV RNA in the CSF, indicative of a viral load of > 200 copies/mL, when the viral load in the plasma is < 50 copies/mL or by an HIV RNA viral load in the CSF that is ≥ 1 log higher than that in the plasma 55 .…”