Phylodynamics of HIV-1 in Lymphoid and Non-Lymphoid Tissues Reveals a Central Role for the Thymus in Emergence of CXCR4-Using Quasispecies

Abstract

BackgroundDuring HIV-1 infection coreceptor switch from CCR5- (R5)- to CXCR4 (X4)-using viruses is associated with disease progression. X4 strains of HIV-1 are highly cytopathic to immature thymocytes. Virtually no studies have evaluated the HIV-1 quasispecies present in vivo within thymic and lymphoid tissues or the evolutionary relationship between R5 and X4 viruses in tissues and peripheral blood.Methodology/Principal FindingsHigh-resolution phylodynamic analysis was applied to virus envelope quasispecies in longitudinal peripheral blood mononuclear cells (PBMCs) and lymphoid and non-lymphoid tissues collected post mortem from therapy naïve children with AIDS. There were three major findings. First, continued evolution of R5 viruses in PBMCs, spleen and lymph nodes involved multiple bottlenecks, independent of coreceptor switch, resulting in fitter quasispecies driven by positive selection. Second, evolution of X4 strains appeared to be a sequential process requiring the initial fixation of positively selected mutations in V1-V2 and C2 domains of R5 variants before the emergence of high charge V3 X4 variants. Third, R5 viruses persisted after the emergence of CXCR4-using strains, which were found predominantly but not exclusively in the thymus.Conclusions/SignificanceOur data indicate that the evolution of X4 strains is a multi-step, temporally structured process and that the thymus may play an important role in the evolution/amplification of coreceptor variants. Development of new therapeutic protocols targeting virus in the thymus could be important to control HIV-1 infection prior to advanced disease.

Towards an understanding of the migration of Crimean-Congo hemorrhagic fever virus

“…Such analysis has been used successfully to determine migration patterns of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) within and between countries (Nakano et al, 2004;Salemi et al, 2008a, b) and to analyse the migration of HIV-1 between different compartments in the brain (Salemi et al, 2005) and between lymphoid and non-lymphoid tissues (Salemi et al, 2007).…”

“…The worldwide migration of CCHFV was analysed by using a modified version of the Slatkin-Maddison test (Slatkin & Maddison, 1989), which counts migration events to and from subpopulations. Such analysis has been used successfully to determine the migration patterns of HIV-1 and HCV within and between countries (Nakano et al, 2004;Salemi et al, 2008a, b) and to analyse the migration of HIV-1 between different compartments in the brain (Salemi et al, 2005) and between lymphoid and nonlymphoid tissues (Salemi et al, 2007).…”

Evolution of the HIV-1 env Gene in the Rag2 −/− γ C −/− Humanized Mouse Model

“…Examination of the tissue distribution of variants in the mouse in which the X4 virus emerged showed that 95% of variants in the MLN were X4 viruses, compared to 15% in the (82). In contrast, the MLN in wild-type mice is responsible for linking both inductive and effector sites of the gut-associated lymphoid tissue (GALT), such as Peyer's patches, the lamina propria, and mucosal epithelium.…”

Tracking the Emergence of Host-Specific Simian Immunodeficiency Virus env and nef Populations Reveals nef Early Adaptation and Convergent Evolution in Brain of Naturally Progressing Rhesus Macaques

“…env gp120 is exposed on the virus surface and is necessary for viral entry into lymphocytes (4). Neutralizing antibodies bind to env variable regions, exerting significant selection pressure on the protein (5,6). HIV-1 Nef, an accessory protein, is also required for the establishment and maintenance of infection in both humans and macaques (7)(8)(9).…”