T-cell line adaptation of human immunodeficiency virus type 1 strain SF162: effects on envelope, vpu and macrophage-tropism

We previously reported coreceptor switch in rhesus macaques inoculated intravenously with R5 simianhuman immunodeficiency virus SF162P3N (SHIV SF162P3N ). Whether R5-to-X4 virus evolution occurs in mucosally infected animals and in which anatomic site the switch occurs, however, were not addressed. We herein report a change in coreceptor preference in macaques infected intrarectally with SHIV SF162P3N . The switch occurred in infected animals with high levels of virus replication and undetectable antiviral antibody response and required sequence changes in the V3 loop of the gp120 envelope protein. X4 virus emergence was associated with an accelerated drop in peripheral CD4؉ T-cell count but followed rather than preceded the onset of CD4 ؉ T-cell loss. The conditions, genotypic requirements, and patterns of coreceptor switch in intrarectally infected animals were thus remarkably consistent with those found in macaques infected intravenously. They also overlapped with those reported for humans, suggestive of a common mechanism for coreceptor switch in the two hosts. Furthermore, two independent R5-to-X4 evolutionary pathways were identified in one infected animal, giving rise to dual-tropic and X4 viruses which differed in switch kinetics and tissue localization. The dual-tropic switch event predominated early, and the virus established infection in multiple tissues sites. In contrast, the switch to X4 virus occurred later, initiating and expanding mainly in peripheral lymph nodes. These findings help define R5 SHIV SF162P3N infection of rhesus macaques as a model to study the mechanistic basis, dynamics, and sites of HIV-1 coreceptor switch.

Section: Discussionmentioning

confidence: 77%

Different Tempo and Anatomic Location of Dual-Tropic and X4 Virus Emergence in a Model of R5 Simian-Human Immunodeficiency Virus Infection

Ren

Tasca

Zhuang

et al. 2010

“…Selection of CXCR4-using variants within a patient could theoretically arise by mutation from a CCR5-tropic ancestor ("coreceptor switch"). This pathway has been described in vitro using serial passage conditions in which CCR5 receptor levels are limiting (9,17). However, other in vitro studies using a range of CCR5-tropic HIV-1 strains suggest that the molecular pathways to coreceptor switching frequently involve multiple mutations throughout the gp160 sequence, with transitional intermediates characterized as having diminished replication fitness and less efficient coreceptor usage (30).…”

Section: Vol 80 2006 Emergence Of Cxcr4-using Virus On Maraviroc Thmentioning

confidence: 99%

Emergence of CXCR4-Using Human Immunodeficiency Virus Type 1 (HIV-1) Variants in a Minority of HIV-1-Infected Patients following Treatment with the CCR5 Antagonist Maraviroc Is from a Pretreatment CXCR4-Using Virus Reservoir

Westby

Lewis

Whitcomb³

et al. 2006

300

236

Antagonists of the human immunodeficiency virus type 1 (HIV-1) coreceptor, CCR5, are being developed as the first anti-HIV agents acting on a host cell target. We monitored the coreceptor tropism of circulating virus, screened at baseline for coreceptor tropism, in 64 HIV-1-infected patients who received maraviroc (MVC, UK-427,857) as monotherapy for 10 days. Sixty-two patients harbored CCR5-tropic virus at baseline and had a posttreatment phenotype result. Circulating virus remained CCR5 tropic in 60/62 patients, 51 of whom experienced an HIV RNA reduction from baseline of >1 log 10 copies/ml, indicating that CXCR4-using variants were not rapidly selected despite CCR5-specific drug pressure. In two patients, viral load declined during treatment and CXCR4-using virus was detected at day 11. No pretreatment factor predicted the emergence of CXCR4-tropic virus during maraviroc therapy in these two patients. Phylogenetic analysis of envelope (Env) clones from pre-and posttreatment time points indicated that the CXCR4-using variants probably emerged by outgrowth of a pretreatment CXCR4-using reservoir, rather than via coreceptor switch of a CCR5-tropic clone under selection pressure from maraviroc. Phylogenetic analysis was also performed on Env clones from a third patient harboring CXCR4-using virus prior to treatment. This patient was enrolled due to a sample labeling error. Although this patient experienced no overall reduction in viral load in response to treatment, the CCR5-tropic components of the circulating virus did appear to be suppressed while receiving maraviroc as monotherapy. Importantly, in all three patients, circulating virus reverted to predominantly CCR5 tropic following cessation of maraviroc.

“…As few as one or two amino acid changes in V3 suffice for coreceptor switching (5,8,14,24,37). Given this minimum requirement for coreceptor switching and the high rate of mutation and recombination in the HIV-1 genome (10,32,35), evolution of X4 variants would be expected to be rapid and frequent.…”

mentioning

confidence: 99%

Intrinsic Obstacles to Human Immunodeficiency Virus Type 1 Coreceptor Switching

Pastore

Ramos

Mosier

2004

105

126

The natural evolution of human immunodeficiency virus type 1 infection often includes a switch in coreceptor preference late in infection from CCR5 to CXCR4, a change associated with expanded target cell range and worsened clinical prognosis. Why coreceptor switching takes so long is puzzling, since it requires as few as one to two mutations. Here we report three obstacles that impede the CCR5-to-CXCR4 switch. Coreceptor switch variants were selected by target cell replacement in vitro. Most switch variants showed diminished replication compared to their parental R5 isolate. Transitional intermediates were more sensitive to both CCR5 and CXCR4 inhibitors than either the parental R5 virus or the final R5X4 (or rare X4) variant. The small number of mutations in viruses selected for CXCR4 use were distinctly nonrandom, with a dominance of charged amino acid substitutions encoded by G-to-A transitions, changes in N-linked glycosylation sites, and isolate-specific mutation patterns. Diminished replication fitness, less-efficient coreceptor use, and unique mutational pathways may explain the long delay from primary infection until the emergence of CXCR4-using viruses.The entry of human immunodeficiency virus type 1 (HIV-1) into target cells requires binding of the viral envelope glycoprotein gp120 to CD4 and one of two chemokine receptors, CCR5 or CXCR4 (1,9,15,17,19). Although other chemokine receptors have been identified as potential entry factors, only CCR5 and CXCR4 appear to be important for infection by clinical isolates of HIV-1 (53, 54). This observation is reflected in the current nomenclature for HIV-1 coreceptor use (E. A. Berger, R. W. Doms, E. M. Fenyo, B. T. Korber, D. R. Littman, J. P. Moore, Q. J. Sattentau, H. Schuitemaker, J. Sodroski, and R. A. Weiss, Letter, Nature 391:240, 1998): R5 for viruses that use only CCR5, X4 for viruses that use only CXCR4, and R5X4 for viruses that can use both receptors. R5 virus isolates are equivalent to macrophage-tropic, non-syncytium-inducing (NSI) viruses, and R5X4 or X4 isolates are T-cell-tropic, syncytium-inducing viruses (43,44,47), with only a few interesting exceptions (51, 52). R5 HIV-1 accounts for the vast majority of primary infections regardless of the route of transmission (12,43). During the evolution of virus populations (quasispecies) within an infected individual, coreceptor switching from R5 to X4 is common in clade B HIV-1 infection (12, 43) and less common in clade C infection (29,40). The R5-to-X4 coreceptor switch is a harbinger of accelerated clinical disease progression and typically occurs after 8 to 10 years of infection (6, 11). The issue of coreceptor switching has become relevant to drug resistance as coreceptor inhibitors enter clinical trials (18,37,48,49). Coreceptor switching is one route to resistance to these compounds (37, 49).Coreceptor use maps to the variable V3 and V2 loops of gp120, and the R5-to-X4 switch is often accompanied by an increase in charged residues in the V3 loop (7,8,20,25,27,42,46). As few as one or two amino...