Impact of antiretroviral treatment on the tropism of HIV-1 plasma virus populations

Early human immunodeficiency virus infection is characterized by the predominance of CCR5-tropic (R5)virus. However, in many individuals CXCR4-tropic (X4) virus appears in late infection. The reasons for this phenotypic switch are unclear. The patterns of chemokine receptor expression suggest that X4 and R5 viruses have a preferential tropism for naïve and memory T cells, respectively. Since memory cells divide approximately 10 times as often as naïve cells in uninfected individuals, a tropism for memory cells in early infection may provide an advantage. However, with disease progression both naïve and memory cell division frequencies increase, and at low CD4 counts, the naïve cell division frequency approaches that of memory cells. This may provide a basis for the phenotypic switch from R5 to X4 virus observed in late infection. We show that a model of infection using observed values for cell turnover supports this mechanism. The phenotypic switch from R5 to X4 virus occurs at low CD4 counts and is accompanied by a rapid rise in viral load and drop in CD4 count. Thus, low CD4 counts are both a cause and an effect of X4 virus dominance. We also investigate the effects of different antiviral strategies. Surprisingly, these results suggest that both conventional antiretroviral regimens and CCR5 receptor-blocking drugs will promote R5 virus over X4 virus.Human immunodeficiency virus type 1 (HIV-1) binding to and entry into cells are mediated by the interaction of the viral gp120 protein with cell surface CD4 molecules. Studies of HIV-1 infection have shown that the virus, in addition to binding to cellular CD4, also binds to a variety of chemokine receptors (3). Usually, in early HIV-1 infection, the virus shows a tropism for the CCR5 receptor (R5 virus). However, strains of virus that bind to the CXCR4 chemokine receptor (X4 virus) appear in late infection in at least 50% of patients (24). This change in viral phenotype is associated with rapid depletion of CD4 cells and disease progression (8). The reason for this phenotypic change in late disease is uncertain (41). It has been suggested that X4 virus may be more virulent than R5 virus. However, if this were the case, it is not clear why X4 virus should not dominate from early infection, since it must arise frequently due to the small number of mutations required to make the shift from CCR5 to CXCR4 tropism (11). It has also been suggested that R5 virus dominates early infection, because its tropism for CCR5 promotes infection of macrophages at the site of infection. However, R5 virus predominates even after parenteral infection (57), and CD4 T cells, not macrophages, are found to be the dominant cell type infected in both early and late infection (47,54). In addition, a recent study has shown that target cell availability, as measured by coreceptor expression, cannot be the driving force for R5-to-X4 viral evolution, since higher levels of CXCR4 expression among both total and CD45 ϩ R0 Ϫ CD4 ϩ cells ("naïve" cells) were associated with a delayed development of ...

Section: Fig 4 Predicted Effects Of Antiretroviral Therapy (Purple supporting

confidence: 90%

Section: Fig 4 Predicted Effects Of Antiretroviral Therapy (Purple mentioning

confidence: 99%

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confidence: 96%

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Naïve and Memory Cell Turnover as Drivers of CCR5-to-CXCR4 Tropism Switch in Human Immunodeficiency Virus Type 1: Implications for Therapy

Ribeiro

Hazenberg

Perelson

et al. 2006

“…Others have previously noted that the V3 loop as well as the V2 loop of HIV-1 gp120 determines coreceptor usage and subsequent signal transduction events (9,26,28,36) for both X4 and R5 viruses. In early infection, the majority of circulating virus in HIV-infected individuals is CCR5 binding (R5), or M-tropic (58,75), and the emergence of X4 viruses is generally associated with a rapid decline in CD4 ϩ cells and an increased likelihood of developing AIDS (17,19,56). The natural ligands for CCR5, macrophage inflammatory protein (MIP)-1␣, MIP-1␤, and RANTES, are potent chemoattractants for monocytes and activated T cells, including CD8…”

Section: Vol 78 2004mentioning

confidence: 99%

Migration ofAntigen-Specific T Cells Away from CXCR4-Binding Human ImmunodeficiencyVirus Type 1gp120

Brainard

Tharp

Granado

et al. 2004

Cell-mediated immunity depends in part on appropriate migration and localization of cytotoxic T lymphocytes (CTL), a process regulated by chemokines and adhesion molecules. Many viruses, including human immunodeficiency virus type 1 (HIV-1), encode chemotactically active proteins, suggesting that dysregulation of immune cell trafficking may be a strategy for immune evasion. HIV-1 gp120, a retroviral envelope protein, has been shown to act as a T-cell chemoattractant via binding to the chemokine receptor and HIV-1 coreceptor CXCR4. We have previously shown that T cells move away from the chemokine stromal cell-derived factor 1 (SDF-1) in a concentration-dependent and CXCR4 receptor-mediated manner. Here, we demonstrate that CXCR4-binding HIV-1 X4 gp120 causes the movement of T cells, including HIV-specific CTL, away from high concentrations of the viral protein. This migratory response is CD4 independent and inhibited by anti-CXCR4 antibodies and pertussis toxin. Additionally, the expression of X4 gp120 by target cells reduces CTL efficacy in an in vitro system designed to account for the effect of cell migration on the ability of CTL to kill their target cells. Recombinant X4 gp120 also significantly reduced antigen-specific T-cell infiltration at a site of antigen challenge in vivo. The repellant activity of HIV-1 gp120 on immune cells in vitro and in vivo was shown to be dependent on the V2 and V3 loops of HIV-1 gp120. These data suggest that the active movement of T cells away from CXCR4-binding HIV-1 gp120, which we previously termed fugetaxis, may provide a novel mechanism by which HIV-1 evades challenge by immune effector cells in vivo.

“…Prescreening of individual Env clones derived from patient C's pretreatment plasma sample estimated that approximately 56% of the circulating virus was CCR5 tropic. Even if this CCR5-tropic virus was decreased by several log 10 copies/ml, with the CXCR4-using component remaining unchanged, the maximum overall reduction in viral load would remain Ͻ0.4 log 10 copies/ml (4,31,38).…”

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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

299

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.