R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L<sup>−</sup>CD4<sup>+</sup>T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors

Gondois-Rey, Françoise; Biancotto, Angélique; Fernandez, Marcelo Antonio; Bettendroffer, Lise; Blažková, Jana; Trejbalová, Kateřina; Pion, Marjorie; Hirsch, Ivan

doi:10.1128/jvi.80.2.854-865.2006

Cited by 11 publications

(7 citation statements)

References 75 publications

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“…We let n t and m t represent the total numbers (i.e., activated + non-activated) of naïve and memory CD4 + T cells, respectively. Because naïve and memory cell counts are initially similar and because R5 virus disproportionately depletes memory CD4 + T cells [40,41], we assume that n t > m t during R5 infection, implying:

m_{t} (1 - a_{m}) < n_{t} (1 - a_{n})

…”

Section: Resultsmentioning

confidence: 99%

Persistence and emergence of X4 virus in HIV infection

Weinberger

Perelson

2011

Mathematical Biosciences and Engineering

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Approximately 50% of late-stage HIV patients develop CXCR4-tropic (X4) virus in addition to CCR5-tropic (R5) virus. X4 emergence occurs with a sharp decline in CD4+ T cell counts and accelerated time to AIDS. Why this “phenotypic switch” to X4 occurs is not well understood. Previously, we used numerical simulations of a mathematical model to show that across much of parameter space a promising new class of antiretroviral treatments, CCR5 inhibitors, can accelerate X4 emergence and immunodeficiency. Here, we show that mathematical model to be a minimal activation-based HIV model that produces a spontaneous switch to X4 virus at a clinically-representative time point, while also matching in vivo data showing X4 and R5 coexisting and competing to infect memory CD4+ T cells. Our analysis shows that X4 avoids competitive exclusion from an initially fitter R5 virus due to X4’s unique ability to productively infect naïve CD4+ T cells. We further justify the generalized conditions under which this minimal model holds, implying that a phenotypic switch can even occur when the fraction of activated naïve CD4+ T cells increases at a slower rate than the fraction of activated memory CD4+ T cells. We find that it is the ratio of the fractions of activated naïve and memory CD4+ T cells that must increase above a threshold to produce a switch. This occurs as the concentration of CD4+ T cells drops beneath a threshold. Thus, highly active antiretroviral therapy (HAART), which increases CD4+ T cell counts and decreases cellular activation levels, inhibits X4 viral growth. However, we show here that even in the simplest dual-strain framework, competition between R5 and X4 viruses often results in accelerated X4 emergence in response to CCR5 inhibition, further highlighting the potential danger of anti-CCR5 monotherapy in multi-strain HIV infection.

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m_{t} (1 - a_{m}) < n_{t} (1 - a_{n})

…”

Section: Resultsmentioning

confidence: 99%

Persistence and emergence of X4 virus in HIV infection

Weinberger

Perelson

2011

Mathematical Biosciences and Engineering

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“…Memory CD4 + T cells separated from PBMC by means of a memory CD4 + T cell isolation kit (Miltenyi Biotech, France) were cultured at the concentration of 10 6 cells per milliliter of RPMI 1640 supplemented with 200-U/ml recombinant IL-2 (Chiron), 15% fetal calf serum, and antibiotics in duplicate in a total volume of 100 µl in the presence of HIV-1-reactivating agents. After a 3-day stimulation, CD4 + T cells were 10-fold serially diluted and co-cultured with PHA-activated CD4 + T cells from an allogeneic healthy donor, as described in detail previously [71] . HIV-1 replication was followed by determination of p24 in the cell-free supernatant by means of Genetic System HIV Ag EIA (BioRad France, Marnes la Coquettes).…”

Section: Methodsmentioning

confidence: 99%

CpG Methylation Controls Reactivation of HIV from Latency

et al. 2009

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DNA methylation of retroviral promoters and enhancers localized in the provirus 5′ long terminal repeat (LTR) is considered to be a mechanism of transcriptional suppression that allows retroviruses to evade host immune responses and antiretroviral drugs. However, the role of DNA methylation in the control of HIV-1 latency has never been unambiguously demonstrated, in contrast to the apparent importance of transcriptional interference and chromatin structure, and has never been studied in HIV-1-infected patients. Here, we show in an in vitro model of reactivable latency and in a latent reservoir of HIV-1-infected patients that CpG methylation of the HIV-1 5′ LTR is an additional epigenetic restriction mechanism, which controls resistance of latent HIV-1 to reactivation signals and thus determines the stability of the HIV-1 latency. CpG methylation acts as a late event during establishment of HIV-1 latency and is not required for the initial provirus silencing. Indeed, the latent reservoir of some aviremic patients contained high proportions of the non-methylated 5′ LTR. The latency controlled solely by transcriptional interference and by chromatin-dependent mechanisms in the absence of significant promoter DNA methylation tends to be leaky and easily reactivable. In the latent reservoir of HIV-1-infected individuals without detectable plasma viremia, we found HIV-1 promoters and enhancers to be hypermethylated and resistant to reactivation, as opposed to the hypomethylated 5′ LTR in viremic patients. However, even dense methylation of the HIV-1 5′LTR did not confer complete resistance to reactivation of latent HIV-1 with some histone deacetylase inhibitors, protein kinase C agonists, TNF-α, and their combinations with 5-aza-2deoxycytidine: the densely methylated HIV-1 promoter was most efficiently reactivated in virtual absence of T cell activation by suberoylanilide hydroxamic acid. Tight but incomplete control of HIV-1 latency by CpG methylation might have important implications for strategies aimed at eradicating HIV-1 infection.

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“…Also, activated and previously activated T cells express both CCR5 and CXCR4 (5,55,58), providing a potential source of mixing of R5 and X4 variants. There is evidence to suggest that the pool of cells supporting the bulk of virus replication is not homogeneous in its susceptibility to infection by X4 and R5 variants (22) and that X4 and R5 variants may be differentially affected by antiretroviral therapy (22,66). However, we found no difference in the decay rates of X4 and R5 variants upon initiation of therapy, and the decay rates of these variants are within the range reported in other studies for the first phase of decay, presumably reflecting the life spans of the activated memory cells supporting ϳ99% of the virus population (34,49,62,63,96).…”

Section: Discussionmentioning

confidence: 99%

“…These and subsequent studies (4,49,62,63) suggested that the average life span of infected cells that produce 99% or more of the bulk HIV-1 population in the peripheral blood is short, with a half-life of 1 to 2 days, presumably reflecting the life span of activated T cells, whereas cells producing 1% or less of the population have a half-life measured in weeks, illustrated by a biphasic decay curve. However, the bulk HIV-1 RNA decay rate of the first phase may oversimplify the dynamics of the underlying viral genetic subpopulations because this rate may represent an average without accounting for possible moderate differences between decay rates of coexisting variants, as might be the case for variants infecting cellular subsets in different stages of maturation or activation (22,59,100). Based on this model, two or more coexisting viral populations with the same rates of decay during HAART could be presumed to be produced by the same cellular subset or, at minimum, two or more subsets with the same turnover rate.…”

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confidence: 99%

Major Coexisting Human Immunodeficiency Virus Type 1envGene Subpopulations in the Peripheral Blood Are Produced by Cells with Similar Turnover Rates and Show Little Evidence of Genetic Compartmentalization

Ince¹,

Harrington²,

Schnell³

et al. 2009

J Virol

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A distinctive feature of chronic human immunodeficiency virus type 1 (HIV-1) infection is the presence of multiple coexisting genetic variants, or subpopulations, that comprise the HIV-1 population detected in the peripheral blood. Analysis of HIV-1 RNA decay dynamics during the initiation of highly active antiretroviral therapy (HAART) has been a valuable tool for modeling the life span of infected cells that produce the bulk HIV-1 population. However, different HIV-1 target cells may have different turnover rates, and it is not clear whether the bulk HIV-1 RNA decay rate actually represents a composite of the decay rates of viral subpopulations compartmentalized in different cellular subsets with different life spans. Using heteroduplex tracking assays targeting the highly variable V3 or V4-V5 regions of the HIV-1 env gene in eight subjects, we found that all detectable coexisting HIV-1 variants in the peripheral blood generally decayed at similar rates during the initiation of HAART, suggesting that all of the variants were produced by cells with similar life spans. Furthermore, single genome amplification and coreceptor phenotyping revealed that in two subjects coexisting HIV-1 variants with distinct CXCR4 or CCR5 coreceptor phenotypes decayed with similar rates. Also, in nine additional subjects, recombination and a lack of genetic compartmentalization between X4 and R5 variants were observed, suggesting an overlap in host cell range. Our results suggest that the HIV-1 env subpopulations detectable in the peripheral blood are produced by cells with similar life spans and are not genetically isolated within particular cell types.

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R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L⁻CD4⁺T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors

Abstract: The persistence of human immunodeficiency virus type 1 (HIV-1) in memory CD4؉ T cells is a major obstacle to the eradication of the virus with current antiretroviral therapy. Here, we investigated the effect of the activation status of CD4

Cited by 11 publications

References 75 publications

Persistence and emergence of X4 virus in HIV infection

Persistence and emergence of X4 virus in HIV infection

CpG Methylation Controls Reactivation of HIV from Latency

Major Coexisting Human Immunodeficiency Virus Type 1envGene Subpopulations in the Peripheral Blood Are Produced by Cells with Similar Turnover Rates and Show Little Evidence of Genetic Compartmentalization

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R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L−CD4+T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors

Abstract: The persistence of human immunodeficiency virus type 1 (HIV-1) in memory CD4؉ T cells is a major obstacle to the eradication of the virus with current antiretroviral therapy. Here, we investigated the effect of the activation status of CD4

Cited by 11 publications

References 75 publications

Persistence and emergence of X4 virus in HIV infection

Persistence and emergence of X4 virus in HIV infection

CpG Methylation Controls Reactivation of HIV from Latency

Major Coexisting Human Immunodeficiency Virus Type 1envGene Subpopulations in the Peripheral Blood Are Produced by Cells with Similar Turnover Rates and Show Little Evidence of Genetic Compartmentalization

Contact Info

Product

Resources

About

R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L⁻CD4⁺T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors