CD4 T cell surface CCR5 density as a host factor in HIV-1 disease progression

Reynes, Jacques; Portalès, Pierre; Segondy, Michel; Baillat, Vincent; André, Pascal; Avinens, Odile; Picot, Marie‐Christine; Clot, J; Eliaou, Jean‐François; Corbeau, Pierre

doi:10.1097/00002030-200109070-00004

Cited by 86 publications

(88 citation statements)

References 16 publications

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“…HIV-1 viral strains preferentially use a number of chemokine receptors including CXCR4, CCR2, 3, and 5 as coreceptors for viral entry into lymphocytes and macrophages (11,84). It has recently been shown that the level of chemokine receptor expression may predict susceptibility to the development of AIDS (14,16,85). Rheumatoid arthritis is another disease that preferentially affects the elderly (86 -88).…”

Section: Discussionmentioning

confidence: 99%

T Cell Chemokine Receptor Expression in Aging

Chen

Yin

et al. 2003

The Journal of Immunology

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Changes in chemokine receptor expression are important in determining T cell migration and the subsequent immune response. To better understand the contribution of the chemokine system in immune senescence we determined the effect of aging on CD4+ T cell chemokine receptor function using microarray, RNase protection assays, Western blot, and in vitro chemokine transmigration assays. Freshly isolated CD4+ cells from aged (20–22 mo) mice were found to express a higher level of CCR1, 2, 4, 5, 6, and 8 and CXCR2–5, and a lower level of CCR7 and 9 than those from young (3–4 mo) animals. Caloric restriction partially or completely restored the aging effects on CCR1, 7, and 8 and CXCR2, 4, and 5. The aging-associated differences in chemokine receptor expression cannot be adequately explained by the age-associated shift in the naive/memory or Th1/Th2 profile. CD4+ cells from aged animals have increased chemotactic response to stromal cell-derived factor-1 and macrophage-inflammatory protein-1α, suggesting that the observed chemokine receptor changes have important functional consequences. We propose that the aging-associated changes in T cell chemokine receptor expression may contribute to the different clinical outcome in T cell chemokine receptor-dependent diseases in the elderly.

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Section: Discussionmentioning

confidence: 99%

T Cell Chemokine Receptor Expression in Aging

Chen

Yin

et al. 2003

The Journal of Immunology

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“…ϩ T cells is a marker of disease progression (39). Collectively, these findings raise the concern that, beyond a series of obvious similarities, the SIVmac-infected RM model does not reproduce correctly the pathogenic events occurring during HIV infection, particularly with respect to the dynamics of the CD4 ϩ CCR5 ϩ T-cell subset.…”

Section: Ccr5mentioning

confidence: 96%

CD4⁺CCR5⁺T-Cell Dynamics during Simian Immunodeficiency Virus Infection of Chinese Rhesus Macaques

Monceaux

Viollet

Petit

et al. 2007

J Virol

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Simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) provides a reliable model to study the relationship between lentivirus replication, cellular immune responses, and CD4؉ T-cell dynamics. Here we investigated, using SIVmac251-infected RMs of a Chinese genetic background (which experience a slower disease progression than Indian RMs), the dynamics of CD4 ؉ CCR5 ؉ T cells, as this subset of memory/activated CD4 ؉ T cells is both a preferential target of virus replication and a marker of immune activation. As expected, we observed that the number of circulating CD4 ؉ CCR5 ؉ T cells decreases transiently at the time of peak viremia. However, at 60 days postinfection, i.e., when set-point viremia is established, the level of CD4 ؉ CCR5 ؉ T cells was increased compared to the baseline level. Interestingly, this increase correlated with faster disease progression, higher plasma viremia, and early loss of CD4 ؉ T-cell function, as measured by CD4 ؉ T-cell count, the fraction of memory CD4 ؉ T cells, and the recall response to purified protein derivative. Taken together, these data show a key difference between the dynamics of the CD4 ؉ CCR5 ؉ T-cell pool (and its relationship with disease progression) in Chinese RMs and those described in previous reports for Indian SIVmac251-infected RMs. As the SIV-associated changes in the CD4؉ CCR5 ؉ T-cell pool reflect the opposing forces of SIV replication (which reduces this cellular pool) and immune activation (which increases it), our data suggest that in SIV-infected Chinese RMs the impact of immune activation is more prominent than that of virus replication in determining the size of the pool of CD4 ؉ CCR5 ؉ T cells in the periphery. As progression of HIV infection in humans also is associated with a relative expansion of the level of CD4 ؉ CCR5 ؉ T cells, we propose that SIV infection of Chinese RMs is a very valuable and important animal model for understanding the pathogenesis of human immunodeficiency virus infection.

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“…Interestingly, the correlation between CCR5 expression and viremia is logarithmic, a small difference in CCR5 density resulting in a marked difference in HIV RNA plasma levels. As a consequence, we have also established that in infected persons CCR5 cell surface density correlates with disease progression (6). The aim of the present study was to analyze the molecular mechanisms responsible for this correlation.…”

mentioning

confidence: 87%

Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection

Lin

Mettling

Portalès

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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102

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We have recently reported that the mean number of CCR5 coreceptors at the surface of CD4 ؉ T cells (CCR5 density) correlates with viral load and disease progression in HIV-1-infected persons. Here, we definitively establish that CCR5 density determines the level of virus production and identify the stages of HIV-1 replicative cycle modulated by this effect. We show, by transducing the CCR5 gene into CCR5 ؉ cells, that CCR5 overexpression resulted in an HIV-1 overinfectability. We sorted HOS-CD4 ؉ -CCR5 ؉ cells into two subpopulations, HOS high and HOS low , the former expressing seven times more cell surface CCR5 molecules than the latter. Virus production was 30 -80 times higher in HOS high cells than in HOS low cells after a single round of infection. In contrast, only twice as many viral particles entered the cytosol of HOS high cells as compared with the cytosol of HOS low cells. Yet, seven times as many early, and 24 times as many late, reverse transcription products were found in HOS high cells as compared with HOS low cells. Moreover, a 24-to 30-fold difference in the number of copies of integrated HIV-1 DNA was observed. No difference in HIV-1 LTR activation between the two cell lines was evident. Finally, we show that the higher virus production observed in HOS high cells is inhibited by pertussis toxin, a G␣i protein inhibitor. Thus, CCR5 density mainly modulates postentry steps of the virus life cycle, particularly the reverse transcription. These data explain why CCR5 density influences HIV-1 disease progression and underline the therapeutic interest of lowering CCR5 expression.coreceptor ͉ chemokine ͉ activation ͉ retrovirus life cycle ͉ AIDS T here is a large interindividual variability in viral load among HIV-1-infected persons. As HIV RNA plasma level is a major predictive indicator of bioclinical outcome (1), it is important to identify the host factors responsible for this variability. The C-C chemokine receptor CCR5 plays a key role during HIV-1 infection. It is used in addition to CD4 as a coreceptor by HIV-1 strains isolated from the blood of infected persons from the beginning of the infection at least until AIDS develops (2). The importance of CCR5 in the physiopathology of HIV-1 infection is illustrated by the effect of a 32-bp deletion in the CCR5 gene, resulting in a mutant gene, ⌬32CCR5, encoding a truncated CCR5 molecule that is not expressed at the cell surface. Homozygotes for this ⌬32 deletion are usually resistant to the infection, and heterozygotes progress slowly in the infection (3, 4). We have recently shown that one of the factors determining the level of viral load in HIV-1-infected persons is the density of CCR5 coreceptors at the single CD4 ϩ T cell level (5). Thus, persons exhibiting high CCR5 expression exhibit high viral loads and persons exhibiting low CCR5 expression exhibit low viral loads. Interestingly, the correlation between CCR5 expression and viremia is logarithmic, a small difference in CCR5 density resulting in a marked difference in HIV RNA plasma levels. As...

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CD4 T cell surface CCR5 density as a host factor in HIV-1 disease progression

Cited by 86 publications

References 16 publications

T Cell Chemokine Receptor Expression in Aging

T Cell Chemokine Receptor Expression in Aging

CD4⁺CCR5⁺T-Cell Dynamics during Simian Immunodeficiency Virus Infection of Chinese Rhesus Macaques

Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection

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CD4 T cell surface CCR5 density as a host factor in HIV-1 disease progression

Cited by 86 publications

References 16 publications

T Cell Chemokine Receptor Expression in Aging

T Cell Chemokine Receptor Expression in Aging

CD4+CCR5+T-Cell Dynamics during Simian Immunodeficiency Virus Infection of Chinese Rhesus Macaques

Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection

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CD4⁺CCR5⁺T-Cell Dynamics during Simian Immunodeficiency Virus Infection of Chinese Rhesus Macaques