The intensity of expression of the chemokine receptor CCR5 is involved in in vitro cell infectability by human immunodeficiency virus (HIV)-1 R5 isolates. Because CCR5 expression varies among individuals, the hypothesis that this expression could determine virus load in HIV-1-infected persons was tested. The mean number of CCR5 molecules per cell was measured on peripheral blood CD4+ T lymphocytes (CCR5 density) from HIV-1-infected, asymptomatic, nontreated adults. There was a strong correlation between HIV RNA plasma level and CCR5 density (P=.009) that was independent of cell activation and was not due to an HIV-induced CCR5 up-regulation. These data are compatible with the hypothesis that CCR5 density is a key factor governing cell infectability and in vivo virus production and explain the protective effect of the Delta32CCR5 deletion, which results in low CCR5 expression. CCR5 density might be of critical predictive value in HIV infection.
These results are compatible with the hypothesis that CCR5 density, which is a key factor of HIV-1 infectability, determines in-vivo HIV production, and thereby the rate of CD4 cell decline. Consequently, CCR5 density quantitation could be a new valuable prognostic tool in HIV-1 infection. Moreover, these data emphasize the therapeutic potential of treatments that reduce functional CCR5 density.
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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