Biology Reference
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de novo infection of permissive cells. The virus variables in¯uencing the level
of systemic HIV activity and cell-free virus dynamics include degree of viral
expression and host cell range, whereas the host variables include the speci®c
(humoral and cytotoxic) immune response and polymorphism of genes coding
for cell receptors of HIV.
The vast majority of quantitative studies carried out in vivo have highlighted
the role of cell-free viremia as a reliable index of mean viral activity in HIV
infection. Indeed, viremia-based studies have provided clear evidence that
changes in HIV load during the di¨erent phases of this infection can be e½-
ciently evaluated by measuring cell-free virus in plasma samples ( Bagnarelli
et al., 1994; Perelson et al., 1996), and that substantial increases in viral load
parallel or even predict (Mellors et al., 1996) the disease progression. These
®ndings have greatly contributed in the last few years to a clearer understand-
ing of the virologic correlates of disease progression, to driving new attempts
at understanding the pathogenic potential of HIV, and to designing e¨ective
antiretroviral strategies. Although recent research has highlighted the diagnos-
tic role of other quantitative parameters, including viral transcription pattern
and provirus copy numbers, and although in some cases virus compartmen-
talization may in¯uence the exact correspondence between cell-free plasma
viremia and systemic viral activity, the analysis of viral genome molecules in
plasma samples is still a major molecular correlate of systemic viral activity at
the level of the whole body in many human viral infections.
The evaluation of patients undergoing potent antiviral treatments has allowed
the dynamics of cell-free virus in plasma to be addressed in vivo (Ho et al.,
1995; Perelson et al., 1996; Wei et al., 1995). Importantly, these studies have
documented the dynamics of cell-free virions in plasma (half-life being approx-
imately 5.7 h) and the turnover of infected cells. Furthermore, the sensitivity
and speci®city performances of most quantitative molecular methods have
provided in the last few years a simple approach to the evaluation of gene
transcription in vivo and in vitro. In HIV infection, consistent evidence has in-
dicated that progression of disease is driven by an increase in viral load eval-
uated as cell-free plasma virus. To address whether this increase is contributed
by the dysregulation of the molecular mechanisms governing virus gene ex-
pression at the transcriptional or post-transcriptional levels, several quantitative
virologic parameters (including provirus transcriptional activity and splicing
pattern) have been analyzed in subjects with nonprogressive HIV infection and
compared with those of matching groups of progressor patients. It was ob-
served not only that high levels of unspliced (US) and multiply spliced (MS)
viral transcripts in peripheral blood mononuclear cells (PBMCs) correlate with
the decrease in CD4
T cells ( Bagnarelli et al., 1996; Furtado et al., 1995) fol-
lowing the general trend of systemic HIV-1 activity, but also that MS mRNA
levels in PBMCs are closely associated with the number of productively infected
cells ( Bagnarelli et al., 1996), because the half-life of this class of transcripts
after administration of a potent protease inhibitor is very consistent with that of
productively infected cells. The transcriptional pattern observed during in vitro
