Biology Reference
In-Depth Information
retroviruses, the genomic HIV RNA is synthesized and processed by the cellu-
lar mRNA handling machinery starting from the proviral HIV DNA. For this
reason, the viral genome contains a cap structure at the 5
0
end and a poly-A tail
at the 3
0
end. Moreover, the diploid lentiviral genome has the additional feature
of being rich in A residues (on average 38±39%) (Myers and Pavlakis, 1992). As
a direct consequence, the HIV codon usage di¨ers dramatically from that of
cellular genes ( Berkhout and van Hemert, 1994; Kypr et al., 1989).
Control of HIV RNA synthesis is complex and requires the presence of
several cellular proteins as well as of viral transactivators and cis-acting viral
elements. Indeed, retroviral long terminal repeats (LTRs) are divided into do-
mains (designated U3, R, and U5) that have distinct functions in transcription
either in regulating basal levels or inducing high levels of HIV gene expression.
The U3 domain of HIV contains basal promoter elements, including the TATA
box for initiation by RNA polymerase II and the site for binding the cellular
transcription factor SP1. Immediately upstream of the core promoter, the virus
contains one or more copies of a 10-bp sequence recognized by the enhancer
factor nuclear factor (NF )-kB. However, whereas in simple retroviruses regu-
lation of viral transcription is passive (i.e., regulated by cellular factors), in HIV
infection, this process is more complex and products of the HIV genome are
required to achieve high levels of expression. Initiation of HIV RNA occurs at
the U3/R level (cap site) of the 5
0
LTR, and the viral transactivator Tat func-
tions through a cis-acting sequence (designated Tat-responsive element, TAR)
an RNA encoded by a region located in R (19 to 43). R-U5 is the leader
sequence of the full-length and spliced viral transcript, whereas the 3
0
ends of
mRNAs are de®ned by the R/U5 border in the 3
0
LTR. Finally, the accessory
genes of HIV (vif, vpr, vpu, and nef ) ( Table 1.1) are generally de®ned as dis-
pensable for viral replication based on studies in tissue culture systems. On the
other hand, accessory genes are expressed in vivo and increasing data indicate
that they play important roles in the virus-host interplay.
MOLECULAR CORRELATES AND DYNAMICS OF HIV ACTIVITY
IN VIVO
The relevant data on mechanisms of HIV replication have been coupled with
the results from in vivo studies, thus obtaining a precise understanding of the
virus-host relationships. Indeed, natural history and pathogenicity studies have
supplied a pro®le of HIV activity during the di¨erent phases of this infection,
have contributed to a better understanding of virus-host interactions, have
allowed the application of mathematical models to evaluate the intrahost HIV
dynamics, and, ®nally, have provided a theoretical basis for therapeutic anti-
viral intervention.
In vivo, systemic HIV activity is a formal entity that consists of a sum of
dynamic processes, including productive infection of target cells, release of
virions outside the infected cell and eventually in the blood compartment, and
