Biology Reference
In-Depth Information
infections of T-cell lines, primary PBMCs, and monocytes/macrophages sup-
ports these ®ndings.
INTER- AND INTRASUBJECT HIV VARIABILITY
Comparative analysis of the sequences of the HIV env gene from a great
number of viral isolates has revealed a pattern of ®ve hypervariable regions
(designated V1 to V5) interspersed with more conserved sequences in the gp120.
This sequence variation consists of mutations (resulting in amino acid sub-
stitutions), insertions, and deletions ( Leigh-Brown, 1991). Among HIV isolates
from geographically di¨erent locations, gp120 amino acid sequences may di-
verge up to 20±25%, whereas other regions of the genome are relatively con-
served. More recently, molecular epidemiology surveys based on env sequences
of numerous HIV isolates have revealed at least nine distinct HIV subtypes (or
clades) in the acquired immunode®ciency syndrome (AIDS) pandemic (Myers,
1994; Myers et al., 1994) (intersubject HIV variability).
Subsequent analysis has revealed that both linear and conformational de-
terminants in¯uence the functional and antigenic structure of the gp120; this is
a crucial pathogenic issue, inasmuch as all neutralizing antibodies are directed
against env-encoded domains in HIV-infected hosts. Indeed, infections with
retroviruses are also characterized by di¨erent (from moderate to high) levels of
intrahost viral genetic variation. This viral variability is dependent upon muta-
tion, recombination, degree of viral replication, and the host's selective pressure
(Dougherty and Temin, 1988; Hu and Temin, 1990; Pathak and Temin, 1990a,
b; Temin, 1993). In HIV infection, the viral population is represented by re-
lated, nonidentical genetic variants (Goodenow et al., 1989; Hahn et al., 1996;
Meyerans et al., 1989; Pedroza Martins et al., 1992), designated quasispecies.
The error-prone nature of the HIV reverse transcriptase ( RT) and the absence
of a 3
0
-exonuclease proofreading activity determine in vitro about 3 10
ÿ5
mutations per nucleotide per replication cycle (Yu and Goodman, 1992).
Although the mutation rate observed in vivo is lower than that predicted from
the ®delity of puri®ed RT (because a number of newly generated variants are
unable to replicate or are cleared by the host's immune system) (Mansky and
Temin, 1995), the viral replication dynamics (Ho et al., 1995) and the host's
selective forces determine a continuous process of intrahost HIV evolution
(Bagnarelli et al., 1999; Holmes et al., 1992; McNearney et al., 1992; Wolinsky
et al., 1996). Overall, the data currently suggest that viral genetic variability is
the molecular counterpart of a continuous dynamic interplay between viral
(i.e., HIV-1 replication dynamics and generation of variants by mutation and
recombination) and host factors (i.e., selective pressure). In this context, intra-
host evolution of HIV-1 populations may be compatible with a Darwinian
model system, as recently suggested ( Bagnarelli et al., 1999; Ganeshan et al.,
1997; Wolinsky et al., 1996).
The complete elucidation of the mechanisms driving intrahost HIV-1 evolu-
