Information Technology Reference
In-Depth Information
frequently from one RNA template to the other during reverse transcription, produc-
ing a DNA copy that is a recombinant of the two RNA copies of the genome. Such
recombination has recently been reported to occur at a rate two orders of magnitude
higher than the mutation rate (~10
-3
crossovers per nucleotide per replication cycle
(Levy, Aldrovandi, Kutsch, and Shaw
2004)). The end result is a double-stranded
DNA copy of the viral genome that is then integrated into the host genome. This
provirus, as the integrated viral genome is called, is eventually transcribed to RNA,
and the RNA translated to protein, by cellular enzymes. Pairs of newly transcribed
strands of viral RNA are packaged into virions formed by newly translated viral
proteins, and these are budded from the host cell as free virions. The entire cycle
takes about 2 days when an activated T-cell is infected
(Perelson, Neuman, Markovitz,
Leonard, and Ho 1996).
9.2.1 The V3 Loop
A virion's interaction with cell-surface chemokine coreceptors during the infection
process is largely determined by the V3 loop of gp120 on the virion surface
(Sharon,
Kessler, Levy, Zoller-Pazner, Gorlach, and Anglister 2003). V3 is a loop of 35
amino acids (typically) defined by a disulfide bond between terminal cysteine resi-
dues. The amino acid sequence of V3 appears to be the primary determinant of
which chemokine coreceptor, CCR5 or CXCR4, is used to enter a cell, or whether
both coreceptors may be used. Hence, virions may be classified by their chemokine
coreceptor-utilization phenotype as exclusively CCR5-utilizing (R5), exclusively
CXCR4-utilizing (X4), or dual tropic (R5X4). This aspect of a virion's phenotype is
important because it determines which cells a virion may infect and because the X4
phenotype has been linked to increased disease pathogenesis
(Mosier 2000).
V3 is also a target of neutralizing antibodies; antibodies that bind to V3 may in-
terfere with chemokine coreceptor interactions. Twenty-two monoclonal antibodies
that target V3 and neutralize primary HIV-1 isolates have been isolated from humans
infected with HIV-1 subtype B, the main North American and European subtype.
These antibodies are listed in the HIV Molecular Immunology Database. These anti-
bodies recognize linear epitopes from the central region of V3, and amino acid
changes in this region have been implicated in escape from neutralization
(McKeating,
Gow, Goudsmit, Pearl, Mulder, and Weiss 1989; McKnight, Weiss, Shotton, Takeu-
chi, Hoshino, and Clapham 1995; Yoshida, Nakamura, and Ohno 1997). Other stud-
ies suggest that polyclonal antibodies in human sera that are capable of neutralizing
HIV-1 target conformational V3 epitopes
(Gorny, Williams, Volsky, Revesz, Cohen,
Polonis, Honnen, Kayman, Krachmarov, Pinter, and Zolla-Pazner 2002). Unfortu-
nately, these epitopes have not been described.
9.2.2 The Neutralizing Antibody Response and the HIV-1
Adaptive Response
Recent studies have laid to rest any doubt that there is a strong neutralizing antibody
response to HIV-1 and that the virus evolves in response to the resulting selection
(Wei,
Decker,
Wang,
Hui,
Kappes,
Wu,
Salazar-Gonzalez,
Salazar,
Kilby,
Saag,
