Biology Reference
In-Depth Information
1993, 1994) at least in part derives from the observation that HIV replication is
relatively controlled in the initial phases of the infection, when the immune
system is powerful and still relatively undamaged.
A long period of clinical asymptomaticity follows primary HIV infection.
This phase is initially characterized by low HIV viral load, reduced HIV repli-
cation in peripheral blood mononuclear cells ( PBMC), and low HIV isolabil-
ity from PBMC ( Levy, 1993). In this period, HIV replicates vigorously within
the lymphatic tissues (Pantaleo et al., 1993). CD4 T-helper cell functions are
nevertheless often disrupted even in the earlier phases of asymptomatic HIV
infection (Clerici et al., 1989). The defects detected in T-helper function of
asymptomatic, HIV-infected individuals are epitomized by the impairment of
the ability of these cells to proliferate and secrete IL-2 in response to nominal
antigens (Clerici et al., 1989). The T-helper defects observed in this phase of the
disease are independent of CD4 counts (Clerici et al., 1989) and predictive for
the subsequent rate of decline in the number of CD4
T lymphocytes (Dolan
et al. 1995), time to onset of AIDS, and time to death ( Dolan et al. 1995).
Abnormalities in T-helper integrity include, besides the defects in IL-2 produc-
tion, a series of other alterations, among which reduced IL-2 receptor expres-
sion ( Prince et al., 1984), preferential loss of the naive T-cell subset ( Roeder
et al., 1995), and down-regulation of the expression of the z chain of the T-cell
receptor ( Trimble and Lieberman, 1998) may have an important role in disease
progression.
In the period of clinical asymptomaticity, the ability of T lymphocytes to
produce cytokines other than IL-2 upon antigenic stimulation is impaired as
well, and this impairment appears to be pivotal in the progression of the infec-
tion. To summarize, in vitro stimulation of blood leukocytes from HIV-infected
patients results in decreased production of IL-2, IFNg, and IL-12 and in in-
creased production of IL-4, IL-5, IL-6, and IL-10 (Clerici and Shearer, 1993,
1994). Decreased IL-2 production and increased IL-10 generation (and the
IL-10/IL-2 ratio) are associated with the isolation of syncytium-inducing ( X4)
strains of HIV (Clerici et al., 1996a), whereas the opposite scenario ( potent
type-1 cytokine secretion and weak production of type-2 cytokines) is corre-
lated with a condition of long-term nonprogression (Clerici et al., 1996b). Thus,
even in the period in which clinical latency is observed, HIV infection is im-
munologically and virologically extremely active and destructive. From a viro-
logical point of view, the remarkably fast rate of HIV replication, and the
enormous ability of this virus to modify in response to exogenous (pharmaco-
logic) and endogenous (immune system) selective pressure, is underlined by the
observation that a wild-type, drug-susceptible HIV strain can be totally re-
placed by a mutant, drug-resistant strain within 2±4 weeks after initiation of
antiretroviral therapy (Ho et al., 1994).
The end of the period of clinical latency coincides with the onset of signs and
symptoms of AIDS, the rapid destruction of CD4
T lymphocytes, and a sig-
ni®cant increase in HIV viral load.
