Biology Reference
In-Depth Information
antiretroviral therapy (HAART) has changed both the morbidity and mor-
tality during this period and some of the immune de®ciencies have been re-
versed. Most opportunistic infections have disappeared since the introduction
of HAART.
The postprimary infection period is a time of high variability in HIV-speci®c
CTL even within a patient (Gamberg et al., 1999). After the attainment of a
quasi-steady state in both viral load and CTL late in primary infection, the ex-
pectation here is that CTL and other immune parameters would maintain good
control of viral replication. The picture, however, is that of failing immune
containment and a decline in absolute and relative CD4
cells following post-
infection lysis of target cells. Viral replication is ongoing at a very high rate
(Perelson et al., 1997). This period is also dominated by the emergence of
the synctitial-inducing (SI ) virus, which utilizes a di¨erent set of coreceptors
(CXCR4) than the NSI virus involved in the initial primary infection (CCR5
coreceptors). This virus is T-cell trophic and its appearance, in most part, cor-
relates with advancing HIV disease.
During this period, diverse epitopes are usually available and CTL responses
may be less e¨ective as a result of the escape mutations taking place (Miedema
and Klein, 1996). The depletion of CD4
T cells caused by the lysis of virus-
infected cells also deprives the system of T-helper activity. This has been sug-
gested as a cause of the failure of CTL to function optimally. Most recently, we
found that a subset of individuals in this period produce TGF-b that accounted
for nonspeci®c inhibition of IFN-g production by CD8
cells.
CTL responses during this period are directed at all of the viral proteins.
Speci®c epitopes for the Env, Gag, Pol, Rev, and Nef proteins have been de-
scribed (Gotch, Gallimore et al., 1996; Haas, Samri et al., 1998). Unlike the
primary infection period where the dominant CTL response is directed at the
Env protein, this period is characterized by a wide range of responses among
individuals and within an individual. CTL response against the Env protein
is complicated by the presence of extensive sequence variations arising from
escape mutations and also by the presence of non-MHC-restricted cell lysis
found to be Env-speci®c. Some studies have shown that Env-speci®c lysis can
actually be inhibited by the use of anti-CD3 and, to some extent, anti-CD8.
Further studies have concluded that both MHC-restricted CTL and antibody-
dependent cell-mediated cytotoxicity (ADCC) are involved in Env-speci®c cell
lysis. The ADCC-mediated killing involved CD16
cells armed with Env-
speci®c cytophilic antibodies. Several overlapping epitopes involving the gp41
and gp120 regions have been described ( Kalams and Walker, 1994).
Most studies however, have shown that the most potent response is seen
against the highly conserved HIV-1 gag gene product at this stage (Johnson et
al., 1991). Indeed, one study involving slow and fast progressors to AIDS has
shown that strong Gag-speci®c CTL in conjunction with lower HIV-infected
CD4
cells correlates with slow but not fast progression to AIDS (Kalams and
Walker, 1994). Gag is a p55 protein that is cleaved to four other subunitsÐp6,
p7, p17, and p24. Most of the Gag-speci®c CTL response is directed at the
