Biology Reference
In-Depth Information
During primary infection, the presence of strong HIV-speci®c CTL has also
been found to correlate with a high number of CD4
cell counts. This correla-
tion was more marked with the presence of env-speci®c CTL. Those patients
with an initially high env-speci®c CTL tend to progress more slowly than
those with relatively lower Env-speci®c CTL in the beginning of their infection
(Musey et al., 1997).
Despite these strong ®ndings and correlation of CTL and control of viral
replication, nearly all individuals ultimately develop acquired immunode®-
ciency syndrome (AIDS) within a decade if untreated. This has led to skepti-
cism as to the value of in vitro measured CTL as it relates to in vivo functions.
It was, however, found that HIV can evade CTL killing by several mechan-
isms ( Price et al., 1997). One mechanism is the presence of naturally occurring
HIV-1 epitopes that impair CTL recognition by induction of anergy. These are
naturally occurring, spontaneous mutations that may or may not play a sig-
ni®cant role in viral escape as the evidence is not conclusive. Other spontaneous
factors described included the lack of proofreading capacity of the HIV-1 rep-
licases, which, coupled with the high viral replication, could lead to a number
of chance mutations that lead to the emergence of fresh epitopes, unknown to
the memory CTL (or unable to bind MHC) thereby escaping recognition and
lysis ( Price et al., 1997; Soudeyns and Pantaleo, 1997).
Studies of adaptive evolution of HIV-1 in the host environment have given
more insight into viral escape mechanisms. These studies were done with due
consideration of the extreme genetic instability of the HIV-1 virus. One such
study focused on the period of the most vigorous CTL responses during pri-
mary infection. The study looked at ®ve HIV-infected individuals with an HLA
B8 allele. Early in the infection, a strong CTL response to an HLA B8-restricted
epitope ( FLKEGGL) that was derived from residues 90±97 of the HIV-1
( HIV-LAI ) Nef protein was seen (Price et al., 1997). One of these patients was
followed for 500 days without antiretroviral therapy (deferred treatment) and
within 22 days following the onset of symptoms, several positively selected
mutations of this epitope that were suboptimal ligands for autologous CTL
were noted. These mutations increased with time and essentially overgrew the
original virus thereby demonstrating escape from CTL lysis.
CTL IN POSTPRIMARY INFECTION
This period could last as long as 10±20 years without treatment. The patient
can be asymptomatic for many years or be symptomatic as early as 2 years
postinfection. The main characteristic of this period is the gradual loss of CD4
cells and corresponding increase in CD8
cells leading to the reversal of CD4
/
CD8
ratio. This period also represents the period of gradual failing of the
immune system and the appearance of opportunistic infections (Miedema and
Klein, 1996). The period ends with the development of AIDS (CD4
<
200/mL) and subsequent death of the patient. Treatment with highly active
