The impact of cytotoxic T lymphocytes on the lifespan of productively infected cells in HIV infection

It is widely assumed that T-cell immunity is required to control HIV-infection,
and current vaccines are developed based on that premise. This is supported by
the fact that certain HLA-molecules are very clearly associated with relatively
slow rates of HIV disease progression, suggesting that CTL (cytotoxic (CD8+) T
lymphocyte) responses restricted by these HLA molecules successfully control
virus replication. Nevertheless, recent studies in rhesus macaques have shown
that the lifespan of productively infected cells is independent of the presence
or absence of CD8+ T cells. These findings have seriously questioned the role
of CTL in shortening the lifespan of HIV-infected cells in humans.
In this study, we aim to reconcile these contradicting findings about the role
of CTL in HIV infection. We postulate that CTL*s are required to control HIV
infection, but only a very distinct group of patients can generate a
*protective CTL response* which is most likely restricted by HLA-alleles
associated with slow progression to AIDS. There is increasing evidence that CTL
responses targeting the HIV-gag protein play an important role in delay of
disease progression. We hypothesize that in patients with such protective CTL
responses the lifespan of productively infected cells is shortened.

The primary objective of this study is to explore if (and which) HIV-specific
CTL responses shorten the lifespan of productively infected cells in
HIV-infected individuals. This will be accomplished by investigating the
estimated life spans of productively infected cells in different HIV-infected
individuals and correlating them with i) the characteristics of the specific
CTL response against the gag protein of HIV, and ii) the presence or absence of
at least one HLA-allele with a low relative hazard of HIV-disease progression
(HLA-A31, B27 or B57).

It has previously been shown that the lifespan of productively infected cells
in HIV-infected individuals can be estimated from the loss of viral load after
successful viral treatment. The rationale of this approach is that during
successful antiretroviral treatment, infection of new cells is prevented, such
that the rate at which the viral load declines after start of antiretroviral
treatment represents the lifespan of productively infected cells before
treatment. We will closely monitor the decline of viral load in patients
directly after the start of their first regimen of highly active antiretroviral
therapy (HAART). In parallel, we will study the lifespan of productively
infected cells by quantifying the number HIV infected cells in different CD4+
subsets over time. The measured lifespan of productively infected cells will be
correlated to different characteristics of the CTL response in these
individuals before start of HAART, and to their HLA-background. Because immune
activation plays a dominant role in HIV infection, we will also measure
different markers of T-cell proliferation and activation.

In total 350 mL of blood will be obtained from each study subject spread over
15 visits (12 months). 6 of these visits coincide with routine visits of the
out-patient clinic during which 20 mL of blood is drawn routinely. 9 visits
within the first 4 months are needed specifically for this study. During these
visits a total of 230 mL blood will be drawn. To accommodate the patients, they
will be offered the option of blood sampling at home. Because viral load is
known to change rapidly after start of HAART, frequent sampling after start of
HAART is necessary to make a reliable estimation of the lifespan of
productively infected cells. We wish to stress that we have tried to keep the
extra visits to an absolute minimum.

The main, group-related, benefit of this study is that the results could gain
us important insights into the role for HIV-specific CTL in the control of HIV,
which are a prerequisite for the successful development of HIV vaccines that
aim to stimulate CTL responses. The insights gained from this project will
specifically help us understand
i) what can be expected from CTL-based HIV vaccines (will they only help
individuals with protective HLA alleles or can the whole population benefit?),
ii) what the correlates of a protective CTL response are,
iii) what a vaccine should contain to boost such a response.
Participation in this study does not have direct advantages for the individual
patient. However, the possibility to see the course of decrease in the HIV RNA
viral load due to its frequent monitoring may provide extra motivation to keep
a good adherence with the antiretroviral medication as it directly illustrates
the effect of the antiretroviral drugs.