Blood, 15 February 2003, Vol. 101, No. 4, pp. 1209-1209
Is SIV infection associated with
CD4+ T-cell depletion?
The progression of HIV disease in humans is characterized by
decreasing blood CD4+ T-cell counts and, during the
asymptomatic phase, increasing CD8 counts. But while the total number
of CD8 T cells in the body likely increases, the fall in CD4 counts is
partly due to redistribution, that is, enhanced trapping of circulating
cells in lymphoid tissues.
Sopper and colleagues (page 1213) report a comprehensive quantitative
study of the changes in lymphocyte numbers in the nonhuman primate
model of HIV infection. This is fundamentally a cross-sectional necropsy analysis of total and proliferating
(Ki-67+) CD4+ versus
CD8+ T cells in a cohort of normal and
SIV-infected rhesus macaques, with or without an "AIDS-defining"
illness. Effort was made to count lymphocytes in samples from all
reasonably accessible sites, weighing the total organ and the
representative sample to calculate total numbers. The main finding is
that CD4 cell numbers increased rather than decreased in asymptomatic
disease, in all the tissues tested except blood. Even in overt AIDS,
the numbers were the same or slightly higher than in uninfected
animals. CD8 numbers showed larger increases everywhere. Thus, CD4 cell
depletion did not seem to be necessary for disease progression, and the
difference between the impact of SIV infection on CD4 and CD8 numbers
appeared to be more quantitative than qualitative, although CD4 T cells are targets for infection by the virus and CD8 cells are not.
This surprising conclusion is consistent with the observation that
SIV-infected macaques often progress to AIDS without a significant
decline in blood CD4 counts and that progression rate may depend more
on the responsive state of CD4 cells than on CD4 T-cell loss (eg, Folks
et al, J Med Primatol. 1997;26:181-189). But the new data
contradict recent studies in macaques that report substantial and
long-lasting depletion of CD4 T cells in the gut lamina propria. Also
surprising is the relatively low estimate for the T-cell content of the
gut, usually considered a major lymphoid organ. In humans, significant
depletion of lymphatic tissue CD4 T cells at all stages of HIV
infection is reported (Schacker et al, J Clin Invest.
2002;10:1133-1139).
Assuming that these findings do not reflect some methodological error
and that the primate model is fundamentally relevant, they can perhaps
be seen in the framework of an ongoing paradigm shift in AIDS research.
Accordingly, disease progression is a multifactorial process driven by
chronic immune hyperactivation induced by antigens and inflammatory
factors. Chronic inflammation impedes immune functions by inducing
functional cellular modifications, local architectural damage to
lymphatic tissue, and selective depletion of "resting"
naive and memory cells, CD4+ and CD8+ alike.
But numbers of activated lymphocytes may increase. The quantitative
differences in CD4/CD8 cells may be more due to physiologic differences
between the subsets than to the selective infection of CD4 cells. In
humans, but perhaps less so in nonhuman primates, such selective
depletion appears to correlate strongly with a generalized CD4 T-cell deficit.
A better resolution of the opposing changes that shape lymphocyte
numbers is required, which could be based in part on detailed criteria
for naive and memory subsets in rhesus macaques reported recently by
Picker and associates. Nevertheless, it becomes evident that,
while blood T-cell counts remain a clinical marker in HIV disease, the
concept of "CD4 T-cell depletion" in itself has limited explanatory
power: one needs to specify who is depleted and where.
Zvi Grossman
Tel Aviv University; National Institute of Allergy and
Infectious
Diseases
