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.