Memory compartment regeneration in SIV infection does not rely on naive CD4 T cells

Among mechanisms hold responsible for the severe CD4 T cell depletion in AIDS are those that contribute to increased apoptosis rates for CD4 T cells (either infected or non-infected) and decreased CD4 T cells regeneration capacity. Pathogenic HIV/SIV clones are in their majority CCR5-tropic. CCR5 is expressed on tissue-resident effector memory CD4 T cell populations and not surprisingly these subsets are decimated during the primary HIV/SIV infection. However, the CCR5-negative central memory subset which resides in secondary lymphoid organs is relatively spared and may form the reservoir for the subsequent effector memory subsets regeneration. The publication I have found investigates details of memory CD4 T cells renewal in non-human primate model infected with SIV and makes an intriguing point about what is not needed to bring back depleted memory compartments.

The link: http://jem.rupress.org/content/209/4/641.abstract

The chief aim of this paper is to assess whether naïve CD4 T cells presence is needed for the memory compartment replenishment during pathogenic SIV infection. Authors employed rhesus macaques and subjected them to a number of manipulations before proper infection. Briefly, experimental groups have been either thymectomized or left intact and subsequently CD4 T cells in each group were depleted with anti-CD4 antibody following which animals were left to regenerate CD4 T cell counts. Such approach allows comparing regeneration of memory subsets and general disease outcome between two different conditions – complete lack vs. normal level of naïve CD4 T cells. If you have read my previous post, note that this report assumes that the thymus is the only place of significant naïve CD4 T cell development.

After complete rebuilding of CD4 T cells counts took place animals from each group were infected with SIVmac239. Then they underwent the long data collection period which included initial untreated infection, anti-retroviral therapy phase and treatment discontinuation in order for animals to develop AIDS-like symptoms. Investigators amassed data relating to multiple parameters – most notably they followed plasma viral load, memory CD4 T cells depletion levels (in blood and at mucosal lung surfaces) and the presence of anti-SIV adaptive immunity over the entire span of experiment. They also observed the disease progression and appearance of opportunistic infections in both groups. The summary conclusion of this study is that in the course of pathogenic SIV infection naïve CD4 cells presence is not necessary for the regeneration of memory CD4 T cells subsets. Additionally, the depletion of naive CD4 T cells do not seem to influence the disease advancement.

Major findings of this publication are very convincing and well supported with data. However, I would like to pose one question – it looks like the depletion of naive CD4 T cells in thymectomized group impairs the scope of adaptive anti-SIV response. For example, anti-SIV CD4 T cell responses (defined as the percentage of memory compartment specific to gag+pol+env+nef) never really start working. Thymectomized animals show much slower seroconversion rate and blunted anti-SIV CD8 T cell reactions as well. Yet the general disease outcome between both groups is remarkably similar at all studied stages. How to explain it?

Okoye, A., Rohankhedkar, M., Abana, C., Pattenn, A., Reyes, M., Pexton, C., Lum, R., Sylwester, A., Planer, S., Legasse, A., Park, B., Piatak, M., Lifson, J., Axthelm, M., & Picker, L. (2012). Naive T cells are dispensable for memory CD4+ T cell homeostasis in progressive simian immunodeficiency virus infection Journal of Experimental Medicine, 209 (4), 641-651 DOI: 10.1084/jem.20112071

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