The Large Intestine is the Major Viral Reservoir and Site of Persistence
An original simian model of long-term non progression shows that the large intestine -rather than the small- is the main location of persistent SIV. According to the authors 'vaccine or antiviral therapy studies can be evaluated by rectal or colon biopsies without the need to examine biopsies from the small intestine', a different finding of what was recently reporded in humans (See here).
Ronald Veazey and his team (1) used Chinese rhesus macaques (Chinese RM) infected with SIVmac. In this model, 70% of animals develop AIDS and 30% are long-term non progressors (LTNP) with, usually, undetectable viremia. Actually, LTNP was defined as persistent low (<1,000 c./ml) to undetectable viremia for months and survival for more than 36 months. In this study, 7 SIV-infected LTNPs and 5 progressors were compared for viral burden in blood and tissues.
Viral RNA in different tissues from LTNPs:
- In the LTNP group, 5 out of 7 animals had undetectable cell-associated viral RNA in PBMC;
- However, viral RNA was detected in all colon specimens and in 5 out of 7 jejunum specimens.
Quantitatively, mean viral RNA levels were also significantly higher in colon specimens and adjacent lymph nodes (LN) than in PBMC.
In contrast, all progressors had detectable viral RNA in all compartments, with significantly higher levels in intestinal tissues than in blood, but lower than in LTNPs.
The large intestine was a major site for viral persistence even when viral RNA was undetectable in peripheral blood of LTNPs.
Researchers also determined a 'target cell index' corresponding to the number of cells expressing CD4 and CCR5 in a sample. This index was not different between blood and LN, but showed differences at the gut level:
- In LTNPs, as in controls, colon specimens had significantly higher levels of target cells than did jejunum specimens;
- In progressors, few target cells remained in jejunum and colon specimens.
Ki-67 was also used to measure cell proloferation in these animals: proliferation was higher in the colon in LTNPs ,and jejunum went second in those with progressive disease.
The distribution of naive, central memory and effector memory CD4+ T cells was similar in blood, jejunum and colon, both for LTNPs and progressors. In general, naive CD4+ T cells were predominant in LN and blood, whereas most CD4+ T cells in gut had a TCM phenotype, both in colon and jejunum.
These date provide evidence that the large intestine is the major site of viral persistence in LTNPs with undetectable viremia. This tissue may provide a better milieu for viral persistence than does jejunum or other lymphoid tissues due to the large proportion of naive T cells, activation status, CCR5 expression and environmental antigens. In contrast, in the jejunum, most CD4+ T cells have an activated memory phenotype and are eliminated in early SIV infection.
Activated CD4+ T cells from colonic sources then migrate to draining lymph nodes and blood.
1-Ling B, Mohan M, Lackner AA, Green LC, et al. The Large Intestine as a Major Reservoir for Simian Immunodeficiency Virus in Macaques with Long-Term, nonprogressing Infection. J Infect Dis 2010; 202 (12): 1846-1854.
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Key words: HIV, Ki-67, SIV, activation, colon, intestine, jejunum, macaque, memory, naive, persistence, reservoir, simian