Rebounding HIV After ART Interruption Does Not Seem To Come From Gut
A recent study on 3 patients who initiated ART during primary HIV infection and decided to stop it thereafter shows that GALT was not the major contributor to rebounding plasma viremia nor were GALT HIV reservoirs rapidly replaced by rebound variants.
Previous studies from this group demonstrated that HIV infection leads to severe CD4+ T cell depletion in gut and that CD4+ T cell restoration in GALT during ART is modest.
As resurging virus after ART interruption is dissimilar from both cell-associated HIV RNA and virus found in resting CD4+ T cells, it is admitted that other compartments, like the gut, may contribute to viremia rebound.
In the present study (1) the authors evaluated longitudinal changes in HIV replication, viral evolution and compartmentalization between GALT and PBMC in 3 patients opting to stop ART after several months of treatment following acute infection.
In these cases, plasma, PBMC and jejunal tissue samples were available.
All three cases experienced a striking increase in plasma viremia following ART interruption. However, all 3 patients maintained CD4+ T cell counts within the range of 500-1500 cells/mm3 for at least 2 years after cessation of therapy.
On the contrary, ART interruption produced a severe loss of gut mucosal CD4+ T cells. This loss coincided with an increase in CD8+ T cells. The magnitude of this CD4+ T cell loss suggested that the gut mucosal system was highly susceptible to HIV infection when ART suppression was removed.
The HIV population from plasma during primary HIV infection showed low diversity comparable to low diversity also found in proviral sequences from GALT and PBMC. However, plasma viral populations showed a significant increase in genomic diversity following ART interruption as compared to viremia prior to ART. Proviral sequences in GALT showed a lack of divergence from the early founder HIV sequences throughout the course of the study.
These findings support the view of dampened viremia in GALT compared to blood after ART cessation and suggest that the gut reservoir is not a significant source for rebounding systemic viremia following therapy interruption.
Proviral envelope sequences from GALT, PBMC and plasma showed that, during acute infection GALT and PBMCs may contribute to plasma viral divergence but that following ART cessation, resurging plasma viremia does not result from seeding by those compartments. However, this does not exclude the participation of other parts of the gut, than the jejunum, which were not analyzed.
This study also suggests that CD4+ T cell depletion in GALT during therapy interruption is largely the result of immune-based pathogenic events or the result of productive infection leading to rapid T cell killing with little reseeding of cellular reservoirs.
1-Lerner P, Guadalupe M, Donovan R, Hung J, Flamm J, Prindiville T, Sankaran-Walters S, Syvanen M, Wong JK, George MD, Dandekar S. Gut mucosal viral reservoir in HIV infected patients is not the major source of rebound plasma viremia following HAART interruption. J Virol. 2011 Feb 23. [Epub ahead of print]
Key words: hiv gut, hiv rebound, hiv reservoirs