13th Conference on Retroviruses and Opportunistic Infections Denver, Colorado - February 5-8, 2006

Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 38

Jason Brenchley¹, T Schacker², D Price¹, M Larson², A Khoruts², G Beilman², A Haase², and D Douek^1
1Vaccine Res Ctr, NIAID, NIH, DHHS, Bethesda, MD, US and ²Univ Minnesota, Minneapolis, US

BACKGROUND: Recent data have demonstrated that mucosal CD4⁺ T cells are massively depleted during acute HIV infection and that this depletion is maintained throughout chronic infection. Moreover, studies from simian immunodeficiency virus (SIV)-infected macaques suggest that this depletion is the result of direct infection by the virus. Here, we sought to determine the degree to which: viral replication is controlled in mucosal CD4⁺ T cells after short- and long-term HAART; immune activation is reduced in blood, lymph node, and mucosal T cells; these sites are reconstituted with CD4⁺ T cells; and reconstitution of CD4⁺ T cells in different tissues is related to viral replication.

METHODS: We used polychromatic flow cytometry to define stringently and to sort T-cell subsets from inguinal lymph nodes, gastrointestinal tract, and blood. Specifically, we sorted gut-homing CD4⁺ T cells from blood and memory, CCR5⁺, and CCR5^­ CD4⁺ T cells from blood and gastrointestinal tract and we measured T cell activation and T-cell memory subsets from all compartments before and after initiation of HAART. We quantified HIV DNA within sorted T-cell subsets by quantitative real-time polymerase chain reaction. Wilcoxon matched pairs and Spearman’s rank tests were used.

RESULTS: CD4⁺ T cells remained massively depleted from mucosal surfaces despite years of otherwise successful HAART and despite reconstitution of blood CD4⁺ T cells to healthy levels. This finding held even in an individual who initiated HAART pre-seroconversion and maintained a strict HAART regimen for 3 years. Furthermore, T cell activation was not immediately reduced once plasma viral loads were controlled and the frequency of infected CD4⁺ T cells remained higher in mucosal CD4⁺ T cells compared to blood CD4⁺ T cells regardless of HAART duration (including treatment naïve time points).

CONCLUSIONS: These data strongly suggest that HAART does not adequately suppress viral replication at mucosal surfaces and this residual viral replication maintains the depletion of mucosal CD4⁺ T cells. Moreover, this continued depletion may be related to high levels of infection within blood CD4⁺ T cells with a mucosal homing phenotype. Taken together, these data explore the dynamics of reconstitution between different anatomical sites and suggest that ongoing viral replication at particular sites may impair immune reconstitution.

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2006-02-05
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