Antiretroviral therapy prior to acute viral replication preserves CD4 T cells in the periphery but not in rectal mucosa during acute simian immunodeficiency virus infection

Abstract

The rectal mucosa is a major site for human immunodeficiency virus entry and CD4 T-cell depletion. The early and near-total loss of these cells from the rectal mucosa severely compromises the ability of the mucosal immune system to control various opportunistic infections. Protecting these cells from infection and destruction can delay disease progression, leading to a better long-term outcome. Here we show that effective suppression of viral infection in memory CD4 T cells from the rectal mucosa and peripheral blood to a very low level with antiretroviral therapy (ART) initiated prior to the peak of infection is associated with opposite outcomes in these tissues. A near-total loss of CD4 T cells in the rectal mucosa contrasted with preservation of most memory CD4 T cells in peripheral blood during the course of treatment. Interestingly, ART significantly reduced viral infection in memory CD4 T cells from both rectal mucosa and peripheral blood. Although early ART was of limited value in protecting the CD4 T cells in the rectal mucosa, the significant preservation of peripheral CD4 T cells could contribute to maintaining immune competence, leading to a better long-term outcome.

FIG. 1.

Kinetics of plasma viral loads. Plasma viral loads peaked at day 14 in untreated animals, whereas they peaked at day 10 in animals treated with ART starting at day 7 p.i. There was a significant suppression of viral replication between days 10 and 14 p.i. in animals that received ART. Lines indicate mean values. The limit of detection is <30 copies/ml of plasma. *, significant; ns, not significant.

FIG. 2.

Dynamics of memory CD4 T cells in the rectal mucosa and peripheral blood. ART was initiated at day 7 p.i., and data are shown for peripheral blood and rectal mucosa from animals that were treated with ART (n = 4) and animals that were not treated with ART (n = 4). Naïve and memory CD4 T cells were discriminated on the basis of CD28 and CD95 expression, with all memory CD4 T cells expressing CD95. Acute infection was associated with a significant decrease in the frequency (a) and absolute count (c) of memory CD4 T cells in peripheral blood of untreated animals, whereas there was no significant difference in the animals that received ART. (b) Unlike in peripheral blood, there was a significant loss of CD4 T cells in the mucosae of both untreated and treated animals by day 63 p.i. compared to day 10 p.i. and preinfection values. Lines represent mean values. P, preinfection samples collected at −day 28; *, significant; ns, not significant.

FIG. 3.

Kinetics of cell-associated viral loads during early ART. Far fewer cells were infected in animals that received ART at day 7 p.i. The cell-associated SIV gag DNA levels in sorted memory CD4 T cells in peripheral blood (a) and rectal mucosa (b) were determined for untreated animals (n = 4) and compared to animals that received ART (n = 4). ART significantly suppressed viral transcription in memory CD4 T cells from both peripheral blood and rectal mucosa within days of initiating therapy. Error bars represent standard errors. *, significant; ns, not significant.