E5 A Convenient Mouse Model for Acute HIV Infection Mimicking Pathogenesis in Humans

Abstract

We have developed a convenient and easy to use mouse model for acute HIV infection. In this approach, human peripheral blood mononuclear cells (PBMC) are inoculated intraperitoneally (IP) into IL-2R gamma chain knockout NOD-SCID mice 4–8 weeks of age. Engraftment is confirmed by detection of human cells in mouse blood at week 3, and subsequently. In infection experiments described here, mice were inoculated with a population of PBMC containing 48%. CD3+ cells; 28% were CD4+. (Few PBMC are CCR5+.) At day 20 following inoculation, human CD3+ cells comprised ∼11% (range 7%–16%) of circulating leukocytes in the animals. Of the T-cells, 29% (19%–36%) were CD4+, 45% (34%–56%) of which were CD4+CCR5+. The CD4:CD8 ratio was 1:2.45 (1.8–3.7). On day 21, the mice were inoculated IP with R5-tropic HIV Ba-L at a dose of 174ng p24. The mice were observed for evidence of HIV infection based on (1) CD4+ T-cell depletion in blood, spleen and bone marrow, (2) detection and relative measure of HIV DNA in tissues using PCR and (3) plasma viremia. The kinetics of CD4+CCR5+ T-cells in blood was also assessed. On day 30 following HIV infection, 2.4% (0.06%–7.5%) of total circulating leukocytes were human CD3+CD4+ cells, and 31% were human CD3+CD8+ cells. The mean human CD4:CD8 ratio was 1:35 (range 7.5%–71%). Of the CD4+ T-cells, 13% were CCR5+. CD4 T-cell depletion with preferential loss of CCR5+ cells was also found in tissues. Plasma viremia averaged 2104 pg/mL at day 7 and 163 pg/mL at day 30 post inoculation. HIV DNA was detected in blood and tissues. These results demonstrate significant acute HIV infection in this strain of mice characterized by parameters that mimic infection in humans. Most notably, there was selective depletion of CCR5+ CD4+ T-cells. Advantages of this model include engraftment following IP inoculation of PBMC, and also establishment of HIV infection using IP inoculation.