Modulation Effect of HIV-1 Viral Proteins and Nicotine on Expression of the Immune-Related Genes in Brain of the HIV-1 Transgenic Rats

Abstract

The human immunodeficiency virus-1 transgenic (HIV-1Tg) rat is a non-infectious rodent model for HIV-1 infection which develops altered immune-responses similar to those in persons infected with HIV-1. HIV-1Tg and F344 rats respond significantly different to morphine, ethanol, nicotine and other psychostimulants, although the molecular mechanisms underlying these differences remain largely undetermined. Here, we compared expression of 52 immune-related genes in the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA) of HIV-1Tg and F344 rats treated with either nicotine (0.4 mg/kg nicotine, base, s.c.) or saline for 27 days, to identify differentially expressed genes in the presence of HIV-1 with and without nicotine treatment. Using quantitative RT-PCR array, we measured RNA expression levels. Results showed that RNA expression of CASP3, CCL5, CX3CL1, CX3CR1, IL1α, LRF4, LFR7, TGFβ1 and TLR4 in NAc, CCL2, CCL5, TGFβ1 and TLR4 in PFC, and CASP3, CX3CR1, IFNα1, IL1β and IL6 in VTA was significantly modulated in HIV-1Tg rats compared with F344 rats. IL1α showed a 58 % (P = 0.000072) decrease and IRF6 showed a 93.7 % increase (P = 0.000227) in the NAc of HIV-1Tg compared with F344 rats; results remained significant after correction for multiple testing. We also found that several genes were significantly modulated by nicotine in HIV-1Tg rats while only a small number of immune-related genes were altered by nicotine in F344 rats. These findings imply that HIV-1 viral proteins greatly impact immune function and alter responsiveness to nicotine in certain immune-related genes.

Keywords: CNS immunity; HIV-1 transgenic rat; Nicotine; Nucleus accumbens; Prefrontal cortex; Ventral tegmental area.

Figure 1

Regulatory effects of nicotine and HIV-1 viral proteins on IRF4 and IL1α in the nucleus accumbens of the HIV-1Tg and F344 rats following 27 days of either saline or nicotine (0.4 mg/kg) treatment. Nicotine treatment had a significantly different effect on IRF4 and IL1α expression in the nucleus accumbens of HIV-1Tg and F344 rats. Expression levels are reported as fold increase in mRNA levels. See Table 2 for detailed statistical analysis results (N = 5–6 animals per group).

Figure 2

Regulatory effects of nicotine and HIV-1 viral proteins on TGFβ1 and TNFRSFF1α in the prefrontal cortex of the HIV-1Tg and F344 rats following 27 days of either saline or nicotine (0.4 mg/kg) treatment. An independent-samples t-test revealed that expression of TGFβ1 and TNFRSFF1α was significantly regulated in HIV-1Tg rats compared to F33 controls. Expression levels are reported as fold increase in mRNA levels. See Table 3 for detailed statistical analysis results (N = 5–6 animals per group).