Abstract
The integrity and function of the gut is impaired in HIV-infected individuals, and gut pathogenesis may play a role in several HIV-associated disorders. Methamphetamine is a popular illicit drug abused by HIV-infected individuals. However, the effect of methamphetamine on the gut and its potential to exacerbate HIV-associated gut pathology is not known. To shed light on this scenario, we evaluated colon barrier pathology in a rat model of the human comorbid condition. Intestinal barrier integrity and permeability were assessed in drug-naïve Fischer 344 HIV-1 transgenic (Tg) and non-Tg rats, and in Tg and non-Tg rats instrumented with jugular cannulae trained to self-administer methamphetamine or serving as saline-yoked controls. Intestinal permeability was determined by measuring the urine content of orally gavaged sugars. Intestinal barrier integrity was evaluated by immunoblotting or immunofluorescence of colon claudin-1 and zonula occludens-1 (ZO-1), two major tight junction proteins that regulate gut epithelial paracellular permeability. Both non-Tg and Tg rats self-administered moderate amounts of methamphetamine. These amounts were sufficient to increase colon permeability, reduce protein level of claudin-1, and reduce claudin-1 and ZO-1 immunofluorescence in Tg rats relative to non-Tg rats. Methamphetamine decreased tight junction immunofluorescence in non-Tg rats, with a similar, but non-significant trend observed in Tg rats. However, the effect of methamphetamine on tight junction proteins was subthreshold to gut leakiness. These findings reveal that both HIV-1 proteins and methamphetamine alter colon barrier integrity, and indicate that the gut may be a pathogenic site for these insults.
Highlights
Combined antiretroviral therapy is highly efficacious in controlling HIV plasma viral replication, and cART-adherence profoundly improves health
We studied the intestine from rats that model key aspects of the human comorbid condition, i.e., HIV-1 transgenic (Tg) rats trained to self-administer methamphetamine
Using the non-infectious HIV-1 Tg rat model of HIV-infected humans on cART, we describe increased colon barrier permeability associated with the expression of toxic HIV-1 proteins and alteration of tight junction protein expression
Summary
Combined antiretroviral therapy (cART) is highly efficacious in controlling HIV plasma viral replication, and cART-adherence profoundly improves health. HIV enteropathy occurs during the acute phase of infection and throughout the advanced disease state, and it persists in patients on cART [1,4]. The structure of the intestinal epithelium is maintained by a complex interaction of tight junction proteins that regulate diffusion of toxins, microbes and various molecules from the lumen into the lamina propria and systemic circulation. A reduction or morphological redistribution in sealing tight junction proteins can lead to intestinal hyperpermeability, so that contents normally restricted to the lumen (e.g., lipopolysaccharide, LPS) may translocate into the lamina propria and circulation to promote systemic inflammation [11]. In HIVinfected patients, reduced tight junction proteins such as claudin-1, claudin-7 and ZO-1 in the colon and small intestine is associated with increased intestinal permeability, increased LPS translocation, and increased systemic inflammation [12]
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