In recent years the life expectancy of human immunodeficiency virus (HIV) infected individuals has dramatically increased due to antiretroviral therapies (ART). However, while ART successfully controls viral replication, a significant number of HIV infected individuals display accelerated symptoms of aging-related diseases, such as cardiovascular disease. Because HIV does not productively infect the heart itself, this is thought to be due to indirect effects of HIV and ART on heart tissue. However, the mechanisms that mediate HIV cardiotoxicity are still very poorly understood. Based on our preliminary studies, we propose that HIV and its proteins target connexin43 (Cx43) containing channels – gap junctions (GJ) and unopposed hemichannels (uHC) – to elicit and spread metabolic/electrical dysfunction and inflammation in cardiomyocytes.

GJs are formed by docking of two uHC on the surfaces of contacting cells and serve to connect the cytoplasm of these cells. GJ facilitate cell-cell communication, including electrical, metabolic and calcium waves required for efficient cardiac muscle contraction. Our laboratory recently demonstrated that undocked uHC connect the cytoplasm with the extracellular space and facilitate the release of intracellular inflammatory factors. Both GJ and uHC enable the diffusion of molecules up to 1.2 kDa, including second messengers, ions, ATP, prostaglandins, small peptides and RNA. Cx43, a major component of both GJ and uHC, is abundantly expressed in the heart, and defects in Cx43 expression or localization are associated with arrhythmias, sudden death, cardiac malformation and heart attacks.  Interestingly, we recently obtained evidence indicating that HIV infection alters Cx43 expression, localization, and channel function. We also found that HIV-tat binds directly to Cx43 promoter, potentially mediating Cx43 expression and function changes. HIV infection also promoted the opening of uHC, allowing the release of pro-inflammatory molecules, such as ATP and PGE2, into the extracellular environment. Consistent with increased uHC opening, we observed high circulating levels of these factors in all HIV infected individuals irrespective of ART and immune reconstitution. We also discovered that hearts obtained from HIV infected individuals had altered Cx43 localization: in HIV infected heart tissue Cx43 was not localized normally at the intercalated disks but instead had a lateralized distribution often associated with heart disease. All areas with compromised Cx43 localization showed signs of calcium overload, mitochondrial dysfunction, and muscle compromise which were independent of viral replication, immune reconstitution or comorbidities. Based on these results we have formulated the hypothesis that “HIV and its proteins upregulate Cx43 expression and alter Cx43 localization in cardiomyocytes, compromising the formation of intercalated disks, calcium coordination and electrical conduction, contributing to cardiovascular disease”.  The proposed studies will elucidate the mechanisms of heart damage operating in HIV-infected individuals during the current antiretroviral era and may guide therapies designed to reduce the devastating consequences of heart disease in the HIV infected population.