Differential Levels of Soluble Inflammatory Markers by Human Immunodeficiency Virus Controller Status and Demographics

The use of antiretroviral therapy (ART) has led to a dramatic decline in the mortality rates of individuals infected with human immunodeficiency virus (HIV). However, the life expectancy of patients with HIV may be shorter compared with the general population, even for individuals on ART with relatively preserved CD4+ cell counts [1, 2]. A significant contributor to the excess mortality is likely from non-acquired immune deficiency syndrome (AIDS)-defining events, which represent a growing cause of morbidity and mortality in patients infected with HIV [3, 4]. In particular, patients infected with HIV have been found to be at higher risk for cardiovascular disease and serious cardiac events [5, 6]. One proposed mechanism involves elevated levels of inflammation found in HIV patients on ART compared with those who are HIV-uninfected. Soluble markers of inflammation have been associated with elevated arterial wall inflammation [7] and coronary artery disease [8, 9] in patients infected with HIV. In addition, soluble markers of inflammation have been found to better predict non-AIDS-defining events than cellular markers of T-cell activation [10]. Human immunodeficiency virus-1 elite controllers (ECs) represent an exceptional group of patients who are able to suppress HIV-1 viremia in the absence of ART. Human immunodeficiency virus-1 ECs represent an ideal population to study the effects of HIV low-level viremia on systemic inflammation in the absence of any ART-specific effects. Elite controllers have stronger HIV-specific CD8+ T-cell responses and higher levels of T-cell activation compared with either chronically HIV-infected patients on suppressive ART or HIV-uninfected individuals [11]. Furthermore, T-cell activation has been linked to lower CD4+ T-cell counts in this population [12]. However, relatively little is known about the effects of systemic inflammation and soluble markers of innate immune activation in HIV-1 ECs. There is evidence that ECs have elevated levels of C-reactive protein [13], innate immune system activation [14], and plasma lipopolysaccharide (LPS), which is related to the mucosal translocation of bacterial products and is associated in noncontrollers with elevated levels of soluble monocyte and macrophage markers of inflammation [8]. In addition, we have previously reported increased sCD14 in HIV-1 ECs compared with HIV-suppressed subjects and increased coronary atherosclerosis compared with HIV-uninfected controls [15]. However, the role that chronic low-level viral replication, which can be suppressed with combination ART, has on this phenomenon is unknown. In this follow-up study, we hypothesize that chronic low-level viral replication is associated with systemic inflammation in ECs and in turn with CD4+ T-cell loss. To test these hypotheses, we have (1) expanded both the number of ECs and the types of inflammatory markers tested, (2) evaluated the relationship between low-level viral load and soluble markers of inflammation in HIV-1 ECs, and (3) determined the relationship between soluble markers of inflammation with viral load and CD4+ T cell decline in HIV-1 ECs.