HIV and co-infections

Abstract

Despite significant reductions in morbidity and mortality secondary to availability of effective combination anti-retroviral therapy (cART), human immunodeficiency virus (HIV) infection still accounts for 1.5 million deaths annually. The majority of deaths occur in sub-Saharan Africa where rates of opportunistic co-infections are disproportionately high. In this review, we discuss the immunopathogenesis of five common infections that cause significant morbidity in HIV-infected patients globally. These include co-infection with Mycobacterium tuberculosis, Cryptococcus neoformans, hepatitis B virus, hepatitis C virus, and Plasmodium falciparum. Specifically, we review the natural history of each co-infection in the setting of HIV, the specific immune defects induced by HIV, the effects of cART on the immune response to the co-infection, the pathogenesis of immune restoration disease (IRD) associated with each infection, and advances in the areas of prevention of each co-infection via vaccination. Finally, we discuss the opportunities and gaps in knowledge for future research.

Fig. 1. Chest x-ray of a patient with TB-IRIS showing massive right paratracheal and left anterior mediastinal lymphadenopathy

The patient exhibited evidence of systemic inflammation, including pronounced fever, for many weeks that eventually resolved on corticosteroid therapy.

Fig. 2. Proposed model of TB-IRIS

In the context of severe CD4⁺ T-cell depletion and probable monocyte dysfunction associated with CCL2 deficiency, the immune system defaults to primarily innate immune responses mediated by macrophages, neutrophils, and NK cells. When HIV infection is suppressed by cART, innate and adaptive immune responses against M. tuberculosis recover with expansion of effector memory T cells (Tem). These processes occur in an uncoordinated manner with production of pro-inflammatory cytokines, such IL-6 and TNF-α, that cause inflammation and production of chemokines and cytokines that enhance Th1 responses, such as IL-18 and CXCL10, leading to increased IFN-γ responses against M. tuberculosis antigens.

Fig. 3. LPS and immune activation in HIV-HBV co-infection

Plasma levels of LPS and soluble (s)CD14 (pg/ml) in untreated HIV-HBV co-infection (blue, n=54), HBV mono-infection (red, n=52), and uninfected controls (black, n=10). Individual dots represent a single patient.

Fig. 4. Proposed model of the role of CXCL10 in liver disease in HIV-HBV co-infection

Interferon-γ and lipolysaccharide promote CXCL10 production from hepatocytes. HIV and HBV infection is associated with increased apopotosis of hepatocytes. CXCL10 can induce hepatocyte apoptosis and recruits pro-inflammatory CXCR3-expressing T cells to the liver in turn promoting chronic liver inflammation, ultimately contributing to liver disease progression.

Fig. 5. Increasing HCV-specific and non-specific T-cell responses, and higher antibody levels after commencement of cART in subjects with evidence of HCV IRD compared to those without

Mean IFN-γ spot forming units (SFU) per 10⁶ peripheral blood mononuclear cells in ELISpot assays, and anti-HCV antibody levels, at each time point after commencement of cART for those with HCV IRD (dashed) and without (solid). Error bars indicate standard deviations. HCV NS: non-structural; CEF: Cytomegalovirus/Epstein-Barr virus/Influenza peptides; OD: sample optical density; CO: cut-off value. Reprinted with permission from Cameron et al. (271).