Complement and HIV-I infection/HIV-associated neurocognitive disorders

Abstract

The various neurological complications associated with HIV-1 infection, specifically HIV-associated neurocognitive disorders (HAND) persist as a major public health burden worldwide. Despite the widespread use of anti-retroviral therapy, the prevalence of HAND is significantly high. HAND results from the direct effects of an HIV-1 infection as well as secondary effects of HIV-1-induced immune reaction and inflammatory response. Complement, a critical mediator of innate and acquired immunity, plays important roles in defeating many viral infections by the formation of a lytic pore or indirectly by opsonization and recruitment of phagocytes. While the role of complement in the pathogenesis of HIV-1 infection and HAND has been previously recognized for over 15 years, it has been largely underestimated thus far. Complement can be activated through HIV-1 envelope proteins, mannose-binding lectins (MBL), and anti-HIV-1 antibodies. Complement not only fights against HIV-1 infection but also enhances HIV-1 infection. In addition, HIV-1 can hijack complement regulators such as CD59 and CD55 and can utilize these regulators and factor H to escape from complement attack. Normally, complement levels in brain are much lower than plasma levels and there is no or little complement deposition in brain cells. Interestingly, local production and deposition of complement are dramatically increased in HIV-1-infected brain, indicating that complement may contribute to the pathogenesis of HAND. Here, we review the current understanding of the role of complement in HIV-1 infection and HAND, as well as potential therapeutic approaches targeting the complement system for the treatment and eradications of HIV-1 infection.

Figure 1. Complement activation and regulation

The complement system is activated through three different activation pathways: classical, alternative and MBL cascades. The three complement activation pathways converge at the C3 level. Formation of C3 or C5 convertases as well as the membrane attack complement (MAC), a final activation complex (as highlighted in red text) are regulated by a number of complement regulators (highlighted within black squares). Ab, Antibody; Ag, Antigen; C1-INH, C1-inhibitor; MBL, Mannose-binding lectin; MASP, MBL-associated serine proteases; DAF, decay-accelerating factor; MCP, membrane co-factor protein; CR, complement receptor; C4BP, C4b-binding protein; and MAC, membrane attack complex.

Figure 2. Roles of complement in the pathogenesis of HIV-1 infection and novel approach for inhibition of complement regulators including CD59 with its inhibitor, ILYd4 (domain 4 of intermedilysin)

MBL, Mannose-binding lectin; MAC, membrane attack complex; and Abs, antibodies.

Figure 3. Potential roles of complement in the pathogenesis of HIV-1-related neurodegenerative disorders

Complement enhances HIV-1 infection through interaction of complement receptors with macrophages and lymphocytes, MAC stimulates the migration of HIV-1-infected macrophages and lymphocytes, which may contributes to HIV-1 trafficking to the brain, thereby infecting brain cells such as microglia and astrocytes. These HIV-1 infected brain cells increase the production of complement, leading to the formation of MAC. Increased MAC may induce neuronal damage, which results in HIV-1-related neurodegenerative disorders. BBB, brain blood barrier.