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 fifteen 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. Also, 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 to the complement system for the treatment and eradications of HIV-1 infection.

Age to End Dreadful Diseases (HIV, Malaria, TB, Cancer and More): A Theory of Intact or Protected Complement (IPC) Immunity

“…It is confirmed that HIV-1 virions isolated from infected individuals have accumulated C3 on their surface, a signal of the initiation of complement reactions, but HIV-1 virions are still very resistant to complement mediated killing, which is a different phenomenon of humoral immune responses induced from the most invaded pathogens [32]. More and more experimental and clinical evidences indicate that MAC pores supposed to be seen on the surface of invaded pathogen are not effectively formed in the case of HIV infection, leading to the escape of virus and all over spreading through the blood and lymph systems in HIV patients [53,54].…”

“…The complement-mediated lysis could be further enhanced through the addition of a blocking antibody against CD55; however, FH binding was shown to be responsible for most of the resistance mechanism in both cases. It has been confirmed that resistance to human complement can be completely overcome if Decay accelerating factor (DAF)/CD55 and FH are set out of function [32, 53,54].…”

Soluble membrane attack complex in the blood and cerebrospinal fluid of HIV-infected individuals, relationship to HIV RNA, and comparison with HIV negatives

“…Natural killer cell activation is present in the setting of HIV and does not normalize despite virologic suppression during cART (Lichtfuss et al, 2012). Additionally, activation of the complement system has been recognized since the early years of the HIV epidemic (Liu et al, 2014, Senaldi et al, 1990). It is possible that the complement system plays a role in HIV neuropathogenesis.…”

The complement system, neuronal injury, and cognitive function in horizontally-acquired HIV-infected youth

“…Complement is activated early in HIV infection via a variety of mechanisms, but it fails to eradicate HIV from infected cells and from the circulation due to the presence of complement regulators within the HIV-1 envelope and on infected cells (Liu et al 2014). Instead, HIV uses complement activation to spread and enhance systemic infection (Liu et al 2014). The role of complement in the neuropathogenesis of HIV is less well understood.…”

“…The role of complement in the neuropathogenesis of HIV is less well understood. Local HIV infection induces C3 production in neuronal and glial cell lines incubated with HIV and in parallel downregulates normal complement inhibitor proteins (CD59) (Stephan et al 2012; Liu et al 2014). In a simian immunodeficiency virus (SIV) model, cerebral synthesis of C1q and C3 was upregulated compared to controls and deposited on neuronal membranes (Speth et al 2004).…”