MBL and HIV-1 Related Neuroinflammation and CNS Impairment
Kumud K. Singh, University of California, San Diego
HIV-1 infection of the brain causes neuroinflammation leading to the initiation and expansion of neuronal injury and death. It is important to understand the immune mechanisms underlying HIV-1 neuropathogenesis and associated central nervous system (CNS) impairment for developing effective therapeutics. In California only, about 139,000 individuals were HIV-1 infected at the end of December 2005 (out of 956,000 infections from USA) as reported by Centers for Disease Control and Prevention. HIV-1 is detected early in CNS and HIV-1 related CNS impairment is likely to be prevalent in 40% of these individuals by the development of encephalitis, minor cognitive motor dysfunction (MCMD) and HIV-1 associated dementia (HAD). Mannose binding lectin (MBL), coded by MBL2 gene, is an active phase protein that mounts innate immune response against risk of infections. MBL recognizes mannose residues present of the surface of several pathogens (e.g. viruses, bacteria) and initiates the complement pathway by activating MBL-associated serine protease-2 (MASP-2). Furthermore, MBL modulates cytokine responses during HIV-1 infection and as a collectin; it is involved in scavenging viral proteins, immune complexes and apoptotic cells. Lower MBL levels have been shown to be associated with Alzheimer's disease, meningococcal disease and Neisseria meningitidis. Our recent studies in about 1000 HIV-1 infected children showed that the presence of MBL genetic variants, that alter the expression and function of MBL are associated with the development of more rapid progression of CNS impairment. Although the presence of such MBL variants has been shown earlier to affect susceptibility of HIV infection and disease progression, their association with progression of CNS impairment is a new finding. MBL binds to high mannose N-linked glycan residues of HIV-1 gp41/120 and is involved in HIV-1 opsonization. This suggests that innate immunity mediated through MBL may potentially affect HIV-1 related neuroinflammation and CNS impairment. The exact mechanisms through which MBL associated innate immune response plays a role in HIV neuropathogenesis is unknown. Our proposed pilot study seeks to extend this new finding by understanding the association between expression and function of MBL and susceptibility and progression of HIV-1 related neuroinflammation and CNS impairment. We hypothesize that altered expression and function of MBL i) impairs MBL-mediated complement activation; ii) modifies MBL-associated cytokine responses; and iii) impairs its scavenger collectin function leading to accumulation of viral proteins and immune complexes in brain, thereby leading to increased susceptibility of HIV-1 infection, neuroinflammation and CNS impairment. Additionally, we hypothesize that the presence of variant MBL alleles will alter expression and function of MBL in CNS. For this purpose, we will evaluate the MBL and MASP-2 levels in paired CSF and plasma from HIV-1 infected adults with and without neuroinflammation. Post-mortem brain tissues and corresponding CSF and plasma levels of MBL will also be evaluated to test these hypotheses. Results from the proposed pilot studies will help to understand the role of innate immunity in the risk of HIV-1 infection in CNS and neuroinflammation and might suggest avenues for development of effective therapeutics.