Could We Harness Human Immunodeficiency Virus Antibodies to Monitor the Brain?

In the quest to control and ultimately eliminate human immunodeficiency virus (HIV) from patients, the brain presents unique and critical challenges. It is well accepted that the brain represents a potential body “compartment” for HIV that is likely colonized in the early days of the infection, and it ultimately may support a degree of independent evolution of the virus not precisely mirrored in systemic blood samples. The blood-brain barrier (BBB) that makes the compartment a reality consists, at a minimum, of a unique endothelial barrier of brain vessels with tight junctions, a basement membrane, and an astrocytic barrier, making distribution of both pathogens and therapies significantly different in brain compared with most other organs. The brain is also too precious and well protected to be sampled repeatedly for research purposes. However, cerebrospinal fluid (CSF) that literally floats the brain has proved to be a meaningful, albeit imperfect, window to the brain environment that can be safely sampled. In this issue of the Journal of Infectious Diseases, Burbelo et al [1] have performed an important analysis on CSF from a series of patients and described important insights gleaned from the analysis of anti-HIV antibodies. The results have implications for optimal therapeutics, enhancing our understanding of persisting HIV-associated cognitive impairment, and efforts to cure HIV infection. Given the challenges for direct sampling of brain tissues, biomarkers reflecting any infection in the brain are of particular value. Perhaps because the fundamental pathophysiology driving disability in HIV/acquired immune deficiency syndrome primarily reflects cellular immune damage, attention to humoral responses has typically been superficial at best. Burbelo et al [1] more carefully consider the potential use of the humoral immune response as a sensitive and semiquantitative monitor for the status of viral expression. Measured antibodies in CSF seem likely to primarily reflect the environment in brain or CSF, but, as done in this investigation, parallel investigation of peripheral antibodies is required for interpretation. Furthermore, the status of the BBB should be monitored because pathologic breakdown of the BBB would degrade the fidelity of the CSF measurements. The modest changes in CSF albumin and other proteins attest to the gross preservation of BBB in the settings studied here. Passive entrance of antibodies through the BBB is modest, and so it appears that much of the humoral response in the CSF is generated within the brain compartment, thus reflecting the status of antigens in the brain. This study includes a description of antibodies in “typical HIV patients” whose disease is discovered after years of chronic infection, after which they are started on HIV therapy. Antibody response to HIV antigens is strong in peripheral blood and in CSF before starting therapy, and only modestly reduced through pharmacologic control of the infection, even after >10 years of excellent control. Although virus is “undetectable” in blood and CSF by clinical assays, it is hypothesized that there is enough ongoing viral expression to maintain robust humoral immunity. This article also provides a fascinating contrast with the “Berlin patient” whose functional HIV cure has resulted in parallel loss of specific HIV antibody responses in brain and in the peripheral blood [2]. Presumably, this is the result of loss of ongoing antigen stimulation that markedly differs from patients in whom virus is simply suppressed by effective antiretroviral therapy (ART). It is notable that the dynamics of building up robust ongoing antigen presentation in the periphery occurs faster than the CSF after acute infection. The dynamics of developing antibodies is tracked during the first months of infection in a small number of cases E D I T O R I A L C O M M E N T A R Y