Brain Advance Access originally published online on November 29, 2005
Brain 2006 129(2):503-516; doi:10.1093/brain/awh695
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
An immune control model for viral replication in the CNS during presymptomatic HIV infection
1 Centre for Infectious Diseases, 2 Department of Pathology, Western General Hospital and 3 Regional Infectious Diseases Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK
Correspondence to: Peter Simmonds, Centre for Infectious Diseases, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, UK E-mail: Peter.Simmonds{at}ed.ac.uk
The brain is targeted by human immunodeficiency virus type 1 (HIV-1) during the course of untreated infection, leading to cognitive impairment, neurological damage and HIV encephalitis (HIVE). To study early dynamics of HIV entry into the brain, we examined a unique autopsy series of samples obtained from 15 untreated individuals who died in the presymptomatic stages of infection from non-HIV causes. HIV was detected and quantified by limiting dilution PCR and genetically characterized in the V3 region of env. Limiting dilution was shown to be essential for correct estimation of genetic partitioning between brain- and lymphoid-associated HIV populations. While no actively expressing HIV-infected cells were detected by immunohistochemistry, variable and generally extremely low levels of proviral DNA were detected in presymptomatic brain samples. V3 region sequences were frequently genetically distinct from lymphoid-associated HIV variants, with association index (AI) values similar to those observed in cases of HIVE. Infiltration of CD8 lymphocytes in the brain was strongly associated with expression of activation markers (MHCII; R = 0.619; P < 0.05), the presence of HIV-infected cells (proviral load; R = 0.608; P < 0.05) and genetic segregation of brain variants from populations in lymphoid tissue (AI value, R = –0.528; P 
0.05). CD8 lymphocytes may thus limit replication of HIV seeded into the brain in early stages of infection. Neurological complications in AIDS occur when this control breaks down, due to systemic immunosuppression from HIV that destroys CD8 lymphocyte function and/or through the evolution of more aggressive neuropathogenic variants.
Key Words: gp120; HIV; phenotype; pre-symptomatic; tropism
Abbreviations: ABC = avidin–biotin complex; AI = association index; AIDS = acquired immunodeficiency syndrome; ART = antiretroviral therapy; BBB = blood–brain barrier; CNS = central nervous system; CTLs = cytotoxic T lymphocytes; HAART = highly active antiretroviral therapy; HIV-1 = human immunodeficiency virus type 1; HIVE = HIV encephalitis; IDUs = individuals with a history of past or current injecting drug use; MHCII = major histocompatibility complex class II; TSA = tyramide signal amplification
Received July 14, 2005. Revised October 17, 2005. Accepted October 24, 2005.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Gorantla, J. Liu, H. Sneller, H. Dou, A. Holguin, L. Smith, T. Ikezu, D. J. Volsky, L. Poluektova, and H. E. Gendelman Copolymer-1 Induces Adaptive Immune Anti-inflammatory Glial and Neuroprotective Responses in a Murine Model of HIV-1 Encephalitis J. Immunol., October 1, 2007; 179(7): 4345 - 4356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. G. Marcondes, T. H. Burdo, S. Sopper, S. Huitron-Resendiz, C. Lanigan, D. Watry, C. Flynn, M. Zandonatti, and H. S. Fox Enrichment and Persistence of Virus-Specific CTL in the Brain of Simian Immunodeficiency Virus-Infected Monkeys Is Associated with a Unique Cytokine Environment J. Immunol., May 1, 2007; 178(9): 5812 - 5819. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Pillai, S. L. K. Pond, Y. Liu, B. M. Good, M. C. Strain, R. J. Ellis, S. Letendre, D. M. Smith, H. F. Gunthard, I. Grant, et al. Genetic attributes of cerebrospinal fluid-derived HIV-1 env Brain, July 1, 2006; 129(7): 1872 - 1883. [Abstract] [Full Text] [PDF]
|
|