Journal Article

An immune control model for viral replication in the CNS during presymptomatic HIV infection

M. McCrossan, M. Marsden, F. W. Carnie, S. Minnis, B. Hansoti, I. C. Anthony, R. P. Brettle, J. E. Bell and P. Simmonds

in Brain

Published on behalf of The Guarantors of Brain

Volume 129, issue 2, pages 503-516
Published in print February 2006 | ISSN: 0006-8950
Published online November 2005 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awh695
An immune control model for viral replication in the CNS during presymptomatic HIV infection

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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.

Keywords: gp120; HIV; phenotype; pre-symptomatic; tropism; 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

Journal Article.  8977 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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