Circular forms of unintegrated human immunodeficiency virus type 1 DNA and high levels of viral protein expression: association with dementia and multinucleated giant cells in the brains of patients with AIDS

Abstract

Thirty-one histologically abnormal brains from patients with AIDS were studied in order to establish the relationship between multinucleated giant cells, viral protein expression, the various forms of human immunodeficiency virus type 1 (HIV-1) DNA, and clinical evidence of dementia. Unintegrated HIV-1 DNA of 2 to 8 kb was found in 22 of the 31 brains. Multinucleated giant cells without any other pathology were found in 14 cases; unintegrated 1-long terminal repeat (1-LTR) circular forms of HIV-1 DNA and strongly positive immunohistochemistry for gp41 and p24 were found in most of these brains. Most of these patients had a clinical diagnosis of HIV-1-associated dementia and cerebral atrophy. In all the other brains studied, 1-LTR circles were absent and immunohistochemistry for gp41 and p24 was usually negative. Very few of these patients had a clinical diagnosis of dementia. Sequence comparison of the LTR region from integrated HIV-1 DNA with that from unintegrated 1-LTR circular forms of HIV-1 DNA in 12 cases showed no significant differences. A further comparison of these brain-derived LTR sequences with LTR sequences derived directly from lymphoid tissue also showed strong sequence conservation. The V3 loop of the virus from the brain was sequenced in 6 cases and had a non-syncytium inducing-macrophage-tropic genotype. Our results show that (i) although unintegrated HIV-1 DNA was present in most brains from patients with AIDS, molecular evidence of high levels of viral replication was associated with the presence of multinucleated giant cells and dementia, and that (ii) the HIV-1 LTR is not a determinant of neurotropism. These observations suggest that replication of HIV-1 and not just the presence of HIV-1 DNA within giant cells makes the important contribution to central nervous system damage.

Monocyte/macrophage traffic in HIV and SIV encephalitis

“…However, it is not clear whether the animals in this study are more similar to rapid progressors and whether they truly have an asymptomatic period [14]. In HIV and SIV, productive infection re-emerges with the development of AIDS [5,11,15,16]. These observations suggest that virus that enter the CNS early after infection can become latent and then re-emerge with AIDS [14] or that productive infection, which results with the development of AIDS, occurs from reseeding new virus from the periphery [11,17].…”

Detection of HIV‐1 DNA in Microglia/ Macrophages, Astrocytes and Neurons Isolated from Brain Tissue with HIV‐1 Encephalitis by Laser Capture Microdissection

“…Moreover, the reproducible and frequent detection of HIV-1 DNA in multiple cell types by LCM and PCR reported here was probably aided by our selection of cases with HIV-1 encephalitis without fulminant microgliosis. Progression of HIV-1 disease in the brain generally correlates with an increase in HIV-1 DNA (4,21,48,49,57,59); and cases with multinucleated giant cells (MNGCs), a common histological hallmark of HIVE, are often associated with a 50 to 100 fold increase in viral copy number in brain tissue (2,57). The variability of viral load that exists from case to case at different stages of HIV-1 disease in the brain may influence the out-come of the attempts to detect HIV-1 infection of neurons.…”

Unintegrated HIV-1 circular 2-LTR proviral DNA as a marker of recently infected cells: Relative effect of recombinant CD4, zidovudine, and saquinavir in vitro

“…If the accumulation of unintegrated HIV-1 DNA represents either de novo cell infection or reinfection of already-infected cells, then it may be a plausible biologic marker for active HIV-1 replication and clinical progression [Pauza et al, 1990;Bush et al, 1993Bush et al, , 1996Donovan et al, 1994aDonovan et al, , 1994bJurriaans et al, 1995;Nicholson et al, 1996;Zazzi et al, 1997;Panther et al, 1998]. For example, patients with neurological manifestations of HIV-1 have a higher ratio of unintegrated to integrated HIV-1 DNA in their brain tissue than HIV-positive patients without clinical symptoms [Pang et al, 1990;Teo et al, 1997]. In addition, initiation of antiretroviral therapy results in decreased levels of unintegrated HIV-1 DNA in the PBMCs of patients followed longitudinally.…”