In HIV-infected subjects taking HAART, in whom HIV replication has been substantially suppressed, HIV infection is not eradicated. Viral latency occurs when HIV DNA becomes integrated into the genome of human cells during the cycle of infection, and then becomes transcriptionally silent (or nearly so). There is a small cache of resting T lymphocytes in the body that contains non-transcribed HIV DNA (or very slowly transcribed) that is integrated into the human genome. Without transcription of HIV genes these infected T cells presumably do not present foreign antigen. They are immunologically inert, their HIV DNA becomes transcriptionally silenced, and the infection is latent. The turning over of T cells that contain latent HIV infection is not rapid enough to achieve their elimination naturally over time while taking HAART. Based primarily upon data gathered from sampling lymphocytes in blood plasma, it is widely suggested that the eradication of HIV infection could be achieved if new measures are taken to eliminate cells that contain latent HIV, especially the small proportion of T cells that harbor HIV latency. To find cellular caches of latent HIV in the body and eliminate them challenges must be faced: 1) Do changes in lymphocytes sampled from blood plasma samples obtained clinically reflect what occurs in deep body compartments, especially non-lymphoid organs including the central nervous system (CNS), in which infection is primarily in macrophages, microglia and astrocytes? 2) Is there a macrophage/microglial phenotype in the CNS and/or tissue histiocytes of deep organ compartments that specifically support HIVlat that should be selectively targeted for elimination? 3) Are the cellular caches of HIVint in the CNS and other deep body compartments distributed homogeneously, and in characteristic cell types? Of special concern is that latency in mononuclear phagocytes, which includes the widespread tissue histiocytes of the body, is not understood. These are the cells that are critical reservoirs in the central nervous system (CNS) and other non-lymphoid types of tissue. These basic questions are difficult to address clinically because access to human tissue specimens is necessary. This program of study will utilize tissue specimens from well characterized subject who were infected with HIV to define the cellular caches of HIV DNA that has been integrated into the human genome, and thus, could contribute to HIV in the body latency.
One aim will define this pool of HIV DNA in the CNS.
A second aim will produce similar data in other deep tissue compartments of the human body. These data will assist the field in targeting cells that harbor latent virus so that they can be eradicated.
This work is important because it will use human pathological specimens to define where latent HIV infections reside in the human body. This information is needed so that new treatments may be found to eradicate those caches of HIV from the body in concert with HAART medicine, which could lead to a cure for HIV infection.
|Obermeit, Lisa C; Beltran, Jessica; Casaletto, Kaitlin B et al. (2017) Evaluating the accuracy of self-report for the diagnosis of HIV-associated neurocognitive disorder (HAND): defining ""symptomatic"" versus ""asymptomatic"" HAND. J Neurovirol 23:67-78|
|Fazeli, Pariya L; Moore, David J; Franklin, Donald R et al. (2016) Lower CSF A? is Associated with HAND in HIV-Infected Adults with a Family History of Dementia. Curr HIV Res 14:324-30|
|Buzhdygan, Tetyana; Lisinicchia, Joshua; Patel, Vipulkumar et al. (2016) Neuropsychological, Neurovirological and Neuroimmune Aspects of Abnormal GABAergic Transmission in HIV Infection. J Neuroimmune Pharmacol 11:279-93|
|Ma, Qing; Vaida, Florin; Wong, Jenna et al. (2016) Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. J Neurovirol 22:170-8|
|Malvar, Jemily; Vaida, Florin; Sanders, Chelsea Fitzsimons et al. (2015) Predictors of new-onset distal neuropathic pain in HIV-infected individuals in the era of combination antiretroviral therapy. Pain 156:731-9|
|Grant, Igor; Franklin Jr, Donald R; Deutsch, Reena et al. (2014) Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology 82:2055-62|