Central Nervous System Complications in Treated HIV Infection

HIV is undoubtedly neurovirulent and neuropathogenic. The prevalence of HIV-associated neurocognitive disorder (HAND) remains high (estimated 30–50%) and persists despite plasma HIV RNA suppression with potent combination antiretroviral therapy. These cognitive dysfunctions range in severity, spanning from the milder deficits of asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND) to more severe deficits in HIV-associated dementia (HAD). These cognitive deficits are not only widespread but impact everyday functioning, and increase morbidity and mortality with critical public health effects. To date, there are no clinically proven therapies for HAND for individuals already on stable, virologically suppressive anti-HIV regimens. Monocytes are thought to contribute to HAND pathogenesis by mediating HIV-neuroinvasion, which ultimately leads to HIV in the brain tissue, neuroinflammation and neuronal damage.

Productive HIV infection in the brain is found within the inflammatory infiltrate, which predominantly consists of macrophages. Although HIV is found in much lower frequency in brain tissues from patients on cART, we have successfully identified HIV-positive cells in cerebellum tissue that are surrounded by infiltrating macrophages using RNAscope, a novel next generation in situ hybridization technique.

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Immune control of HIV-1 reservoirs
 infection contributes substantially to global morbidity and mortality, with no immediate promise of an effective vaccine. One major obstacle to vaccine development and therapy is to understand why HIV-1 replication persists in a person despite the presence of viral specific immune responses. The emerging consensus has been that these immune cells are functionally ‘exhausted’ or anergic, and thus, although they can recognize HIV-1 specific target cells, they are unable to effectively keep up with rapid and dynamic viral replication in an individual.
Persistence of the cellular latent HIV reservoir has been a major barrier to the eradication of HIV. One proposed strategy is to ‘Shock’ the latently infected cells to flush out virus with latency reversal agents (LRAs).  The development of the ‘Shock’ strategies is advancing at a rapid pace with in vivo studies yielding activity in reactivating of latent virus. However, the ‘Kill’ component is less well developed. We reveal novel inhibitory pathway involved in the suppression of T cell responses during HIV infection, the blockade of which may contribute to the reversal of T cell dysfunction in the control or elimination of HIV infection.

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