HIV Associated Neurodegenerative Disorders: Extracellular and Intracellular Mechanisms.

We would like to thank Dr. Zhao for the interest in our study. His correspondence “HIV Associated Neurodegenerative Disorders: Role of Endoplasmic Reticulum in gp120-Mediated Neurotoxicity” (AIDS-D-20–00481) is of great interest^[1]. Indeed, we and others have shown that the envelope protein gp120 initiates several neurotoxic pathways by either binding to chemokine co-receptors expressed in neurons or other brain cells or by the disruption of the neuronal cytoskeleton. All these proposed mechanisms do not exclude each other and are the result of the experimental conditions used by experimenters (e.g. concentration, in vitro and in vivo models). We also agree that experiments with a pure viral protein do not reproduce a clinical situation seen in people living with HIV; however, animal models, gp120 or other viral proteins are useful tools to study mechanisms of neurotoxicity caused by HIV. Lastly, we also agree with Dr. Zhao that more studies, in which one can combine gp120 and other viral proteins, are needed to establish the role of viral proteins in the pathogenesis of HIV-associated neurocognitive disorders (HAND).

The importance of studying all molecular mechanisms utilized by HIV to reduce synapses and the survival of brain cells is exemplified by the persistence of HIV in the central nervous system (CNS) despite the use of the antiretroviral therapy. HIV causes axonal injury^{[2, 3]} and loss of cognitive and motor function^[4]. Whether synaptic simplification is caused only by HIV encephalitis (HIVE), a neuro-inflammatory condition characterized by the presence of activated microglia, multinucleated giant cells, astrogliosis and myelin loss^[5–7], or by a combination of factors, including viral proteins, drug abuse and comorbidities is a debate not easily solved. Activated microglia is consistent with non-neuronal cells being the primary target cells for HIV; nevertheless, their infection alone does not provide an obvious explanation for the neurological impairment seen in these subjects. Microglia has the ability to release viral proteins; however, this property cannot be tested in humans. Thus, more studies using experimental animals are needed to reveal the mechanisms whereby HIV is neurotoxic and provide new therapeutic targets for an effective prevention of the HIV-mediated neuronal injury.

Aside from microglia activation; HIV, through its viral proteins, activates apoptotic pathways that lead to neuronal dysfunction and loss^[8]. Such pathways include dysregulated calcium homeostasis^[9], activation of oxidative stress^[10], and induction of the proapoptotic transcription factor p53^[11]. These features could also be seen in neurons with impaired mitochondrial homeostasis. Mitochondria control high energy intermediates, such as ATP, as well as balance calcium homeostasis and reactive oxygen species, all of which are also crucial for neuronal survival^[12]. Neurons rely particularly on viable mitochondria for their survival and function because these cells have a high energy demand and need ATP supply to distant regions such as axonal and dendritic synapses^[13–15]. In fact, disruption of energy because of mitochondrial dysfunction has been linked to numerous neurodegenerative diseases^[16] including HAND^[17–19]. We have shown that gp120 transgenic mice exhibit altered mitochondrial morphology and function in their neurons similar to neurons of HIVE subjects^[17]. This is another example of a finding that gp120 can reproduce experimentally the neuropathology of HAND.

Dr. Zhang has also proposed the endoplasmic reticulum (ER) as a target for gp120. We concur with this idea because we ^[20] and others ^[21] have shown that gp120 is endocytosed into neurons and it is retrogradely transported around the soma, where ER is localized. The axonal transport is important for neurons because it is necessary to maintain energy homeostasis, as well to distribute mitochondria, synaptic vesicles and neurotrophic factors to axons and dendrites. The axonal transport depends upon the polarity and organization of neuronal microtubules (MTs) [reviewed in^[22]]. Changes in the integrity and dynamics of MTs are sufficient to alter proper energy supply within neurites and synapses which, consequently, lead to axon and dendrite simplification and reduction of their normal function. Gp120, after endocytosis, ^{[21, 23]}, binds to carboxy terminal tail of neuronal specific tubulin through a conserved α-helix region^[24]. Thus, in addition to ER, gp120 may promote loss of axons by altering the axonal transport and consequently their function. These observations prompted our interest to study neuronal MTs and their relations with HIV/gp120 which was published in AIDS^[25]. There is also new evidence that gp120 causes a loss of dendritic spine and therefore impairs dendritic-mediated synaptic transmission by activating a death receptor called p75 neurotrophin receptor^[26]. This receptor is particularly abundant in brain areas that are implicated in neurocognitive functions. In conclusion, in addition to immune cells infiltrating the brain and the release of pro-inflammatory cytokines, there are other mechanisms that may explain why neuronal loss occurs in people living with HIV despite the fact that HIV does not infect neurons.