The nerve growth factor reduces APOBEC3G synthesis and enhances HIV-1 transcription and replication in human primary macrophages

Abstract

Macrophages infected with HIV-1 sustain viral replication for long periods of time, functioning as viral reservoirs. Therefore, recognition of factors that maintain macrophage survival and influence HIV-1 replication is critical to understanding the mechanisms that regulate the HIV-1–replicative cycle. Because HIV-1–infected macrophages release the nerve growth factor (NGF), and NGF neutralization reduces viral production, we further analyzed how this molecule affects HIV-1 replication. In the present study, we show that NGF stimulates HIV-1 replication in primary macrophages by signaling through its high-affinity receptor Tropomyosin-related Kinase A (TrKA), and with the involvement of reticular calcium, protein kinase C, extracellular signal-regulated kinase, p38 kinase, and nuclear factor-κB. NGF-induced enhancement of HIV-1 replication occurred during the late events of the HIV-1–replicative cycle, with a concomitant increase in viral transcription and production. In addition, NGF reduced the synthesis of the cellular HIV-1 restriction factor APOBEC3G and also overrode its interferon-γ–induced up-regulation, allowing the production of a well-fitted virus. Because NGF-TrKA signaling is a crucial event for macrophage survival, it is possible that NGF-induced HIV-1 replication plays a role in the maintenance of HIV-1 reservoirs. Our study may contribute to the understanding of the immunopathogenesis of HIV-1 infection and provide insights about approaches aimed at limiting viral replication in HIV-1 reservoirs.

Suppression of Immunodeficiency Virus-Associated Neural Damage by the p75 Neurotrophin Receptor Ligand, LM11A-31, in an In Vitro Feline Model

“…No significant changes were seen in FIV replication although a very small effect was seen on macrophage FIV synthesis in agreement with Souza, et al (Souza et al, 2011). Although this will have to be verified in vivo , these observations indicate that LM11A-31 can be used in infected cats with minimal risk of accelerating viral replication.…”

The Effects of Neurotrophins and the Neuropeptides VIP and PACAP on HIV-1 Infection: Histories with Opposite Ends

“…In a more recent investigation, we reported that NGF (as well as BDNF and proNGF) enhanced HIV-1 replication in human primary monocyte-derived macrophages via PKC, NF-κB, extracellular signal-regulated kinase and p38 kinase-dependent signaling pathways that were triggered by the NGF-TrkA interaction [57]. We also reported that NGF increased HIV-1 proviral DNA transcription, eventually leading to increased HIV-1 production in macrophages.…”

“…Although the results of such studies point to neuroprotective effects of both NTs with obvious benefits for patients with AIDS-associated dementia, the therapeutic use of NGF or BDNF should be examined carefully due to the enhancer activities of NGF and other NTs on HIV-1 replication [57,125]. Thus, it is critical to identify the ideal balance between the neuroprotective and the HIV-1-productive infection-promoting effects of NTs.…”

“…The degree of immune system activation has now been considered the best predictor of HIV-1 disease progression, and decreased viral loads in HIV-1-infected patients who receive antiretroviral drugs are associated with steady reductions in systemic immune activation levels [52]. Many experimental studies have also consistently shown that endogenous molecules can promote enhanced HIV-1 production, including the cytokines TNF-α, IL-1β, IL-6, macrophage migration inhibitory factor and NGF, whereas other natural soluble mediators can induce the opposite effect by diminishing HIV-1 growth, including the cytokines IL-10, IL-27 and interferon (IFN) α/β, the β-chemokines CCL3, CCL4 and CCL5, and the neuropeptides VIP and PACAP [53,54,55,56,57,58,59,60,61]. …”

Tissue-Specific HIV-1 Infection: Why it Matters

“…Taken together, it is likely that these cell types act as long-lived viral reservoirs within the CNS [50-52]. Virus replication and assembly in macrophages can diverge from what is observed in CD4 + T cells, with unintegrated HIV DNA serving as a source of transcription factors such as Tat and altering HIV replication [28]; the involvement of membrane-bound vacuoles in virus processing [54,56]; and replication enhancement by environmental nerve growth factor [57]. Latent HIV infection of the abundant and functionally diverse astrocytes, as defined by the presence of HIV DNA within these cells, occurs rather infrequently, and the clinical relevance of this cellular reservoir is unclear since HIV infection of astrocytes is reportedly not productive in vivo [58-64].…”