FUTURE PERSPECTIVES: IMPLICATIONS FOR THERAPY

As discussed, neuronal apoptosis in HIV-1 infection is, in part, mediated through an excitotoxic pathway involving hyperstimulation of the NMDA receptor. Therefore, antagonists of the NMDA receptors may represent potential therapeutic agents (Table 22.1).

As previously discussed, the proapoptotic transcription factor p53 was proposed as a candidate mediator of HIV-induced neuronal injury. Recent findings from our group demonstrated that human growth hormone (GH) prevents HIV-1 Tat-induced neuronal death by inhibiting p53 expression in neurons.¹⁴⁵ In addition, in vivo treatment with human GH reduced Tat-related neurobehavioral and

TABLE 22.1

Potential Therapeutic Interventions

CNS

Note: PAF, platelet-activating factor; MMP, matrix metalloproteinase; TNF-α, tumor necrosis factor-α; NGF, nerve growth factor.

neuropathological changes in an animal model. Finally, human GH was well tolerated among patients with HIV-related cognitive impairment and, more importantly, within this small group of patients, GH improved their neurocognitive performance without adverse effects on systemic immune param- eters.²1³ Hence, these findings suggest that GH may be protective in a neurodegenerative disease. These observations reflect previous studies indicating that GH protects neurons during hypoxic ischemia²¹³ and enhances rescue of neurons after spinal cord injury.²¹⁴ Results from previous clinical trials have demonstrated that recombinant human GH treatment is tolerated and increases body weight, physical function, and quality of life in HIV-1-infected individuals with HIV-associated weight loss.^215,216 In addition, concomitant administration of recombinant human GH with HAART has been shown to enhance T cell maturation, differentiation, and function in HIV-1-infected patients.²¹⁷ Thus, recombinant human GH treatment seems to be an exciting approach, benefiting not only neurological disorders associated with HIV-1 infection but also metabolic and immunologic concerns.

Another potential therapy for HAD is the tetracycline derivative minocycline, a broad-spectrum antimicrobicide with anti-inflammatory properties. In the CNS, minocycline was shown to exert many effects, including the prevention of microglial activation, inhibiting IL-1β activation by interfering with the induction of IL-1-converting enzyme mRNA, decreasing induction of iNOS mRNA and preventing NOS protein expression, inhibiting NO-induced neurotoxicity, and reducing COX-2 expression and PGE2 production.^218-221 Minocycline also inhibits cytochrome c release from mitochondria,²²² which is a potent stimulus for activation of caspase-9 and caspase-3 and subsequent apoptosis. Thus, minocycline may interfere with many of the potential pathways that were suggested to play a role in mediating neuronal cell death in HAD.

The recent findings from our laboratory highlighting the selective pathological proteolysis of tissue proteins by proteases in the brain have revealed a new therapeutic target that could potentially be used to treat HAD. Reducing the cleavage of SDF-1 with synthetic MMP inhibitor drugs such as Prinomastat, which are already in phase 3 clinical trials for the treatment of cancer,^225,226 would have a twofold benefit, both in stabilizing full-length SDF-1, which protects CD4⁺CXCR4⁺ cells from further infection and subsequent signal transduction via CXCR4 on neurons, and in protecting neurons by reducing the levels of the toxic cleaved SDF-1 product.

Although the introduction of HAART regimens has led to a drastic decline in the death rate due to AIDS, they do not provide complete protection from developing HAD, possibly as a result of the poor penetration of these drugs into the CNS.²⁶ A potential neuroprotective role for HIV-1 protease inhibitors was demonstrated, in which the HIV-1 protease inhibitor ritonavir protected hippocampal neurons against oxidative stress-induced apoptosis.²²⁷ Thus, with the development of improved systems to deliver these drugs to the CNS, HAART regimens may also play a more significant role in the treatment of HAD.

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