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Chapter 1 : HIV-1-Associated Neurocognitive Disorders in the HAART Era
Category: Viruses and Viral Pathogenesis
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Early in the HIV/AIDS epidemic, the deleterious consequences of HIV-1 infection in the central and peripheral nervous system were described. They were considered to be due to severe immunosuppression, and encephalitis was considered predominantly attributable to concomitant cytomegalovirus (CMV) infection. Antiretroviral agents (ARVs) was further noted that patients with HIV-1-associated neurocognitive disorders would initially improve but later progress despite the continued use of zidovudine (ZDV). In December 1995, the highly active antiretroviral therapy (HAART) era began when the protease inhibitors (PIs) were introduced into practice with the FDA approval of saquinavir. A number of changes have occurred across the spectrum of HIV-1-associated neurocognitive disorders since the introduction of HAART. The incidence of HIV-1-associated dementia (HAD) is widely reported to have decreased following the introduction of HAART; however, the incidence of HIV-1 encephalopathy (as defined neuropathologically) appears to have increased, although interestingly, both the neuropathological and the clinical aspects of the syndrome seem to be less severe than those observed in the pre-HAART era. In addition to the above-mentioned changes in clinical manifestations of HIV-1-associated neurocognitive disorders, their underlying pathophysiology has also evolved. Aside from the original focus on virologic (pathogen), inflammatory/immunologic (host response), and comorbid infection factors, there are now three additional categories of pathogenic factors that demand attention. These are the vascular, medication toxicity, and genetic factors. Molecular investigations of multidrug resistance (MDR) resulted in the isolation and characterization of genes coding for several associated proteins, including P-glycoprotein and the MDR-associated protein MRP1.
Steps at which ARVs interfere with the replication cycle of HIV-1. Regarding the structure of HIV-1, the glycoprotein coat is comprised of two portions, the outer envelope, gp120, and the transmembrane portion, gp41. The matrix protein, p17, bridges the glycoprotein coat, with the cone-shaped structure forming the viral capsid protein, p24. The viral genomic RNA, the processed nucleocapsid (p7/p9), Pol proteins, the reverse transcriptase enzyme, and the integrase enzyme are located within the capsid core. The life cycle of HIV-1 is depicted from left to right. The first FDA-approved ARVs were the nRTIs, which interfere with the step of reverse transcription, in which the RNA of HIV-1 is reverse transcribed into a complementary DNA copy. Soon afterward, members of two new ARV classes were FDA approved, the NNRTIs and the PIs. The NNRTIs act at the same point as the nRTIs but at a different site of the reverse transcriptase enzyme. The PIs, however, were the first ARVs approved to work at a different step in the viral replicatory cycle, which is a late step in which posttranslational modification of viral preproteins into active proteins occurs prior to virus assembly. Subsequently, the first of the fusion/entry inhibitors (including the CCR5 antagonists) was FDA approved. These drugs act by inhibiting the process of fusion between the viral envelope and the host cell membrane or in the immediately subsequent process of virus entry into the cell. Most recently, another class of ARVs was FDA approved, the integrase inhibitors, which interfere with the process of integration of complementary viral DNA into the host cell DNA in the nucleus. Also shown are several steps of the replicatory cycle that have yet to be targeted by FDA-approved ARVs.
Contributory factors to HIV-1-associated neurocognitive-disorder pathogenesis. Studies of HIV-1-associated neurocognitive-disorder pathogenesis have become more complex in the HAART era. Viral and inflammatory/immunologic factors had been the major concerns pre-HAART. In a subset of cases, comorbid infection was also a concern as a contributory factor pre-HAART. A number of additional factors have been identified to be important post-HAART. In particular, a vascular factor is now a routine consideration for pathogenesis. Moreover, newly identified medication toxicity factors (including those due to the ARVs themselves) and host genetic factors have also come to the fore.
The changing manifestations of HAD pre- and post-HAART
Role of cytokines in the pathogenesis of HIV-1-associated neurocognitive impairment and disorder