13-35 Drugs that block HIV replication lead to a rapid decrease in titer of infectious virus and an increase in CD4 T cells.
Studies with drugs that block HIV replication indicate that the virus is repli cating rapidly at all phases of infection, including the asymptomatic phase.
Three viral proteins in particular have been the target of drugs aimed at arrest ing viral replication. These are viral reverse transcriptase, which is required for synthesis of the provirus; viral integrase, which is required for insertion of the viral provirus into the host genome; and viral protease, which cleaves viral polyproteins to produce virion proteins and viral enzymes. Reverse tran scriptase is inhibited by nucleoside analogs such as zidovudine (AZT), which was the first antiHIV drug to be licensed in the United States. Inhibitors of reverse transcriptase, integrase, and protease prevent infection of uninfected
Therapy with antiretroviral drugs (% of patient days)
Fig. 13.37 The mortality of patients with advanced HIV infection fell in the United States in parallel with the introduction of combination antiretroviral drug therapy. the graph shows the number of deaths, expressed each calendar quarter as the deaths per 100 person-years. Figure based on data from F. Palella.
Fig. 13.38 The time-course of reduction of HIV circulating in the blood during drug treatment. the production of new HiV particles can be arrested for prolonged periods by treatment using combinations of protease inhibitors and viral reversetranscriptase inhibitors. after the initiation of such treatment, virus production is curtailed as the infected cells die and no new cells are infected. the half-life of virus decay occurs in three phases. in the first phase the half-life (t1/2) is about 2 days, reflecting the half-life of productively infected CD4 t cells; this phase lasts about 2 weeks, during which time viral production declines cells; cells that are already infected can continue to produce virions because, once the provirus is established, reverse transcriptase and integrase are not needed to make new virus particles, and while the viral protease acts at a very late maturation step of the virus, inhibition of the protease does not prevent virus from being released. However, in all cases, further cycles of infection by released virions are blocked, and replication is therefore prevented.
The introduction of combination therapy with a cocktail of viral protease inhibitors and nucleoside analogs, also known as highly active antiretroviral therapy (HAART), dramatically reduced mortality and morbidity in patients with advanced HIV infection in the United States between 1995 and 1997 (Fig. 13.37). Many patients treated with HAART show a rapid and dramatic reduction in viremia, eventually maintaining levels of HIV RNA close to the limit of detection (50 copies per ml of plasma) for a long period (Fig. 13.38). It is unclear how the virus particles are removed so rapidly from the circulation after the initiation of HAART. It seems most likely that they are opsonized by specific antibody and complement and removed by cells of the mononuclear phagocyte system. Opsonized HIV particles may also be trapped in lymphoid follicles on the surface of follicular dendritic cells.