HAART is also accompanied by a slow but steady increase in CD4 T cells, despite the fact that many other compartments of the immune system remain compromised. Three complementary mechanisms have been established for the recovery in CD4 Tcell numbers. The first is a redistribution of CD4 T memory cells from lymphoid tissues into the circulation as viral replication as the lymphocytes that were productively infected at the onset of treatment die. Released virus is rapidly cleared from the circulation, where it has a half-life of 6 hours, and there is a decrease in virus levels in plasma of more than 95% during this first phase. the second phase lasts for about 6 months; the virus now has a half-life of about 2 weeks. During this phase, virus is released from infected macrophages and from resting, latently infected CD4 t cells stimulated to divide and develop productive infection. it is thought that there is then a third phase of unknown length that results from the reactivation of integrated provirus in memory t cells and other long-lived reservoirs of infection. this reservoir of latently infected cells might remain present for many years. Measurement of this phase of viral decay is impossible at present because viral levels in plasma are below detectable levels (dotted line). Data Months on treatment courtesy of G.M. Shaw.
is controlled; this occurs within weeks of starting treatment. The second is a reduction in the abnormal levels of immune activation as HIV infection is controlled; this is associated with reduced killing of infected CD4 T cells by cytotoxic T lymphocytes. The third is much slower and is caused by the emergence of new naive T cells from the thymus, which is indicated by the presence of Tcell receptor excision circles (TRECs) in these laterarriving cells (see Section 59).
Although HAART is effective at inhibiting HIV replication, thereby preventing the progression to AIDS and greatly decreasing transmission by those infected, it is ineffective at eradicating all viral stores. Cessation of HAART therefore leads to a rapid rebound of virus multiplication, so that patients require treatment indefinitely. This, coupled with the sideeffects and high cost of HAART, have stimulated investigation into other targets to block viral replication (Fig. 13.39) as well as ways of eliminating viral reservoirs to eradicate infection permanently. New classes of antiHIV replication drugs include viral entry inhibitors, which block the binding of gp120 to CCR5 or block viral fusion by inhibiting gp41; and viral integrase inhibitors, which block the insertion of the reversetranscribed viral genome into the host DNA. Another approach under development is to enhance the activity of HIV restriction factors, including APOBEC (see Section 1327) and TRIM 5α. APOBEC causes extensive mutation of newly formed HIV cDNA to destroy its coding and replicative capacity, and TRIM 5α limits HIV1 infections by targeting the viral nucleocapsid and preventing the uncoating and release of viral RNA after it enters cells.