Infection with HIV generates an immune response that contains the virus but only very rarely, if ever, eliminates it. A timecourse of the response of various adaptive immune elements to HIV in adults is shown, together with the levels of infectious virus in plasma, in Fig. 13.34. As was noted earlier, in the acute phase, virusmediated cytopathicity results in a substantial depletion of CD4 T cells, particularly in mucosal tissues. There is a good initial recovery of Tcell numbers and transition to the asymptomatic phase of disease as the immune response develops and curbs viral replication (see Fig. 13.33). However, replication of the virus persists, and, after a variable period lasting from a few months to more than 20 years, the CD4 Tcell numbers fall too low to maintain effective immunity, and AIDS develops (defined as less than 200 CD4 T cells per microliter in peripheral blood). Several factors conspire to progressively deplete CD4 T cells until they can no longer maintain immunity: destruction by cytotoxic lymphocytes directed against HIVinfected cells, immune activation (direct and indirect) that induces activation of latent virus, ongoing viral cytopathic effects, and insufficient Tcell regeneration in the thymus. In this section we consider in turn the roles of CD8 cytotoxic T cells, CD4 T cells, antibodies, and soluble factors in mounting the immune response to HIV infection that initially contains the infection but ultimately fails.
Studies of peripheral blood cells from infected individuals reveal cytotoxic T cells specific for viral peptides that can kill infected cells in vitro. In vivo, cytotoxic T cells traffic to sites of HIV replication, where they are thought to kill many productively infected cells before any infectious virus is released, thereby containing viral load at the quasistable levels that are characteristic of the asymptomatic period. Evidence for the clinical importance of the control of HIVinfected cells by CD8 cytotoxic T cells comes from studies relating the numbers and activity of CD8 T cells to viral load. There is also direct evidence from experiments in macaques infected with SIV that CD8 cytotoxic T cells control retrovirusinfected cells; treatment of infected animals with monoclonal antibodies that remove CD8 T cells is rapidly followed by a large increase in viral load.
In addition to direct cytotoxicity mediated by recognition of cells infected with virus, a variety of factors produced by CD4, CD8, and NK cells are important in antiviral immunity. Chemokines that bind CCR5, such as CCL5, CCL3, and CCL4, are released at the site of infection by CD8 T cells and inhibit virus spread by competing with R5 strains of HIV1 for the engagement of coreceptor CCR5, whereas factors still unknown compete with R4 strains for binding to CXCR4. Cytokines such as IFNα and IFNγ may also be involved in controlling virus spread.
Evidence shows that in addition to being a major target for HIV infection, CD4 T cells also have an important role in the host response to HIVinfected cells.
Fig. 13.34 The immune response to HIV. infectious virus is present at relatively low levels in the peripheral blood of infected individuals during a prolonged asymptomatic phase, during which the virus is replicated persistently in lymphoid tissues. During this period, CD4 t-cell counts gradually decline (see Fig. 13.33), although antibodies and CD8 cytotoxic t cells directed against the virus remain at high levels. two different antibody responses are shown in the figure, one to the envelope protein (env) of HiV, and one to the core protein p24. eventually, the levels of antibody and HiV-specific cytotoxic t lymphocytes (Ctls) also decline, and there is a progressive increase in infectious HiV in the peripheral blood.