B Cell Function in HIV Infection. Although B cells cannot be infected by HIV, they may show profound abnormalities. Paradoxically, there is spontaneous B-cell activation and hypergammaglobulinemia in association with an inability to mount antibody responses to newly encountered antigens. The defective antibody responses may be due to lack of T-cell help as well as acquired defects in B cells.
Pathogenesis of Central Nervous System Involvement
Like the lymphoid system, the nervous system is a target of HIV infection. Macrophages and microglia, cells in the CNS that belong to the macrophage lineage, are the predominant cell types in the brain that are infected with HIV. It is believed that HIV is carried into the brain by infected monocytes. In keeping with this, the HIV isolates from the brain are almost exclusively M-tropic. The mechanism of HIV-induced damage of the brain, however, remains obscure. Because neurons are not infected and the extent of neuropathologic changes is often less than might be expected from the severity of neurologic symptoms, most clinicians believe that the neurologic deficit is caused indirectly by viral products and by soluble factors produced by infected microglia, such as the cytokines IL-1, TNF, and IL-6.
Virus entry into cells: RequiresCD4andcoreceptors,whicharereceptorsforchemokines;involvesbindingofviralgp120andfusionwiththecellmediatedbyviralgp41protein;maincellulartargets:CD4+ helperTcells,macrophages,DCs
Viral replication: IntegrationofprovirusgenomeintohostcellDNA;triggeringofviralgeneexpressionbystimulithatactivateinfectedcells(e.g.,infectiousmicrobes,cytokinesproducedduringnormalimmuneresponses)
Progression of infection: AcuteinfectionofmucosalTcellsandDCs;viremiawithdisseminationofvirus;latentinfectionofcellsinlymphoidtissue;continuingviralreplicationandprogressivelossofCD4+ Tcells
Mechanisms of immune deficiency:
LossofCD4+ Tcells:Tcelldeathduringviralreplicationandbudding(similartoothercytopathicinfections);apoptosisoccurringasaresultofchronicstimulation;decreasedthymicoutput;functionaldefects http://ebooksmedicine.net
HIV disease begins with acute infection, which is only partly controlled by the host immune response, and advances to chronic progressive infection of peripheral lymphoid tissues (
Figs. 5.39 5.40 • Acute phase. Virus typically enters through mucosal surfaces, and acute (early) infection is characterized by infection of memory CD4+ T cells (which express CCR5) in mucosal lymphoid tissues, and the death of many of these infected cells. Because the mucosal tissues are the largest reservoir of T cells in the body, and a major site of residence of memory T cells, this local loss results in considerable depletion of lymphocytes. At this stage, few infected cells are detectable in the blood and other tissues.
Mucosal infection is followed by dissemination of the virus and the development of host immune responses. DCs in epithelia at sites of virus entry capture the virus and then migrate into the lymph nodes. Once in lymphoid tissues, DCs pass HIV on to CD4+ T cells through direct cell–cell contact. Within days after the first exposure to HIV, viral replication can be detected in lymph nodes. This replication leads to viremia, during which high numbers of HIV particles are present in the patient’s blood. The virus disseminates throughout the body and infects helper T cells, macrophages, and DCs in peripheral lymphoid tissues.