MULTIPLE-MODES OF CELLULAR ACTIVATION AND VIRUS TRANSMISSION IN HIV-INFECTION - A ROLE FOR CHRONICALLY AND LATENTLY INFECTED-CELLS IN SUSTAINING VIRAL REPLICATION

CD4(+) T cell activation, required for virus replication in these cell s, occurs in local microenvironmental domains in transient bursts. Thu s, although most HIV originates from short-lived virus-producing cells , it is unlikely that chronic infection is generally sustained in rapi d continuous cycles of productive infection as has been proposed. Such continuity of productive infection cycles would depend on efficient l ong-range transmission of HIV from one set of domains to another, in t urn requiring the maintenance of sufficiently high concentrations of c ell-free virus across lymphoid tissues at all times, By contrast, long -lived cellular sources of HIV maintain the capacity to infect newly a ctivated cells at close range despite the temporal and spatial discont inuities of activation events. Such proximal activation and transmissi on (PAT) involving chronically and latently infected cells may be resp onsible for sustained infection, particularly when viral loads are low , Once CD4 cells are productively infected through PAT, they can infec t other activated cells in their immediate vicinity. Such events propa gate locally but generally do not spread systemically, unlike in the a cute phase of the infection, because of the early establishment of pro tective anergy, Importantly, antiretroviral drug treatment is likely t o differentially impact long-range transmission and PAT.