Viral latency in HIV disease

The term "latency" is often applied to infections caused by herpesviruses, wherein viral replication and disease manifestations appear concordantly after long intervals of silence. In the case of the human immunodeficiency virus (HIV), an asymptomatic period of "clinical latency" can intervene between infection and the development of the acquired immune deficiency syndrome (AIDS). Freedom from symptoms does not, however, imply an absence of viral replication. Recent experiments studying the kinetics of viral turnover have estimated that, in patients with CD4 counts of 500 or less, 10~-109 virions are produced per day, resulting in a peripheral viremia of 104-107 RNA molecules/ml and in the destruction of approximately 2 x 109 CD4 ÷ T cells/day (Ho et al., 1995; Wei et al., 1995). Most (>98%) of the plasma virus is apparently produced within recently infected cells, with little contribution from chronically infected cells or from latently infected cells that then become activated. On the basis of these studies, the possibility has been raised that the kinetics of viral and cellular turnover found in late-stage disease may persist from the outset, leading ultimately to immune system collapse and AIDS (Coffin, 1995). If so, then cells with latent viral genomes may be inconsequential to disease progression. This view of "virological mayhem" (Wain-Hobson, 1995) may be correct, but it is currently an inference. The kinetics of viral and cell turnover in late-stage disease were deduced upon perturbation of the steady state with combinations of antiretroviral compounds. For populations of patients with early-stage and asymptomatic disease, data from such an intervention have yet to be reported. Indeed, this phase of disease appears to be associated not simply with clinical latency, but also with easily detectable levels of cells with latent viral genomes. In this review, previous findings on viral latency in HIV disease are discussed in relation to emerging paradigms of persistent and high level viral replication and cytopathicity.