Implications of Proximal Immune Activation and Virus Transmission

Zvi Grossman1,2

1Department of Physiology and Pharmacolgy, Sackler Faculty of Medicine, Tel Aviv University (Israel), and  2Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, MD (USA)

Background: Activated CD4+ T cells are thought to be the preferential target for infection by HIV.  Yet, only a small fraction of lymphocytes with recent activation and proliferation history are infected in untreated patients.  Constraints on the rate and continuity of viral replication in vivo are imposed by the requirement of proximity between virus-producing cells and co-activated target cells, as demonstrated by in-situ analyses of viral sequences and T-cell receptors (Wain-Hobson and associates, 1994, 1998) which revealed the local nature of virus spreading in lymphoid tissue at the microscopic level.

Proximal Activation & Transmission (PAT): PAT is a conceptual model which posits that maintenance of HIV infection depends on the activation of latently infected memory cells in the context of localized immune activation bursts, sparking localized cell-to-cell infection bursts that also reseed the latent reservoir (Grossman et al., 1998, 1999).  Localized immune activation bursts are recurrently triggered in lymphoid tissues by foreign and self antigens, including in particular HIV itself.  That immune activation during HIV/SIV infections involves multiple lymphocyte expansion-and-contraction bursts is supported by analyses of cell-DNA labelling experiments (Grossman et al., 1999, 2002).

Implications: PAT implies that disease progression is driven primarily by the increase in number and diversity of latently infected cells.  It has also suggested that the substantial fall in viral load after HAART initiation does not reflect a virtually complete inhibition of infection at the single cell level but is consistent with a much less effective inhibition.  In particular, PAT leads to the following interrelated predictions:  (a) active replication of virus under effective HAART is sustained as long as the latently infected pool continues to be reseeded; (b) such ongoing replication occurs preferentially within lymphocyte clones that are recurrently activated; (c) when infection bursts are largely isolated, the virus may evolve quite independently within CD4 T-cell subpopulations of distinct specificities; (d) drug-resistance may develop in a minority of infected cells without immediately spreading systemically.