The Case for Active Virus Replication under Effective ART

Zvi Grossman^1,2

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: Theoretical considerations (viremia as the product of multiple infection bursts), coupled to a careful analysis of HIV RNA decline kinetics following HAART initiation and of their dependence on the treatment regimen, suggested that the substantial fall in viral load required a much less efficient inhibition of infection at the single cell level than previously thought (Grossman et al., 1998, 1999).  According to the Proximal Activation and Infection hypothesis (PAT), the infection process is intimately linked to a hierarchy of lymphocyte proliferation, differentiation and memory generation events.  Given that some of the associated infection events are more easily inhibited by drugs than others, we predicted that HIV replication may not be extinguished when it becomes undetectable but may approach a stable steady-state level which depends on drug efficacy. Indirect evidence for ongoing productive infection includes the presence of HIV RNA in cells, viral evolution, and rapid rebound of virus after therapy interruption.

Recent Evidence: Havlir et al. (2003) reported that even after years of highly suppressive therapy, HIV RNA levels declined rapidly upon intensification of treatment, suggesting that productive infection contributes to residual viremia.  Moreover, residual viremia levels are predicted by baseline proviral DNA, implicating long-lived infected cells in such ongoing infection. Deeks and associates have found that viremia levels sufficient to cause significant increases in overall immune activation were required for a substantial increase in the risk of treatment failure.  Viremia and generalized immune activation appear to act synergistically to accelerate the development of systemic drug resistance by facilitating interclonal transmission of HIV.  Hamer and associates have found that HIV-specific CD4 T cells function as a distinct reservoir for HIV evolution.  All these findings are interpretable in terms of PAT.

In patients who maintain suppression of viremia for long periods of time, the virus may continue to actively replicate in lymphoid tissues, to evolve, and even to cryptically develop drug resistance.  The stability of the suppressed state may critically depend on the frequency and range of microscopic immune-activation episodes.