Killing of primary CD4⁺ T cells by non-syncytium-inducing macrophage-tropic human immunodeficiency virus type 1

Understanding the mechanism by which human immunodeficiency virus type 1 (HIV-1) kills CD4⁺ T lymphocytes is important to the development of therapeutic and prophylactic strategies. Recent studies have indicated that, in some cases, progression to AIDS is associated with the appearance of syncytium-inducing, T cell line-tropic HIV-1 variants. Nevertheless, approximately 50% of subjects with AIDS harbor only non-syncytium-inducing, macrophagetropic (NSI-M) variants of HIV-1. In most asymptomatic patients, NSI-M HIV-1 isolates are the predominant virus type found. We report here that cytopathicity of NSI-M HIV-1 for primary CD4⁺ T lymphocytes can be directly detected in vitro. The extent of CD4⁺ T-cell killing was not completely correlated with the rate of viral replication, suggesting that other characteristics of HIV-1 contribute to its cytopathicity. Our findings suggest that: (i) direct killing by NSI-M HIV-1 may contribute to CD4⁺ T-lymphocyte depletion in vivo, and (ii) the determinants of HIV-1 cytopathicity for CD4⁺ T lymphocytes and cell tropism or syncytia-forming ability are not necessarily tightly linked.