Induction of a virus-specific effector–memory CD4⁺ T cell response by attenuated SIV infection

We investigated simian immunodeficiency virus (SIV)-specific CD4⁺ T cell responses in rhesus macaques chronically infected with attenuated or pathogenic SIV strains. Analysis of SIVΔnef-infected animals revealed a relatively high frequency of SIV-specific CD4⁺ T cells representing 4–10% of all CD4⁺ T lymphocytes directed against multiple SIV proteins. Gag-specific CD4⁺ T cells in wild-type SIV-infected animals were 5–10-fold lower in frequency and inversely correlated with the level of plasma viremia. SIV-specific CD4⁺ cells from SIVΔnef animals were predominantly CD27⁻CD28⁻CD45RA^lowCCR7⁻CCR5⁻, consistent with an effector–memory subset, and included a fully differentiated CD45RA⁺CCR7⁻ subpopulation. In contrast, SIV-specific CD4⁺ T cells from SIV-infected animals were mostly CD27⁺CD28⁺CD45RA⁻CCR7⁺CCR5⁺, consistent with an early central memory phenotype. The CD45RA⁺CCR7⁻CD4⁺ subset from SIVΔnef animals was highly enriched for effector CD4⁺ T cells, as indicated by the perforin expression and up-regulation of the lysosomal membrane protein CD107a after SIV Gag stimulation. SIV-specific CD4⁺ T cells in attenuated SIV-infected animals were increased in frequency in bronchioalveolar lavage and decreased in lymph nodes, consistent with an effector–memory T cell population. The ability of SIVΔnef to induce a high frequency virus-specific CD4⁺ T cell response with direct effector function may play a key role in protective immunity produced by vaccination with attenuated SIV strains.