Abstract
HIV infection affects 37 million people and about 1.7 million are infected annually. Among the phase III clinical trials only the RV144 vaccine trial elicited significant protection against HIV-1 acquisition, but the efficacy and immune memory were inadequate. To boost these vaccine functions we studied T stem cell memory (TSCM) and innate immunity. TSCM cells were identified by phenotypic markers of CD4+ T cells and they were further characterised into 4 subsets. These expressed the common IL-2/IL-15 receptors and another subset of APOBEC3G anti-viral restriction factors, both of which were upregulated. In contrast, CD4+ TSCM cells expressing CCR5 co-receptors and α4β7 mucosal homing integrins were decreased. A parallel increase in CD4+ T cells was recorded with IL-15 receptors, APOBEC3G and CC chemokines, the latter downmodulating CCR5 molecules. We suggest a novel mechanism of dual memory stem cells; the established sequential memory pathway, TSCM →Central →Effector memory CD4+ T cells and the innate pathway consisting of the 4 subsets of TSCM. Both pathways are likely to be activated by endogenous HSP70. The TSCM memory stem cell and innate immunity pathways have to be optimised to boost the efficacy and immune memory of protection against HIV-1 in the clinical trial.
Highlights
HIV infection affects 37 million people and about 1.7 million are infected annually
In this study of the RV144 HIV-1 vaccine trial, in which ALVAC-HIV and AIDSVAX B/E were used we found significant increases in CD4+ T stem cell memory (TSCM) cells, which were further differentiated into CD122+, APOBEC 3 G (A3G), CCR5+ and α4β7 expressing subsets of cells
We found an increase in the population of CD4+ CD45RO− CCR7+ CD95+ TSCM cells (2.33 ± 0.27) before vaccination to 2.86 ± 0.43 (p = 0.12) at 2 weeks and (3.12 ± 0.36 p = 0.018) at 28 weeks after the last vaccination (Fig. 1A)
Summary
Among the phase III clinical trials only the RV144 vaccine trial elicited significant protection against HIV-1 acquisition, but the efficacy and immune memory were inadequate To boost these vaccine functions we studied T stem cell memory (TSCM) and innate immunity. The efficacy of protection of HIV-1 acquisition decreased from 60% in the 1st year, to 36% in the 2nd and 32.3% in the 3rd year[8], despite expressing significant Env-specific CD4+ effector memory T cells[4]. This led us to examine long-term T stem cell memory (TSCM) cells, defined by expressing CD45RO− CCR7+ CD62L+ CD95+ T cell phenotypic markers[9, 10]. These immune mechanisms may play a significant role in early control of HIV infection by affecting the efficiency of mucosal HIV transmission and dissemination as well as influencing acute viral replication[20, 21]
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